Updated on 2022/05/11

写真a

 
MATSUURA Eiji
 
Organization
Neutron Medical Research Center Professor
Position
Professor
External link

Degree

  • 博士(医学) ( 岡山大学 )

  • 修士(薬学) ( 岡山大学 )

Research Interests

  • 脂質代謝学

  • 生化学

  • 分子イメージング学

  • 腫瘍生物学

  • 臨床診断学

  • 免疫学

Research Areas

  • Life Science / Connective tissue disease and allergy

  • Others / Others  / Laboratory medicine

  • Life Science / Metabolism and endocrinology

  • Life Science / Immunology

  • Life Science / Pathological biochemistry

  • Life Science / Radiological sciences

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Education

Research History

  • Okayama University   Neutron Therapy Research Center

    2017.4

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  • - Professor,Neutron Medical Research Center,Okayama University

    2017

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  • Okayama University   Graduate School of Medicine , Dentistry and Pharmaceutical Sciences

    2011.1

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  • 岡山大学医歯薬学総合研究科病態制御科学専攻病態機構学講座(細胞化学分野)准教授

    2007.4 - 2011.1

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  • Associate Professor,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University

    2007 - 2011

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  • 岡山大学大学医学部附属分子細胞医学研究施設 細胞工学部門 助教授

    2001.4 - 2007.3

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  • 岡山大学医学部附属分子細胞医学研究施設細胞工学部門 講師

    1997.5 - 2001.3

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  • 北海道大学医学部生化学第一講座 助手

    1995.11 - 1997.4

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  • ヤマサ醤油(株)診断薬部免疫研究室 主任研究員

    1988.11 - 1995.10

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  • Department of Pediatrics and Medicine, National Jewish Center for Immunology and Respiratory Medicine (affiliated to Colorado University Health Science Center), Denver, CO, USA, Research Associate

    1986.9 - 1988.11

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  • Okayama University   Faculty of Pharmaceutical Sciences

    1985.4 - 1986.8

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Professional Memberships

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Papers

  • Role of urinary H2O2, 8-iso-PGF2α, and serum oxLDL/β2GP1 complex in the diabetic kidney disease Reviewed

    Rani Sauriasari, Afina Irsyania Zulfa, Andisyah Putri Sekar, Nuriza Ulul Azmi, Xian Wen Tan, Eiji Matsuura

    PLoS One   17 ( 4 )   e0263113   2022.5

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    Authorship:Last author   Language:English  

    DOI: 10.1371/journal.pone.0263113

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  • Evolution of biomarker research in autoimmunity conditions for health professionals and clinical practice

    Arthur Silverstein, Anton Dudaev, Maria Studneva, John Aitken, Sofya Blokh, Andrew David Miller, Sofia Tanasova, Noel Rose, John Ryals, Christoph Borchers, Anders Nordstrom, Marina Moiseyakh, Arturo Solís Herrera, Nikita Skomorohov, Trevor Marshall, Alan Wu, R. Holland Cheng, Ksenia Syzko, Philip D. Cotter, Marianna Podzyuban, William Thilly, Paul David Smith, Paul Barach, Khaled Bouri, Yehuda Schoenfeld, Eiji Matsuura, Veronika Medvedeva, Ilya Shmulevich, Liang Cheng, Paul Seegers, Yekaterina Khotskaya, Keith Flaherty, Steven Dooley, Eric J. Sorenson, Michael Ross, Sergey Suchkov

    Progress in Molecular Biology and Translational Science   2022.4

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    Publishing type:Part of collection (book)   Publisher:Elsevier  

    DOI: 10.1016/bs.pmbts.2022.02.004

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  • Lactosome-Conjugated siRNA Nanoparticles for Photo-Enhanced Gene Silencing in Cancer Cells International journal

    Melissa Siaw Han Lim, Yuki Nishiyama, Takashi Ohtsuki, Kazunori Watanabe, Hirotsugu Kobuchi, Kazuko Kobayashi, Eiji Matsuura

    Journal of Pharmaceutical Sciences   110 ( 4 )   1788 - 1798   2021.4

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    The A3B-type Lactosome comprised of poly(sarcosine)3-block-poly(l-lactic acid), a biocompatible and biodegradable polymeric nanomicelle, was reported to accumulate in tumors in vivo via the enhanced permeability and retention (EPR) effect. Recently, the cellular uptake of Lactosome particles was enhanced through the incorporation of a cell-penetrating peptide (CPP), L7EB1. However, the ability of Lactosome as a drug delivery carrier has not been established. Herein, we have developed a method to conjugate the A3B-type Lactosome with ATP-binding cassette transporter G2 (ABCG2) siRNA for inducing in vitro apoptosis in the cancer cell lines PANC-1 and NCI-H226. The L7EB1 peptide facilitates the cellular uptake efficiency of Lactosome but does not deliver siRNA into cytosol. To establish the photoinduced cytosolic dispersion of siRNA, a photosensitizer loaded L7EB1-Lactosome was prepared, and the photosensitizer 5,10,15,20-tetra-kis(pentafluorophenyl)porphyrin (TPFPP) showed superiority in photoinduced cytosolic dispersion. We exploited the combined effects of enhanced cellular uptake by L7EB1 and photoinduced endosomal escape by TPFPP to efficiently deliver ABCG2 siRNA into the cytosol for gene silencing. Moreover, the silencing of ABCG2, a protoporphyrin IX (PpIX) transporter, also mediated photoinduced cell death via 5-aminolevulinic acid (ALA)-mediated PpIX accumulated photodynamic therapy (PDT). The synergistic capability of the L7EB1/TPFPP/siRNA-Lactosome complex enabled both gene silencing and PDT.

    DOI: 10.1016/j.xphs.2021.01.026

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  • Immunologically Inert Nanostructures as Selective Therapeutic Tools in Inflammatory Diseases

    Laura Talamini, Eiji Matsuura, Luisa De Cola, Sylviane Muller

    Cells   10 ( 3 )   707 - 707   2021.3

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    Publishing type:Research paper (scientific journal)   Publisher:MDPI AG  

    The current therapies based on immunosuppressant or new biologic drugs often show some limitations in term of efficacy and applicability, mainly because of their inadequate targeting and of unwanted adverse reactions they generate. To overcome these inherent problems, in the last decades, innovative nanocarriers have been developed to encapsulate active molecules and offer novel promising strategies to efficiently modulate the immune system. This review provides an overview of how it is possible, exploiting the favorable features of nanocarriers, especially with regard to their immunogenicity, to improve the bioavailability of novel drugs that selectively target immune cells in the context of autoimmune disorders and inflammatory diseases. A focus is made on nanoparticles that selectively target neutrophils in inflammatory pathologies.

    DOI: 10.3390/cells10030707

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  • A Novel 89Zr-labeled DDS Device Utilizing Human IgG Variant (scFv): “Lactosome” Nanoparticle-Based Theranostics for PET Imaging and Targeted Therapy

    Melissa Siaw Han Lim, Takashi Ohtsuki, Fumiaki Takenaka, Kazuko Kobayashi, Masaru Akehi, Hirotaka Uji, Hirotsugu Kobuchi, Takanori Sasaki, Eiichi Ozeki, Eiji Matsuura

    Life   11 ( 2 )   158 - 158   2021.2

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    Publishing type:Research paper (scientific journal)   Publisher:MDPI AG  

    “Theranostics,” a new concept of medical advances featuring a fusion of therapeutic and diagnostic systems, provides promising prospects in personalized medicine, especially cancer. The theranostics system comprises a novel 89Zr-labeled drug delivery system (DDS), derived from the novel biodegradable polymeric micelle, “Lactosome” nanoparticles conjugated with specific shortened IgG variant, and aims to successfully deliver therapeutically effective molecules, such as the apoptosis-inducing small interfering RNA (siRNA) intracellularly while offering simultaneous tumor visualization via PET imaging. A 27 kDa-human single chain variable fragment (scFv) of IgG to establish clinically applicable PET imaging and theranostics in cancer medicine was fabricated to target mesothelin (MSLN), a 40 kDa-differentiation-related cell surface glycoprotein antigen, which is frequently and highly expressed by malignant tumors. This system coupled with the cell penetrating peptide (CPP)-modified and photosensitizer (e.g., 5, 10, 15, 20-tetrakis (4-aminophenyl) porphyrin (TPP))-loaded Lactosome particles for photochemical internalized (PCI) driven intracellular siRNA delivery and the combination of 5-aminolevulinic acid (ALA) photodynamic therapy (PDT) offers a promising nano-theranostic-based cancer therapy via its targeted apoptosis-inducing feature. This review focuses on the combined advances in nanotechnology and material sciences utilizing the “89Zr-labeled CPP and TPP-loaded Lactosome particles” and future directions based on important milestones and recent developments in this platform.

    DOI: 10.3390/life11020158

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  • Soluble Vascular Biomarkers in Rheumatoid Arthritis and Ankylosing Spondylitis: Effects of 1-year Antitumor Necrosis Factor-α Therapy

    Anita Pusztai, Attila Hamar, Ágnes Horváth, Katalin Gulyás, Edit Végh, Nóra Bodnár, György Kerekes, Monika Czókolyová, Szilvia Szamosi, Levente Bodoki, Katalin Hodosi, Andrea Domján, Gábor Nagy, Ibolya Szöllősi, Luis R. Lopez, Eiji Matsuura, Zoltán Prohászka, Sándor Szántó, Zoltán Nagy, Yehuda Shoenfeld, Zoltán Szekanecz, Gabriella Szűcs

    The Journal of Rheumatology   jrheum.200916 - jrheum.200916   2020.12

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    Publishing type:Research paper (scientific journal)   Publisher:The Journal of Rheumatology  

    <sec><title>Objective</title> Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) have been associated with cardiovascular disease. The treatment of arthritis by tumor necrosis factor-α (TNF-α) inhibitors may decrease the serum concentrations of vascular biomarkers. We determined circulating levels of oxidized low-density lipoprotein (oxLDL)/β2 glycoprotein I (β2-GPI) complexes, antibodies to 60 kDa heat shock protein (anti-Hsp60), soluble urokinase plasminogen activator receptor (suPAR), and B-type natriuretic peptide (BNP) fragment in sera of RA and AS patients undergoing anti-TNF treatment.

    </sec><sec><title>Methods</title> Fifty-three patients with RA/AS were treated with etanercept or certolizumab pegol for 1 year. Circulating oxLDL/β2-GPI complex (AtherOx), anti-Hsp60 IgG, and BNP8-29 fragment levels were assessed by ELISA. suPAR levels were determined by suPARnostic Quick Triage test. Flow-mediated vasodilation (FMD), carotid intima-media thickness (CIMT), and arterial pulse wave velocity (PWV) were determined by ultrasound.

    </sec><sec><title>Results</title> One-year anti-TNF treatment significantly decreased oxLDL/β2-GPI levels, as well as suPAR levels in patients with critically high suPAR levels at baseline. In RA, BNP levels were higher in seropositive vs seronegative patients. Serum levels of these vascular biomarkers variably correlated with lipids, anticitrullinated protein antibodies, rheumatoid factor, and C-reactive protein. CIMT positively correlated with BNP, and PWV with suPAR and anti-Hsp60, whereas FMD inversely associated with anti-Hsp60. In repeated measures ANOVA analysis, disease activity supported the effects of anti-TNF treatment on 12-month changes in oxLDL/β2-GPI. CIMT supported the effects of therapy on changes in anti-Hsp60 and suPAR.

    </sec><sec><title>Conclusion</title> These biomarkers may be involved in the pathogenesis of atherosclerosis underlying RA/AS. TNF inhibition variably affects the serum levels of oxLDL/β2-GPI, suPAR, and BNP.

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    DOI: 10.3899/jrheum.200916

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  • Antioxidative attributes of rice bran extracts in ameliorative effects of atherosclerosis-associated risk factors

    Xian Wen Tan, Kazuko Kobayashi, Lianhua Shen, Junko Inagaki, Masahiro Ide, Siaw San Hwang, Eiji Matsuura

    Heliyon   6 ( 12 )   e05743 - e05743   2020.12

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    DOI: 10.1016/j.heliyon.2020.e05743

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  • Identification and visualization of oxidized lipids in atherosclerotic plaques by microscopic imaging mass spectrometry-based metabolomics Reviewed

    Lianhua Shen, Takushi Yamamoto, Xian Wen Tan, Koretsugu Ogata, Eiji Ando, Eiichi Ozeki, Eiji Matsuura

    Atherosclerosis   2020.8

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    Authorship:Corresponding author   Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.atherosclerosis.2020.08.001

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  • Rapid and specific detection of oxidized LDL/β2GPI complexes via facile lateral flow immunoassay Reviewed

    Xian Wen Tan, Fumiaki Takenaka, Hironori Takekawa, Eiji Matsuura

    Heliyon   6 ( 6 )   e04114 - e04114   2020.6

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    DOI: 10.1016/j.heliyon.2020.e04114

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  • Tithonia diversifolia ‐derived orizabin suppresses cell adhesion, differentiation, and oxidized LDL accumulation by Akt signaling suppression via PTEN promotion in THP‐1 cells Reviewed

    Masahiro Ide, Izumi Yoshida, Momochika Kumagai, Takashi Mishima, Yushi Takahashi, Kazuhiro Fujita, Tomoji Igarashi, Eiji Matsuura

    Journal of Food Biochemistry   2020.5

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    Authorship:Last author   Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    DOI: 10.1111/jfbc.13268

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    Other Link: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/jfbc.13268

  • Sera anti-P53 antibody provides new information which explains the link between diabetes and cancer Reviewed

    Sauriasari R, Sekar AP Andisyah N, Syahdi RR, Matsuura E

    Diabetes Metab Syndr Obes   11 ( 13 )   325 - 331   2020.2

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  • Novel single‐chain variant of antibody against mesothelin established by phage library Reviewed

    Hiromasa Yakushiji, Kazuko Kobayashi, Fumiaki Takenaka, Yoshiro Kishi, Midori Shinohara, Masaru Akehi, Takanori Sasaki, Eiji Ohno, Eiji Matsuura

    Cancer Science   110 ( 9 )   2722 - 2733   2019.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    DOI: 10.1111/cas.14150

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    Other Link: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.14150

  • Novel human anti-mesothelin scFv for cancer targeted therapy

    Hiromasa Yakushiji, Kazuko Kobayashi, Fumiaki Takenaka, Masaru Akehi, Eiji Ohno, Eiji Matsuura

    CANCER SCIENCE   109   549 - 549   2018.12

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  • Mutants of β2-glycoprotein I: their features and potent applications Reviewed

    Lianhua Shen, Nuriza Ulul Azmi, Xian Wen Tan, Shinsuke Yasuda, Arum Tri Wahyuningsih, Junko Inagaki, Kazuko Kobayashi, Eiji Ando, Takanori Sasaki, Eiji Matsuura

    Best Practice & Research: Clinical Rheumatology   32 ( 4 )   856 - 862   2018.8

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  • Platelet-activating factor acetylhydrolase in primary antiphospholipid syndrome. Reviewed

    Ames PRJ, Lopez LL, Merashli M, Matsuura E

    Autoimmun Highlights   9   2   2018

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  • PET Imaging Utilizing 89Zr-labeled Human Antibody Variant and Theranostics Technologies Provided by a Novel DDS Carrier Invited

    33   214 - 222   2018

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  • Anti-high Mobility Group Box 1 Antibody Ameliorates Albuminuria in MRL/lpr Lupus-Prone Mice Reviewed

    Haruki Watanabe, Katsue S. Watanabe, Keyue Liu, Sumie Hiramatsu, Sonia Zeggar, Eri Katsuyama, Noriko Tatebe, Akiya Akahoshi, Fumiaki Takenaka, Takahisa Hanada, Masaru Akehi, Takanori Sasaki, Ken-ei Sada, Eiji Matsuura, Masahiro Nishibori, Jun Wada

    MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT   6   31 - 39   2017.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:CELL PRESS  

    We evaluated the efficacy of a neutralizing anti-high mobility group box 1 (HMGB1) monoclonal antibody in MRL/lpr lupus-prone mice. The anti-HMGB1 monoclonal antibody (5 mg/kg weight) or class-matched control immunoglobulin G2a (IgG2a) was administered intravenously twice a week for 4-15 weeks. Urine albumin was monitored, and histological evaluation of the kidneys was conducted at 16 weeks. Lymphadenopathies were evaluated by 1-(2'-deoxy-2'-[F-18]fluoro-beta-D-arabinofuranosyl) cytosine ([F-18] FAC) positron emission tomography/computed tomography (PET/CT) at 12 weeks. Following 4-week treatment, [F-18]FAC-PET/CT showed similar accumulation in cervical and axillary lymph nodes at 12 weeks of age. However, anti-HMGB1 monoclonal antibody sufficiently inhibited the increase in albuminuria compared to an isotype control following 15-week treatment. Complement deposition was also improved; however, there were no significant differences in IgG deposition and renal pathological scores between the two groups. Anti-double-stranded DNA (dsDNA) antibody titers and cytokine and chemokine levels were also unaltered. Although there were no significant differences in glomerular macrophage infiltration, neutrophil infiltration was significantly decreased by the anti-HMGB1 monoclonal antibody. Antagonizing HMGB1 treatment suppressed HMGB1 translocation from nuclei in the kidney and suppressed neutrophil extracellular traps. The anti-HMGB1 monoclonal antibody demonstrated therapeutic potential against albuminuria in lupus nephritis by inhibiting neutrophil recruitment and neutrophil extracellular traps.

    DOI: 10.1016/j.omtm.2017.05.006

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  • The lipid moiety 7-ketocholesteryl-9-carboxynonanoate mediates binding interaction of oxLDL to LOX-1 and upregulates ABCA1 expression through PPAR gamma

    Jingda Li, Zhilong Xiu, Renjun Wang, Chengjie Yu, Yan Chi, Jianzhong Qin, Changzhen Fu, Eiji Matsuura, Qingping Liu

    LIFE SCIENCES   177   27 - 40   2017.5

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:PERGAMON-ELSEVIER SCIENCE LTD  

    Aim: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a specific membrane receptor for oxidized low-density lipoprotein (oxLDL), plays a crucial role in atherosclerosis progression. The aim of this study was to elucidate the role of 7-ketocholesteryl-9-carboxynonanoate (oxLig-1), a lipid component of oxLDL, in the binding of oxLDL to LOX-1 and to determine whether oxLig-1 binding to LOX-1 is involved in the upregulation of ABCA1 expression.
    Main methods: OxLig-1 binding to LOX-1 was analysed by AutoDock 4.2.6 and confirmed by fluorescence immunocytochemistry and enzyme-linked immunosorbent assays (ELISAs). LOX-1, LXR alpha and ABCA1 protein expression induced by oxLig-1 or methylated oxLig-1 was measured by western blotting. In addition, PPAR gamma activation was investigated using a dual-luciferase reporter system. Furthermore, the signalling cascade involved in oxLig-1-induced ABCA1 expression was assessed using inhibitors for PPAR gamma and LXR alpha and specific siRNAs against LOX-1, PPAR gamma and LXR alpha.
    Key findings: Docking, fluorescence immunocytochemistry and ELISA analyses showed that oxLig-1 bound LOX-1 and that the omega-carboxyl group was critical for this binding. Moreover, oxLig-1, but not methylated oxLig-1, increased LOX-1, LXR alpha, and ABCA1 expression. Luciferase reporter assays indicated that oxLig-1 activated PPAR gamma in the presence of LOX-1. Additionally, the inhibitor and siRNA experiments showed that oxLig-1 triggered the PPAR gamma-LXR alpha signalling pathway, leading to upregulation of ABCA1, and that this process required the participation of LOX-1.
    Significance: Our observations indicate that oxLig-1 is a critical epitope of oxLDL that mediates the binding of oxLDL to LOX-1 and initiates PPAR gamma signal transduction to upregulate the expression of ABCA1. (C) 2017 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.lfs.2017.03.024

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  • Tracking and Imaging of Tumor Progression and Immune Function in a Preclinical Mouse Model

    Peng Huang, Naijin Xu, Eiji Matsuura, Masami Watanbe, Hiromi Kumon, Yasutomo Nasu, Chunxiao Liu

    MOLECULAR THERAPY   25 ( 5 )   98 - 98   2017.5

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  • Synergistic effects of the immune checkpoint inhibitor CTLA-4 combined with the growth inhibitor lycorine in a mouse model of renal cell carcinoma

    Xiezhao Li, Peng Xu, Chongshan Wang, Naijin Xu, Abai Xu, Yawen Xu, Takuya Sadahira, Motoo Araki, Koichiro Wada, Eiji Matsuura, Masami Watanabe, Junxia Zheng, Pinghua Sun, Peng Huang, Yasutomo Nasu, Chunxiao Liu

    ONCOTARGET   8 ( 13 )   21177 - 21186   2017.3

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:IMPACT JOURNALS LLC  

    Renal cell carcinoma (RCC) management has undergone a major transformation over the past decade; immune checkpoint inhibitors are currently undergoing clinical trials and show promising results. However, the effectiveness of immune checkpoint inhibitors in patients with metastatic RCC (mRCC) is still limited. Lycorine, an alkaloid extracted from plants of the Amaryllidaceae family, is touted as a potential anti-cancer drug because of its demonstrative growth inhibition capacity (induction of cell cycle arrest and inhibition of vasculogenic mimicry formation). Moreover, T cell checkpoint blockade therapy with antibodies targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) has improved outcomes in cancer patients. However, the anti-tumor efficacy of combined lycorine and anti-CTLA-4 therapy remains unknown. Thus, we investigated a combination therapy of lycorine hydrochloride and anti-CTLA-4 using a murine RCC model. As a means of in vitro confirmation, we found that lycorine hydrochloride inhibited the viability of various RCC cell lines. Furthermore, luciferase-expressing Renca cells were implanted in the left kidney and the lung of BALB/c mice to develop a RCC metastatic mouse model. Lycorine hydrochloride and anti-CTLA-4 synergistically decreased tumor weight, lung metastasis, and luciferin-staining in tumor images. Importantly, the observed anti-tumor effects of this combination were dependent on significantly suppressing regulatory T cells while upregulating effector T cells; a decrease in regulatory T cells by 31.43% but an increase in effector T cells by 31.59% were observed in the combination group compared with those in the control group). We suggest that a combination of lycorine hydrochloride and anti-CTLA-4 is a viable therapeutic option for RCC patients.

    DOI: 10.18632/oncotarget.15505

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  • In vivo distribution of single chain variable fragment (scFv) against atherothrombotic oxidized LDL/beta(2)-glycoprotein I complexes into atherosclerotic plaques of WHHL rabbits: Implication for clinical PET imaging Reviewed

    Takanori Sasaki, Kazuko Kobayashi, Shoichi Kita, Kazuo Kojima, Hiroyuki Hirano, Lianhua Shen, Fumiaki Takenaka, Hiromi Kumon, Eiji Matsuura

    AUTOIMMUNITY REVIEWS   16 ( 2 )   159 - 167   2017.2

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ELSEVIER SCIENCE BV  

    Background: Oxidized LDL (oxLDL) can exist as a complex with beta(2)-glycoprotein I (beta(2)GPI) in plasma/serum of patients with non-autoimmune atherosclerotic disease or antiphospholipid syndrome (APS). Nonetheless, direct in vivo evidence supporting the pathophysiological involvement of oxLDL/beta(2)GPI complexes and specific autoantibody against the complexes in developing atherothrombosis has yet been established. In the present study, we demonstrated in vivo distribution of single chain variable fragment of IgG anti-oxLDL/beta(2)GPI complexes (3H3-scFv) in Watanabe heritable hyperlipidemic (WHHL) rabbits by PET/CT imaging.
    Methods: An antibody-based PET probe, Cu-64-3H3-scFv, was established, and WHHL rabbits were applied for a non-autoimmune atherosclerotic model to demonstrate in vivo distribution of the probe.
    Results: 3H3-scFv has exhibits specificity towards beta(2)GPI complexed with oxLDL but neither a free form of beta(2)GPI nor oxLDL alone. Post-intravenous administration of Cu-64-3H3-scFv into WHHL rabbits has demonstrated a noninvasive approach for in vivo visualization of atherosderotic lesion. The imaging probe achieved ideal blood clearance and distribution for optimal imaging capacity in 24 h, significantly shorter than that of an intact IgG-based imaging probe. Cu-64-3H3-scFv targeted on atherosclerotic plaques in aortas of WHHL rabbits where extensive accumulation of lipid deposits was observed by lipid staining and autoradiography. The accumulation of Cu-64-3H3scFv in aortic segments of WHHL rabbits was 2.8-folds higher than that of controls (p = 0.0045).
    Conclusions: The present in vivo evidence supports the pathophysiological involvement of oxLDL/beta(2)GPI complexes in atherosclerotic complications of WHHL rabbits. Cu-64-3H3-scFv represents a novel PET imaging probe for non-invasive pathophysiological assessment of oxLDL/beta(2)GPI complexes accumulated in atherosclerotic plaques. (C) 2016 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.autrev.2016.12.007

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  • Real-time monitoring of tumor progression and drug responses in a preclinical mouse model of prostate cancer Reviewed

    Peng Xu, Naijin Xu, Kai Guo, Abai Xu, Fumiaki Takenaka, Eiji Matsuura, Chunxiao Liu, Hiromi Kumon, Peng Huang

    ONCOTARGET   7 ( 22 )   33025 - 33034   2016.5

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    Monitoring disease progression through imaging is playing an increasingly important role in the treatment of prostate cancer. Here, we report that primary mouse prostate cancer cell lines stably expressing luciferase and tumor biomarkers can be monitored through bioluminescence imaging along with assays of serum biomarkers and immune function. Tumorigenesis in immunocompetent C57BL/6 mice can be monitored in by collecting samples from the dorsal flank, dorsolateral prostate, and tail vein to obtain real-time subcutaneous, orthotopic, and metastasis indicators, respectively. We used this technique to confirm the therapeutic effect of immune checkpoint blockade. Our findings suggest the presented indicators are ideally suited for real-time tracking of drug responses, tumor progression and immune function.

    DOI: 10.18632/oncotarget.8846

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  • The Function of beta 2-glycoprotein I in Angiogenesis and Its in Vivo Distribution in Tumor Xenografts Reviewed

    Arum Tri Wahyuningsih, Lianhua Shen, Kazuko Kobayashi, Takanori Sasaki, Fumiaki Takenaka, Takahisa Hanada, Masaru Akehi, Akiya Akahoshi, Eiichi Ozeki, Eiji Ando, Eiji Matsuura

    ACTA MEDICA OKAYAMA   70 ( 1 )   13 - 24   2016.2

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:OKAYAMA UNIV MED SCHOOL  

    Intact beta 2-glycoprotein I (i beta 2GPI) is a glycoprotein that regulates coagulation and fibrinolysis. Nicked beta 2GPI (n beta 2GPI) possesses an angiogenic property at a relatively low concentration, and an anti-angiogenic property at a high concentration. Here we investigated the functions of i beta 2GPI and n beta 2GPI in vascular endothelial growth factor (VEGF)-A-induced endothelial cell proliferation and tube formation. We used noninvasive PET imaging to analyze the in vivo distribution of intravenously injected beta 2GPI variants in tumor lesions in mice. i beta 2GPI was incubated with plasmin to obtain n beta 2GPI, and its N-terminal sequence was analyzed. n beta 2GPI had at least one other cleavage site upstream of the beta 2GPFs domain V, whereas the former plasmin-cleavage site locates between K-317 and T-318. Both of intact and nicked beta 2GPI significantly inhibited the VEGF-A-induced cell proliferation and the tube formation of human umbilical vein endothelial cells (HUVECs). PET imaging visualized considerably distributed intensities of all tested beta 2GPI variants in tumor lesions of pancreatic tumor cell-xenografts. These results indicate that beta 2GPI may be physiologically and pathophysiologically important in the regulation of not only coagulation and fibrinolysis, but also angiogenesis.

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  • Enhanced cellular uptake of lactosomes using cell-penetrating peptides Reviewed

    Akiya Akahoshi, Eiji Matsuura, Eiichi Ozeki, Hayato Matsui, Kazunori Watanabe, Takashi Ohtsuki

    SCIENCE AND TECHNOLOGY OF ADVANCED MATERIALS   17 ( 1 )   245 - 252   2016

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    Polymeric micelles that are composed of synthetic polymers are generally size controllable and can be easily modified for various applications. Lactosomes (A(3)B-type) are biodegradable polymeric micelles composed of an amphipathic polymer, including three poly(sarcosine) blocks and a poly(L-lactic acid) block. Lactosomes accumulate in tumors in vivo through the enhanced permeability and retention (EPR) effect, even on frequently administering them. However, lactosomes cannot be efficiently internalized by cells. To improve cellular uptake of lactosomes, cell-penetrating peptide (CPP)-modified lactosomes were prepared. Seven CPPs (including EB1 and Pep1) were used, and most of them improved the cellular uptake efficiency of lactosomes. In particular, EB1- and Pep1-modified lactosomes were efficiently internalized by cells. In addition, by using CPP-modified and photosensitizer-loaded lactosomes, we demonstrated the photoinduced killing of mammalian cells, including human cancer cells. Accumulation of the EB1-modified lactosomes in NCI-N87 tumors was shown by in vivo imaging. Thus, this study demonstrated that the CPP-modified lactosome is a promising drug carrier.
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  • Cytoprotective and Cytotoxic Effects of Rice Bran Extracts in Rat H9c2(2-1) Cardiomyocytes Reviewed

    Xian Wen Tan, Mrinal Bhave, Alan Yean Yip Fong, Eiji Matsuura, Kazuko Kobayashi, Lian Hua Shen, Siaw San Hwang

    OXIDATIVE MEDICINE AND CELLULAR LONGEVITY   2016   2016

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    This study was aimed at preliminarily assessing the cytoprotective and antioxidative effects of rice bran extracts (RBEs) from a Sarawak local rice variety (local name: "BJLN") and a commercial rice variety, "MR219," on oxidative stress in rat H9c2(2-1) cardiomyocytes. The cardiomyocytes were incubated with different concentrations of RBE and hydrogen peroxide (H2O2), respectively, to identify their respective IC50 values and safe dose ranges. Two nonlethal and close-to-IC50 doses of RBE were selected to evaluate their respective effects on H2O2 induced oxidative stress in cardiomyocytes. Both RBEs showed dose-dependent cytotoxicity effects on cardiomyocytes. H2O2 induction of cardiomyocytes pretreated with RBE further revealed the dose-dependent cytoprotective and antioxidative effects of RBE via an increase in IC50 values of H2O2. Preliminary analyses of induction effects of RBE and H2O2 on cellular antioxidant enzyme, catalase (CAT), also revealed their potential in regulating these activities and expression profile of related gene on oxidative stress in cardiomyocytes. Pretreated cardiomyocytes significantly upregulated the enzymatic activity and expression level of CAT under the exposure of H2O2 induced oxidative stress. This preliminary study has demonstrated the potential antioxidant effects of RBE in alleviating H2O2-mediated oxidative injuries via upregulation in enzymatic activities and expression levels of CAT.

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  • A combination of YM-155, a small molecule survivin inhibitor, and IL-2 potently suppresses renal cell carcinoma in murine model Reviewed

    Kai Guo, Peng Huang, Naijin Xu, Peng Xu, Haruki Kaku, Shaobo Zheng, Abai Xu, Eiji Matsuura, Chunxiao Liu, Hiromi Kumon

    ONCOTARGET   6 ( 25 )   21137 - 21147   2015.8

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    YM155, a small molecule inhibitor of the antiapoptotic protein survivin, has been developed as a potential anti-cancer drug. We investigated a combination therapy of YM155 and interleukin-2 (IL-2) in a mouse model of renal cell carcinoma (RCC). YM155 caused cell cycle arrest and apoptosis in renal cancer (RENCA) cells. Next, luciferase-expressing RENCA cells were implanted in the left kidney and the lung of BALB/c mice to develop RCC metastatic model. In this orthotopic renal and metastatic lung tumors models, YM155 and IL-2 additively decreased tumor weight, lung metastasis, and luciferin-stained tumor images. Also, the combination significantly suppressed regulatory T cells and myeloid-derived suppressor cells compared with single agent treatment. We suggest that a combination of YM155 and IL-2 can be tested as a potential therapeutic modality in patients with RCC.

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  • Improvement of Plasma Biomarkers after Switching Stroke Patients from Other Angiotensin II Type I Receptor Blockers to Olmesartan Reviewed

    Yoshiteru Tada, Kenji Yagi, Masaaki Uno, Nobuhisa Matsushita, Yasuhisa Kanematsu, Kazuyuki Kuwayama, Kenji Shimada, Kyoko Nishi, Motohiro Hirasawa, Junichiro Satomi, Keiko T. Kitazato, Teruyoshi Kageji, Eiji Matsuura, Shinji Nagahiro

    JOURNAL OF STROKE & CEREBROVASCULAR DISEASES   24 ( 7 )   1487 - 1492   2015.7

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    Background: Managing hypertension is crucial for preventing stroke recurrence. Some stroke patients experience resistant hypertension. In our experimental stroke model, olmesartan increased the expression of angiotensin (Ang) II converting enzyme-2. We hypothesized that switching to olmesartan affects biomarkers and the blood pressure (BP) in stroke patients whose BP is insufficiently controlled by standard doses of Ang II type I receptor blockers (ARBs) other than olmesartan. Methods: We recruited 25 patients to study our hypothesis. All had a history of stroke or silent cerebral infarction. We switched them to olmesartan (10-40 mg per day) for 12 weeks and determined their plasma level of Ang-(1-7), peroxiredoxin, oxidized low-density lipoprotein (oxLDL)/beta-2-glycoprotein I (beta 2GPI) complex, adiponectin, high mobility group box 1 (HMGB1), and tumor necrosis factor-alpha (TNF alpha) and recorded their BP before and after olmesartan treatment. Results: After switching the patients to olmesartan, their plasma level of Ang-(1-7) as a vasoprotective indicator and adiponectin regulating metabolic syndrome was increased, and peroxiredoxin and the oxLDL/beta 2GPI complex indicating its antioxidative stress and its proatherogenicity were lower than their baseline. This suggests that olmesartan may be more effective than other ARBs to improve these conditions. Neither HMGB1 nor TNF alpha reflecting an inflammatory response was affected, suggesting that the anti-inflammatory effects of olmesartan are similar to those of other ARBs. The recommended BP (&lt;140/90) was obtained in 10 of the 25 patients after switching to olmesartan. No adverse events occurred. Conclusions: Switching from other ARBs to olmesartan may be a promising therapeutic option in patients with resistant hypertension.

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  • Positron Emission Tomography to Elucidate Pharmacokinetic Differences of Regioisomeric Retinoid X Receptor Agonists Reviewed

    Toshiki Kobayashi, Yuki Furusawa, Shoya Yamada, Masaru Akehi, Fumiaki Takenaka, Takanori Sasaki, Akiya Akahoshi, Takahisa Hanada, Eiji Matsuura, Hiroyuki Hirano, Akihiro Tai, Hiroki Kakuta

    ACS MEDICINAL CHEMISTRY LETTERS   6 ( 3 )   334 - 338   2015.3

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    RXR partial agonist NEt-41B (2a, 6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: EC50 = 169 nM, E-max = 55%) showed a blood concentration higher than its Emax after single oral administration at 30 mg/kg to mice, and repeated oral administration at 10 mg/kg/day to KK-A(y) mice afforded antitype 2 diabetes activity without the side effects caused by RXR full agonists. However, RXR full agonist NEt-3IB (la), in which the isobutoxy and isopropyl groups of 2a are interchanged, gave a much lower blood concentration than 2a. Here we used positron emission tomography (PET) with tracers [C-11] la, [C-11]2a and fluorinated derivatives [F-18] lb, [F-18]2b, which have longer half-lives, to examine the reason why la and 2a exhibited significantly different blood concentrations. As a result, the reason for the high blood concentration of 2a after oral administration was found to be linked to higher intestinal absorbability together with lower biliary excretion, compared with la.

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  • A6.13 Effects of anti-tnf therapy on circulating oxLDL-BETA2GPI complex levels in arthritis

    A Pusztai, E Végh, A Váncsa, N Bodnár, S Szamosi, G Nagy, I Szöllösi, P Csomor, L Lopez, E Matsuura, G Szűcs, S Szántó, Z Nagy, Y Shoenfeld, Z Szekanecz

    Annals of the Rheumatic Diseases   74 ( Suppl 1 )   A60.2 - A61   2015.3

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  • A Novel PET Imaging Using Cu-64-Labeled Monoclonal Antibody against Mesothelin Commonly Expressed on Cancer Cells Reviewed

    Kazuko Kobayashi, Takanori Sasaki, Fumiaki Takenaka, Hiromasa Yakushiji, Yoshihiro Fujii, Yoshiro Kishi, Shoichi Kita, Lianhua Shen, Hiromi Kumon, Eiji Matsuura

    JOURNAL OF IMMUNOLOGY RESEARCH   2015:268172. doi: 10.1155/2015   2015

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    Mesothelin (MSLN) is a 40-kDa cell differentiation-associated glycoprotein appearing with carcinogenesis and is highly expressed in many human cancers, including the majority of pancreatic adenocarcinomas, ovarian cancers, and mesotheliomas, while its expression in normal tissue is limited to mesothelial cells lining the pleura, pericardium, and peritoneum. Clone 11-25 is a murine hybridoma secretingmonoclonal antibody (mAb) against human MSLN. In this study, we applied the 11-25 mAb to in vivo imaging to detect MSLN-expressing tumors. In in vitro and ex vivo immunochemical studies, we demonstrated specificity of 11-25 mAb to membranous MSLN expressed on several pancreatic cancer cells. We showed the accumulation of Alexa Fluor 750-labeled 11-25 mAb in MSLN-expressing tumor xenografts in athymic nude mice. Then, 11-25 mAb was labeled with Cu-64 via a chelating agent DOTA and was used in both in vitro cell binding assay and in vivo positron emission tomography (PET) imaging in the tumorbearing mice. We confirmed that Cu-64-labeled 11-25 mAb highly accumulated in MSLN-expressing tumors as compared to MSLN negative ones. The Cu-64-labeled 11-25 mAb is potentially useful as a PET probe capable of being used for wide range of tumors, rather than F-18-FDG that occasionally provides nonspecific accumulation into the inflammatory lesions.

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  • 創薬を加速する技術の新潮流.最先端の分子イメージングで医療イノベーションを実現 Invited

    松浦栄次

    日経サイエンス   2015年5月号   2015

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  • Recombinant Domain V of beta 2-Glycoprotein I Inhibits the Formation of Atherogenic oxLDL/beta 2-Glycoprotein I Complexes Reviewed

    Jingda Li, Yan Chi, Shuqian Liu, Le Wang, Renjun Wang, Xiaofei Han, Eiji Matsuura, Qingping Liu

    JOURNAL OF CLINICAL IMMUNOLOGY   34 ( 6 )   669 - 676   2014.8

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    beta 2-glycoprotein I (beta 2-GPI) is a plasma protein that interacts with oxidized low-density lipoproteins (oxLDL) via beta 2-GPI domain V to form oxLDL/beta 2-GPI complexes, potential autoantigens promoting atherogenesis in patients with antiphospholipid syndrome (APS). Such a interaction would expose beta 2-GPI domain I or/and IV, structures recognized by anti-beta 2-GPI autoantibodies. IgG immune complexes with oxLDL/beta 2-GPI complexes can interact with macrophages via Fc gamma receptor, causing oxLDL/beta 2-GPI endocytosis and foam cell formation, contributing to atherosclerosis. Here, we use recombinant domain V to study the interaction between oxLDL and beta 2-GPI and hypothesized that domain V would interfere with this interaction thereby reducing oxLDL macrophage uptake and foam cell formation. The beta 2-GPI domain V sequence was expressed by using the Pichia pastoris expression system to obtain recombinant domain V of beta 2-GPI (P.r beta 2-GPI DV). ELISA tests demonstrated that P.r beta 2-GPI DV interacted with oxLDL via 7-ketocholesteryl-9-carboxynonanoate (oxLig-1), a negatively charged lipid moiety of oxLDL. The omega-carboxyl residue of oxLig-1 is required for the interaction. Serologic tests showed a significant increase in oxLDL and oxLDL/beta 2-GPI levels in patients with APS (p &lt; 0.05 compared to controls). P.r beta 2-GPI DV was able to bind oxLDL in high affinity and competitively inhibited native beta 2-GPI (n beta 2-GPI) binding to free oxLDL as well as to oxLDL from the oxLDL/beta 2-GPI complexes. These observations suggest that P.r beta 2-GPI DV may be used to inhibit the formation of the oxLDL/beta 2-GPI complexes, a potential approach for reducing foam cell development and mitigating atherogenesis in patients with APS. The present work provides a new effective strategy to prevent the progression of atherothrombotic vascular complications in APS patients.

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  • Elucidation of the pharmacokinetic difference of regioisomeric retinoid X receptor agonists having an alkoxy group by PET imaging

    Toshiki Kobayashi, Kohei Kawata, Mariko Nakayama, Yuki Furusawa, Shoya Yamada, Hiroyuki Hirano, Fumiaki Takenaka, Masaru Akehi, Takanori Sasaki, Eiji Matsuura, Akihiro Tai, Hiroki Kakuta

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   248   2014.8

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  • SIGNIFICANT ACCUMULATION OF OXLDL/BETA2-GLYCOPROTEIN I COMPLEXES IN ARTERIAL LESIONS OF WHHL RABBITS: PET/CT IMAGING USING AN AUTO ANTIBODY'S SCFV VARIANT

    T. Sasaki, Y. Matsunami, F. Takenaka, S. Kita, H. Hirano, L. Shen, K. Kobayashi, E. Matsuura

    ATHEROSCLEROSIS   235 ( 2 )   E68 - E68   2014.8

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  • CIRCULATING PRO-ATHEROGENIC OXIDIZED-LDL/beta 2-GLYCOPROTEIN I COMPLEXES ARE DETECTED IN ARTERIAL AND VENOUS DISEASES AND ARE INDEPENDENT PREDICTORS OF CAROTID ARTERIAL DISEASE

    L. R. Lopez, E. Matsuura, K. E. Guyer, C. B. Rockman, J. S. Berger

    ATHEROSCLEROSIS   235 ( 2 )   E218 - E218   2014.8

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  • 7-Ketocholesteryl-9-carboxynonanoate enhances ATP binding cassette transporter A1 expression mediated by PPAR gamma in THP-1 macrophages Reviewed

    Yan Chi, Le Wang, Yuanyuan Liu, Yanhua Ma, Renjun Wang, Xiaofei Han, Hui Qiao, Jiabin Lin, Eiji Matsuura, Shuqian Liu, Qingping Liu

    ATHEROSCLEROSIS   234 ( 2 )   461 - 468   2014.6

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    Background: ATP binding cassette transporter A1 (ABCA1) is a member of the ATP-binding cassette transporter family. It plays an essential role in mediating the efflux of excess cholesterol. It is known that peroxisome proliferator-activated receptor gamma (PPAR gamma) promoted ABCA1 expression. We previously found 7-ketocholesteryl-9-carboxynonanoate (oxLig-1) upregulated ABCA1 partially through CD36 mediated signals. In the present study, we intended to test if PPARg signally is involved in the upregulation mediated by oxLig-1.
    Methods and results: First, we docked oxLig-1 and the ligand-binding domain (LBD) of PPAR gamma by using AutoDock 3.05 and subsequently confirmed the binding by ELISA assay. Western blotting analyses showed that oxLig-1 induces liver X receptor alpha (LXR alpha), PPAR gamma and consequently ABCA1 expression. Furthermore, oxLig-1 significantly enhanced ApoA-I-mediated cholesterol efflux. Pretreatment with an inhibitor for PPAR gamma (GW9662) or/and LXRa (GGPP) attenuated oxLig-1-induced ABCA1 expression. Under PPAR gamma knockdown by using PPAR gamma-shRNA, oxLig-1-induced ABCA1 expression and cholesterol efflux in THP-1 macrophages was blocked by 62% and 25% respectively.
    Conclusions: These observations suggest that oxLig-1 is a novel PPAR gamma agonist, promoting ApoA-I-mediated cholesterol efflux from THP-1 macrophages by increasing ABCA1 expression via induction of PPAR gamma. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

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  • PETイメージングを用いたアルコキシ基を有するレチノイドX受容体アゴニストの体内動態解析

    加来田 博貴, 小林 俊貴, 古沢 優貴, 山田 翔也, 竹中 文章, 明日 卓, 佐々木 崇了, 松浦 栄次, 田井 章博

    ビタミン   88 ( 4 )   213 - 213   2014.4

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  • Is atherosclerosis an autoimmune disease? Reviewed

    Eiji Matsuura, Fabiola Atzeni, Piercarlo Sarzi-Puttini, Maurizio Turiel, Luis R. Lopez, Michael T. Nurmohamed

    BMC MEDICINE   12   47   2014.3

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    Immunologic research into pathogenic mechanisms operating in autoimmune-mediated atherosclerosis initially focused on adaptive immunity. Current interest is directed to more basic inflammatory mechanisms. Chronic inflammation (innate immunity-associated) may trigger initial events that can lead to atherosclerotic cardiovascular disease. This chronic inflammation may start early in life and be perpetuated by classic atherosclerosis risk factors. Lipid peroxidation of low-density lipoprotein seems to be a key event in the initiation and progression of atherosclerosis. Oxidized low-density lipoprotein triggers inflammatory and immunogenic events that promote endothelial dysfunction and the synthesis and secretion of pro-inflammatory cytokines, leading to an autoimmune response capable of accelerating the intracellular accumulation of lipids within atherosclerotic plaques. Oxidized low-density lipoprotein binds beta 2-glycoprotein I to form circulating complexes found in both autoimmune and non-autoimmune atherosclerosis. It is likely that beta 2-glycoprotein I and/or these complexes contribute to early atherogenesis by stimulating pro-inflammatory innate immunity through endogenous sensors and inflammasome/ interleukin-1 pathways. We discuss the chronic inflammatory (innate) and autoimmune (adaptive) responses operating in atherosclerosis to discern the role of autoimmunity in atherosclerotic cardiovascular disease.

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  • アルコキシ基を有するレチノイドX受容体アゴニストの位置異性体間における体内動態差の解明とその応用

    小林 俊貴, 古沢 優貴, 山田 翔也, 平野 裕之, 竹中 文章, 明日 卓, 佐々木 崇了, 松浦 栄次, 田井 章博, 加来田 博貴

    日本薬学会年会要旨集   134年会 ( 4 )   81 - 81   2014.3

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  • Ectopic calcification: Importance of common nanoparticle scaffolds containing oxidized acidic lipids Reviewed

    Hiromi Kumon, Eiji Matsuura, Noriyuki Nagaoka, Toshio Yamamoto, Shinya Uehara, Motoo Araki, Yukana Matsunami, Kazuko Kobayashi, Akira Matsumoto

    Nanomedicine: Nanotechnology, Biology, and Medicine   10 ( 2 )   441 - 450   2014.2

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    The term nanobacteria, sometimes referred to as nanobacteria-like particles (NLPs), is presently recognized as a misnomer for inert calcified nanoparticles. However, misinterpretation of its propagation as a living organism still continues. Ultrastructural and elemental analyses, combining immuno-electron microscopy with an original NLP isolate (P-17) derived from urinary stones, and an IgM monoclonal antibody (CL-15) raised against P-17 have now revealed that, oxidized lipids with acidified functional groups were key elements in NLP propagation. Lamellar structures composed of acidic/oxidized lipids provided structural scaffolds for carbonate apatite crystals. During in vitro culture, lipid peroxidation induced by γ-irradiation of FBS was a major cause of accelerated NLP propagation. In pathological tissue samples from hyperlipidemic atherosclerosis-prone mice, CL-15 co-localized with fatty plaques, macrophage infiltrates and osteocalcin staining of aortic valve lesions. These observations indicate that naturally occurring NLP composed of mineralo-oxidized lipids complexes are generated as by-products rather than etiological agents of chronic inflammation. From the Clinical Editor: The term "nanobacteria-like particles (NLPs)" is presently recognized as a misnomer for inert calcified nanoparticles as opposed to living organisms. This study convincingly demonstrates that naturally occurring NLPs composed of mineralo-oxidized lipid complexes are generated as by-products rather than etiological agents of chronic inflammation. © 2014 Elsevier Inc.

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  • Platelet thromboxane (11-dehydro-thromboxane B2) and aspirin response in patients with diabetes and coronary artery disease. Reviewed

    Lopez LR, Guyer KE, Torre IG, Pitts KR, Matsuura E, Ames PR

    World J Diabetes   5   115 - 127   2014

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  • Atherosclerosis in primary antiphospholipid syndrome: Summary of clinical and pathogenic evidence

    P. R J Ames, L. R. Lopez, E. Matsuura, A. Margarita

    Journal of Clinical and Experimental Cardiology   5 ( 2 )   2014

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    The Antiphospholipid Syndrome (APS) was described in the early '80s as a combination of thrombosis, thrombocytopenia and recurrent miscarriages associated with persistent high titers of Antiphospholipid Antibodies (aPL). In subsequent years, it became apparent that aPL were also associated with premature atherosclerosis in Systemic Lupus Erythematosus (SLE) and more recently in primary APS (PAPS). The studies exploring atherosclerosis in PAPS were heterogeneous in conception and size, but overall, provided enough evidence that Intima Media Thickness (IMT) of carotid arteries and endothelial function are abnormal in PAPS. In keeping with the general view that atherosclerosis is a low grade inflammatory and "auto"immune disorder characterized by oxidative and nitrative stress, several studies have confirmed similar findings in PAPS, though a specific relation with the severity of atherosclerosis is lacking. Given its development at an earlier age than average, atherosclerosis should be taken into account in the overall management of PAPS patients as it may significantly add to the vascular risk. © 2014 Ames PRJ, et al.

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  • β2-Glycoprotein I Autoantibodies Reviewed

    Eiji Matsuura, Luis R. Lopez

    Autoantibodies: Third Edition   689 - 698   2013.12

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    Elevated serum levels of antiphospholipid antibodies, venous or arterial thrombosis, and/or pregnancy morbidity (miscarriages, recurrent fetal loss) are the major serologic and clinical features of the antiphospholipid syndrome (APS). Antiphospholipid antibodies belong to a heterogeneous family of autoantibodies that play a crucial role in the development of thrombosis in patients with APS. These antibodies may react with negatively charged phospholipids, phospholipid/protein complexes, and certain plasma proteins attached to suitable surfaces (i.e., activated cell membranes, oxygenated polystyrene). Most antiphospholipid antibodies derived from patients with APS require the presence of certain plasma proteins for optimal phospholipid binding activity. β2-Glycoprotein I (β2GPI), a phospholipid-binding plasma protein, is now recognized as the most clinically relevant antigenic target for antiphospholipid antibodies. Antibodies to β2GPI are more specific for thrombosis (and APS) than anticardiolipin (aCL) antibodies. Recent prospective studies have shown that β2GPI-dependent aCL and anti-γ2GPI antibodies were significant predictors of arterial thrombosis (myocardial infarction and stroke). In addition to natural anticoagulant properties, β2GPI may also bind to oxidized low-density lipoprotein (oxLDL) likely to quench its proinflammatory and atherogenic effects. Circulating oxLDL/β2GPI complexes are immunogenic, and anti-oxLDL/β2GPI antibodies accelerate their macrophage uptake and the development of autoimmune-mediated atherothrombosis. Autoantibodies against oxLDL/β2GPI complexes strongly correlated with arterial thrombosis in patients with systemic lupus erythematosus (SLE) and APS. These findings suggest that β2GPI and anti-γ2GPI antibodies play a central pathogenic role in thrombosis, and particularly in autoimmune-mediated atherosclerosis. © 2014 Elsevier B.V. All rights reserved.

    DOI: 10.1016/B978-0-444-56378-1.00081-2

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  • Laminin-1 (LM-111) in preeclampsia and systemic lupus erythematosus Reviewed

    Maria-Carolina Paez, Eiji Matsuura, Luis A. Diaz, Yehuda Shoenfeld, Norma C. Serrano, Juan-Manuel Anaya

    AUTOIMMUNITY   46 ( 1 )   14 - 20   2013.2

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    Background: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of antibodies. SLE has been associated with placental pathology, a finding that is also the determinant in preeclampsia (PE). Genetic evidence and serologic reports suggest laminin-1 (LM-111) as an immunogenic molecule and its polymorphic gene as a candidate gene for both disorders. Objective: To evaluate the association between LAMA1 (rs543355) and LAMC1 (rs20563) polymorphisms and the presence of SLE and PE as well as to determine serum levels of anti-LM-111 autoantibodies in the PE group. Methods: Group A: 169 women with PE and 172 healthy pregnant women. Group B: 204 women with SLE and 204 healthy women. Anti-LM-111 for group A was measured by ELISA and the genotyping was done by using a PCR system. Results: Group A: Levels of anti-LM-111 was similar in women with PE and the control group (p = 0.3). The allelic frequencies and genotypes did not show statistically significant differences for LAMA1 and LAMC1 polymorphisms. Group B: Significant differences between SLE patients and controls for rs543355 polymorphism were not observed. Nevertheless, LAMC1 rs20563 A-allele provided protection against the development of SLE (OR 0.73, 95% CI 0.55-0.96). Conclusions: Serum levels of anti-LM-111 at the third trimester of gestation do not seem to have any direct relationship with the presence of PE, and the SNPs evaluated are not associated with the risk of developing this disorder. LAMC1 polymorphism could be a protective factor for SLE.

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  • 7-Ketocholesteryl-9-carboxynonanoate enhances the expression of ATP-binding cassette transporter A1 via CD36 Reviewed

    Wenzhe Li, Dan Wang, Yan Chi, Renjun Wang, Fan Zhang, Guang Ma, Zilong Chen, Jingda Li, Zhe Liu, Eiji Matsuura, Qingping Liu

    ATHEROSCLEROSIS   226 ( 1 )   102 - 109   2013.1

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    Background: CD36 signal transductions have been reported by a variety of lipid moiety of oxidized low-density lipoprotein (oxLDL), however, CD36 signal induced by 7-ketocholesteryl-9-carboxynonanoate (oxLig-1), a lipid moiety of oxLDL has not been elucidated.
    Methods and results: OxLig-1 leads to activation and recruitment of Src kinase Fyn, Lyn and caveolin-1 to CD36 in J774A.1 cells, but not in CD36 knockdown cells. The mitogen-activated protein (MAP) kinases c-Jun N-terminal kinase 2 (JNK2) and extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) are specifically phosphorylated in J774A.1 cells after treatment with oxLig-1 and inhibited by pretreatment of Src inhibitor, AG1879. The expression of ABCA1 is up-regulated by treatment with oxLig-1in J774A.1 cells, and the increased expression of ABCA1 is dramatically down-regulated by pretreatment with pharmacological inhibitors of ERK (PD98059) and JNK (SP600125).
    Conclusions: The specific CD36 signal induced by oxLig-1 initiated the activation of Fyn, Lyn, caveolin-1, JNK2 and ERK1/2, and resulted in the up-regulation of ABCA1. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

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  • A purification system for 64Cu produced by a biomedical cyclotron for antibody PET imaging Reviewed

    Teruaki Toyota, Tadashi Hanafusa, Takashi Oda, Iwane Koumura, Takanori Sasaki, Eiji Matsuura, Hiromi Kumon, Tsuneo Yano, Toshiro Ono

    Journal of Radioanalytical and Nuclear Chemistry   298 ( 1 )   295 - 300   2013

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    Ion exchange is a simple and efficient method for separating no-carrier-added 64Cu from an irradiated Ni target. We developed a semi-automated two-round 64Cu separation system equipped with a strong-base anion exchange resin column. We first verified the efficiency of the system using a non-radioactive substitute consisting of 25 mg of Ni and 127 ng of Cu, and confirmed that Cu was completely eluted at the second round of the separation step. After the bombardment, separation of 64Cu from the Ni target was achieved with high radiochemical purity. 64Cu produced and separated in this study had an extremely low level of Ni impurity. It could be used for labeling monoclonal antibodies for antibody positron emission tomography imaging and synthesizing radiopharmaceuticals. © 2012 The Author(s).

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  • 岡山大学におけるPET研究施設の治験薬GMP(Good Manufacturing Practice)体制 Invited

    佐々木崇了, 松浦栄次, 公文裕巳, 矢野恒夫

    Pharm Tech Japan   29   123 - 128   2013

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  • beta 2-glycoprotein I and oxidative inflammation in early atherogenesis: A progression from innate to adaptive immunity? Reviewed

    Eiji Matsuura, Luis R. Lopez, Yehuda Shoenfeld, Paul R. J. Ames

    AUTOIMMUNITY REVIEWS   12 ( 2 )   241 - 249   2012.12

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    The innate immune system represents the first line of host defense against a wide variety of pathogens and endogenous danger signals. It relies on trans-membrane signaling and cytoplasmic receptors (danger sensors) to trigger early inflammatory responses. As with the adaptive immunity, an innate immune response can cause tissue injury, chronic inflammation and disease. Nucleotide-binding leucine-rich proteins (NLRs) are a family of cytoplasmic receptors for endogenous danger signals. Inflammasomes are multi-molecular complexes of pyrin-containing NLRs (NLRPs) that regulate pro-inflammatory caspases and interleukin 1 cytokines in response to various stimuli. Cholesterol crystals and oxidation-specific epitopes (oxLDL, ROS) are some of the endogenous signals capable of activating NLRP inflammasomes. Thus, an inflammasome-induced IL-1 beta dysregulation may represent an early atherogenic mechanism that initiates atherosclerosis. The plasma protein, beta 2-glycoprotein I (beta 2GPI), complexed to anionic phospholipids is the main antigenic target for antiphospholipid antibodies. In addition to anticoagulant properties, circulating beta 2GPI has more pleiotropic functions affecting fibrinolysis, angiogenesis, apoptosis and atherogenesis. OxLDL interacts with beta 2GPI to form oxLDL/beta 2GPI pro-atherogenic complexes in both autoimmune-mediated and non-autoimmune atherothrombotic diseases. Due to its interaction with oxLDL, the contribution and implication of beta 2GPI in early atherogenesis via the innate (inflammasome/IL-1) system are hypothesized. (C) 2012 Elsevier B.V. All rights reserved.

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  • Two young-adult female cases of dermatomyositis with antibodies for transcriptional intermediary factor 1-gamma Reviewed

    Eri Matsuura, Naoko Ishiguro, Yasuhiro Katsumata, Wako Urano, Hisashi Yamanaka, Mitsuko Kondo, Masataka Kuwana, Kenzo Kaji, Yasuhito Hamaguchi, Manabu Fujimoto, Makoto Kawashima

    EUROPEAN JOURNAL OF DERMATOLOGY   22 ( 5 )   668 - 671   2012.9

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    A variety of myositis-specific autoantibodies (MSAs) have been detected in patients with dermatomyositis (DM). We analyzed MSAs in 20 cases with DM. Eleven of the 20 cases were positive. Out of those 11 cases, 3 were positive for antibodies against aminoacyl-tRNA synthetase and 3 had antibodies to anti-melanoma differentiation-associated gene 5 detected using an immunoprecipitation assay and/or a specific enzyme-linked immunosorbent assay. One case had anti-NXP-2 antibodies and 4 cases had anti-transcriptional intermediary factor 1 (TIF1)-alpha/gamma antibodies detected by immunoprecipitation and Western blotting. Two of those 4 cases had antibodies for both TIE1-alpha and TIF1-gamma, and the 2 other cases had antibodies for TIF1-gamma alone. We report the 2 cases with antibodies for TIF1-gamma only, who were young-adult females without an internal malignancy or interstitial pneumonia. Those 2 cases had clinically amyopathic DM. Among DM patients with antibodies against TIF1 family proteins, there seems to be a subgroup of young-adult cases who have clinically amyopathic DM and show good prognosis without malignancy.

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  • On aspirin treatment but not baseline thromboxane B2 levels predict adverse outcomes in patients with acute coronary syndromes Reviewed

    E. Matsuura, K. Guyer, H. Yamamoto, L. R. Lopez, K. Inoue

    JOURNAL OF THROMBOSIS AND HAEMOSTASIS   10 ( 9 )   1949 - 1951   2012.9

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    DOI: 10.1111/j.1538-7836.2012.04845.x

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  • Aspirin insensitive thromboxane generation is associated with oxidative stress in type 2 diabetes mellitus Reviewed

    Paul R. J. Ames, Joana R. Batuca, Ivana J. Muncy, Ignacio Garcia De la Torre, Sara Pascoe-Gonzales, K. Guyer, E. Matsuura, Luis R. Lopez

    THROMBOSIS RESEARCH   130 ( 3 )   350 - 354   2012.9

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    Introduction: Aspirin (ASA) irreversibly inhibits platelet cyclooxygenase-1 (COX-1) leading to decreased thromboxane-mediated platelet activation. The effect of ASA ingestion on platelet activation, thromboxane generation, oxidative stress and anti-oxidant biomarkers was studied in type 2 diabetes mellitus (DM). Material and methods: Baseline and post-ASA samples (100/325 mg x 7 days) were obtained from 75 DM patients and 86 healthy controls for urinary 11-dehydro-thromboxane B2 (11dhTxB2), 8-iso-prostaglandin-F2 alpha (8-isoPGF2 alpha) and serum sP-Selectin, nitrite (NO2-), nitrate (NO3-) and paraoxonase 1 (PON1) activity. Results: Compared to baseline controls, baseline DM had higher mean levels of 11dhTxB2 (3,665 +/- 2,465 vs 2,450 +/- 1,572 pg/mg creatinine, p=0.002), 8-isoPGF2 alpha (1,457 +/- 543 vs 1,009 +/- 412 pg/mg creatinine, p&lt;0.0001), NO2-(11.8 +/- 7.3 vs 4.8 +/- 5.3 mu M, p&lt;0.0001), NO3-(50.4 +/- 39.3 vs 20.9 +/- 16.7 mu M, p&lt;0.0001) and sP-Selectin (120.8 +/- 56.7 vs 93.0 +/- 26.1 ng/mL, p=0.02), and the same held for post-ASA levels (p&lt;0.0001). ASA demonstrated no effect on 8-isoPGF2 alpha, NO2-, NO3-, sP-Selectin or PON1 activity in either DM or controls. Post ASA inhibition of urinary 11dhTxB2 was 71.5% in DM and 75.1% in controls. There were twice as many ASA poor responders in DM than in controls (14.8% and 8.4%) based on systemic thromboxane reduction. Urinary 8-isoPGF2 alpha excretion was greater in DM ASA poor responders than good responders (p&lt;0.009). Conclusions: This suggests that oxidative stress may maintain platelet function irrespective of COX-1 pathway inhibition and/or increase systemic generation of thromboxane from non-platelet sources. (C) 2012 Elsevier Ltd. All rights reserved.

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  • Persimmon (Diospyros Kaki Thunb ‘Saijo’) peel improved dyslipidemia and its related production of atherogenic autoantigen complexes in low-density lipoprotein receptor-deficient mice. Reviewed

    Quan N, Kobayashi K, Matsunami Y, Ide M, Makarova M, Shen L, Ohno S, Zheng Y, Kobayashi H, Lopez LR, Matsuura E

    Open Nutr J   6   12 - 20   2012

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  • Aspirin inhibition of thromboxane does not affect oxidative stress, nitric oxide metabolites, paraoxonase activity or P-selectin levels in diabetes

    L. R. Lopez, J. R. Batuca, I. J. Muncy, I. Garcia De La Torre, E. Matsuura, P. R. J. Ames

    DIABETOLOGIA   54   S305 - S305   2011.9

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  • A Possible Mechanism of Autoimmune-Mediated infertility in Women with Endometriosis Reviewed

    Junko Inagaki, Lin Hao, Mikiya Nakatsuka, Tatsuji Yasuda, Yuji Hiramatsu, Yehuda Shoenfeld, Eiji Matsuura

    AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY   66 ( 2 )   90 - 99   2011.8

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    Problem
    Endometriosis has been proposed to be an autoimmune disease because of the presence of a variety of autoantibodies specific for endometrial or ovarian antigens. The object of the present study is to characterize binding specificity of anti-laminin-111 autoantibodies in infertile patients with endometriosis and to investigate whether these autoantibodies affect the in vitro embryo development.
    Method of study
    An ELISA analysis using overlapping synthesized peptides that covered the entire G domain of laminin-alpha 1 chain was performed in infertile patients with endometriosis (n = 45). Mouse blastocysts were cultured in media containing the purified IgG from one antibody-positive serum on laminin-111-coated dishes.
    Results
    Anti-laminin-111 autoantibodies were directed to several particular biologically functional peptide sequences in laminin-alpha 1 chain G domain. The tested IgG significantly inhibited the extent of in vitro trophoblast outgrowth.
    Conclusion
    Anti-laminin-111 autoantibodies may have major pathogenic roles on early reproductive failure including endometriosis-associated infertility.

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  • Rosuvastatin decreases serum levels of oxidized low-density lipoprotein/beta2-glycoprotein I complex through the nitric oxide pathway in diabetes mellitus

    L. R. Lopez, E. Matsuura, J. Batuca, I. G. De La Torre, P. R. J. Ames

    JOURNAL OF THROMBOSIS AND HAEMOSTASIS   9   650 - 650   2011.7

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  • Simultaneous occurrence of natural immunity, atherogenic in vivo LDL oxidation and thromboxane-mediated platelet activation in atherosclerosis-prone (LDLR-/- and apoE-/-) mice

    E. Matsuura, L. Shen, Y. Matsunami, N. Quan, K. Kobayashi, Y. Shoenfeld, K. Oguma, L. R. Lopez

    JOURNAL OF THROMBOSIS AND HAEMOSTASIS   9   906 - 906   2011.7

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  • Distinctive aspirin effect on the arachidonic acid pathway, oxidative stress, nitric oxide metabolites and P-selectin in diabetes mellitus

    L. R. Lopez, Muncy, I, E. Matsuura, J. Batuca, K. Guyer, I. G. De La Torre, P. R. J. Ames

    JOURNAL OF THROMBOSIS AND HAEMOSTASIS   9   338 - 339   2011.7

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  • Anti-atherogenic plaque reduction, inhibition of oxLDL/B2GPI autoantigen and thromboxane platelet activation by persimmon (diospyros Kaki) peel in LDLR-/- deficient mice

    E. Matsuura, N. Quan, K. Kobayashi, Y. Matsunami, M. Ide, M. Makarova, L. Shen, S. Ohno, Y. Zheng, H. Kobayashi, L. R. Lopez

    JOURNAL OF THROMBOSIS AND HAEMOSTASIS   9   906 - 907   2011.7

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  • ATHEROGENIC IN VIVO LDL OXIDATION, THROMBOXANE-MEDIATED PLATELET ACTIVATION AND SIMULTANEOUS OCCURRENCE OF NATURAL IMMUNITY IN ATHEROSCLEROSIS-PRONE (LDLR-/- AND APOE(-/-)) MICE

    E. Matsuura, L. Shen, Y. Matsunami, N. Quan, K. Kobayashi, Y. Shoenfeld, K. Oguma, L. R. Lopez

    ATHEROSCLEROSIS SUPPLEMENTS   12 ( 1 )   85 - 85   2011.6

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  • ANTI-ATHEROGENIC EFFECTS OF PERSIMMON (DIOSPYROS KAKI) PEEL IN LDLR-/--DEFICIENT MICE: PLAQUE REDUCTION, INHIBITION OF OXLDL/beta 2GPI AUTOANTIGEN AND THROMBOXANE PLATELET ACTIVATION

    E. Matsuura, N. Quan, K. Kobayashi, Y. Matsunami, M. Ide, M. Makarova, L. Shen, S. Ohno, Y. Zheng, H. Kobayashi, L. R. Lopez

    ATHEROSCLEROSIS SUPPLEMENTS   12 ( 1 )   52 - 52   2011.6

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  • In Vivo Oxidation, Platelet Activation and Simultaneous Occurrence of Natural Immunity in Atherosclerosis-Prone Mice Reviewed

    Lianhua Shen, Yukana Matsunami, Nanhu Quan, Kazuko Kobayashi, Eiji Matsuura, Keiji Oguma

    ISRAEL MEDICAL ASSOCIATION JOURNAL   13 ( 5 )   278 - 283   2011.5

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    Background: Several murine models are susceptible to atherosclerosis, such as low density-lipoprotein receptor-deficient (LDLR(-/-)) and apolipoprotein E-deficient (apoE(-/-)) mice, and are used for studying pathophysiological mechanisms. Atherosclerotic lesions in the aortic valve and thoracic/abdominal aorta are commonly associated with hyperlipidemia. We recently demonstrated the development of large atherosclerotic plaques in Helicobacter pylori-infected heterozygous LDLR(+/-) apoE(+/-) mice.
    Objectives: To measure novel biomarkers related to atherosclerosis, blood coagulation, and oxidative stress in order to investigate their possible pathogenic roles in atherosclerosis-prone mice.
    Methods: Mice were fed with a normal chow diet or high-fat diet and sacrificed at different age intervals to measure aortic plaque size. Plasma cholesterol was enzymatically measured. Enzyme-linked immunosorbent assay was used to measure oxidized LDL (oxLDL)/beta-2-glycoprotein I (beta 2GPI) complexes, immunoglobulin M (IgM) antibodies against native LDL, oxLDL, or oxLDL/beta 2GPI, and urine 11-dehydrothromboxane B2 (11-dhTxB(2)) or 8-hydroxy-deoxyguanosine.
    Results: There was a parallel increase in plaque size, plasma cholesterol, and urinary 11-dhTxB(2) in atherosclerosis-prone mice. In contrast to atherosclerosis-prone strains, an elevation of urinary 11-dhTxB(2) with no significant plaque generation was observed in LDLR(+/-) apoE4 mice. The atherogenic autoantigen oxLDL/beta 2GPI complex was detected only in LDLR(-/-) mice. These levels seem to depend on plaque size. IgM antibodies against oxLDL in apoE(-/-) mice were found, accompanied by atherosclerotic progression.
    Conclusions: Progression of atherosclerotic lesions was associated not only with hypercholesterolemia but also with platelet activation and natural autoimmune-mediated regulatory mechanism(s) in murine models. IMAJ 2011; 13: 278-283

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  • Recombinant domain V of beta(2)-glycoprotein I inhibits the formation of a 7-ketocholesteryl-9-carboxynonanoate and beta(2)-glycoprotein I complex Reviewed

    Yingbiao Zhang, Wenzhe Li, Yan Chi, Renjun Wang, Dan Wang, Fan Zhang, Zhe Liu, Eiji Matsuura, Qingping Liu

    JOURNAL OF BIOCHEMISTRY   149 ( 1 )   35 - 42   2011.1

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    Our prior study has been reported the formation of the oxidized low-density lipoprotein (oxLDL)/beta(2)-glycoproteinI (beta(2)-GPI)/autoantibody complex facilitated the antiphospholipid syndrome (APS) process. The domain V of beta(2)-GPI binds to the negatively charged molecules, e.g. 7-ketochoresteryl-9-caboxynonanoate (oxLig-1) derived from the oxLDL and mediates the interaction between oxLDL and beta(2)-GPI. In the present study, the oxLig-1/beta(2)-GPI/anti-beta(2)-GPI Ab (WB-CAL-1) model was established. The recombinant domain V of beta(2)-GPI (r beta(2)-GPI DV) expressed in Escherichia coli competitively inhibits the interaction between beta(2)-GPI and oxLig-1 in the enzyme-linked immunoassay. Moreover, the r beta(2)-GPI DV significantly inhibits the formation of the oxLig-1/beta(2)-GPI/autoantibody complex in an APS patient. The present work suggests a novel possibility that r beta(2)-GPI DV could be used to inhibit the formation of oxLDL/beta(2)-GPI/autoantibody complex, and give us a hint for the development of new therapeutic strategies to prevent the APS process.

    DOI: 10.1093/jb/mvq111

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  • 自己免疫・感染免疫が惹起する動脈硬化〜岡山発の“自己抗体に世路次世代標的医療” Invited

    松浦栄次

    BIOTOVO   2011年11月号   2011

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  • Rosuvastatin treatment is associated with a decrease of serum oxidised low-density lipoprotein/beta2-glycoprotein i complex concentration in type 2 diabetes Reviewed

    Paul Rj Ames, Alfredo Ortiz-Cadenas, Ignacio Garcia-De La Torre, Arnulfo Nava, Aldo Oregon-Miranda, Joana R Batuca, Kazuo Kojima, Luis R Lopez, Eiji Matsuura

    British Journal of Diabetes and Vascular Disease   10 ( 6 )   292 - 299   2010.11

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    Aims To evaluate the effect of rosuvastatin on oxidised low-density lipoprotein/beta2-glycoprotein I (oxLDL/ β2GPI) complex concentration in type 2 diabetes mellitus. Methods: open label 2:1 assignment of consecutive diabetic patients into oral rosuvastatin (10 mg daily for six weeks) arm or observational arm with measurements of serum oxLDL/ β2GPI complexes, nitric oxide metabolites, asymmetric dimethyl arginine, nitrotyrosine alongside routine biochemistry at baseline and end of study in all patients. Results After rosuvastatin treatment the mean serum concentration of oxLDL/β2GPI decreased from 0.79±0.49 units/mL to 0.53±0.36 units/mL (p&lt
    0.001). The decrease was statistically independent from the decrements of mean cholesterol, LDL and triglyceride concentrations (p&lt
    0.001) but probably dependent on the decrement of nitrate (p&lt
    0.001). Conclusion In type 2 diabetes, treatment with rosuvastatin was associated with a significant reduction of serum concentrations of oxLDL/β2GPI complexes, which is in further support of the already proposed effects of the drug on the oxidative metabolism of lipids and/or LDL. The oxLDL/β2GPI complex may represent a surrogate marker of oxidative stress in type 2 diabetes. © The Author(s), 2010.

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  • 7-Ketocholesteryl-9-carboxynonanoate induced nuclear factor-kappa B activation in J774A.1 macrophages Reviewed

    Zhenyu Huang, Wenzhe Li, Renjun Wang, Fan Zhang, Yan Chi, Dan Wang, Zhe Liu, Yingbiao Zhang, Eiji Matsuura, Qingping Liu

    LIFE SCIENCES   87 ( 19-22 )   651 - 657   2010.11

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    Aims: 7-Ketocholesteryl-9-carboxynonanoate (oxLig-1), a lipid moiety of oxidized low-density lipoprotein (oxLDL), has been reported to be a crucial ligand of beta2-glycoprotein I (beta(2)-GPI), and plays a potential role in the development of atherosclerosis (AS), however, the role of the sole oxLig-1 in the development of AS remains unclear.
    Main methods: Expression and phosphorylation levels of several proteins, such as nuclear factor-kappaB (NF-kappa B), protein kinase C (PKC), I kappa B alpha and inter-cellular adhesion molecule 1 (ICAM-1) were determined by Western blot; nuclear localization of NF-kappa B was studied by immunocytochemistry; NF-kappa B activation was assayed by electrophoretic mobility shift assay (EMSA); and expressions of genes associated with AS process were investigated by Mouse Atherosclerosis RT(2) Profiler PCR Array assay.
    Key findings: The present work indicated that oxLig-1 induced I kappa B alpha phosphorylation and results in the nuclear translocation of NF-kappa B in J774A.1 macrophages. Moreover, oxLig-1-induced NF-kappa B DNA binding activity was detected by EMSA. Indeed, oxLig-1 led to the activation of PKC prior to activating NF-kappa B. The treatment of oxLig-1 in J774A.1 macrophages up-regulates the expression of NF-kappa B target genes including ICAM-1
    Significance: OxLig-1 on the oxLDL plays an important role in AS process, as evidenced by the NF-kappa B activation and up-regulation of genes involved in AS development in oxLig-1 challenged J774A.1 macrophages. (C) 2010 Elsevier Inc. All rights reserved.

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  • Nicked β2-glycoprotein I binds angiostatin 4.5 and attenuates its anti-angiogenic property

    NAKAGAWA Hisako, YASUDA Shinsuke, MATSUURA Eiji, KOBAYASHI Kazuko, IEKO Masahiro, KATAOKA Hiroshi, HORITA Tetsuya, ATSUMI Tatsuya, KOIKE Takao

    Japanese Journal of Thrombosis and Hemostasis   21 ( 3 )   314 - 318   2010.6

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    DOI: 10.2491/jjsth.21.314

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  • OXIDIZED-LDL/beta 2-GLYCOPROTEIN I COMPLEXES AND ANTIPHOSPHOLIPID ANTIBODIES ARE ASSOCIATED WITH DISEASE SEVERITY AND RISK FOR ADVERSE OUTCOMES IN ACUTE CORONARY SYNDROME

    L. Lopez, T. Greco, A. M. Conti-Kelly, R. Anthony, J. Geske, M. Boisen, E. Matsuura

    ATHEROSCLEROSIS SUPPLEMENTS   11 ( 2 )   41 - 41   2010.6

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  • ROSUVASTATIN PROMOTES ANTIOXIDANT EFFECT THROUGH NITRIC OXIDE PATHWAY AND REDUCES SERUM LEVELS OF OXIDIZED-LDL/beta 2GPI COMPLEXES IN PATIENTS WITH DIABETES MELLITUS

    L. Lopez, P. Ames, J. Batuca, I. Garcia De la Torre, K. Kojima, E. Matsuura

    ATHEROSCLEROSIS SUPPLEMENTS   11 ( 2 )   68 - 68   2010.6

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  • Oxidized-LDL/beta(2)-Glycoprotein I Complexes Are Associated With Disease Severity and Increased Risk for Adverse Outcomes in Patients With Acute Coronary Syndromes Reviewed

    Thomas P. Greco, Ann Marie Conti-Kelly, J. Robert Anthony, Thomas Greco, Robin Doyle, Matt Boisen, Kazuo Kojima, Eiji Matsuura, Luis R. Lopez

    AMERICAN JOURNAL OF CLINICAL PATHOLOGY   133 ( 5 )   737 - 743   2010.5

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    Oxidized low-density lipoprotein (oxLDL)/beta(2)-glycoprotein I (beta 2GPI) complexes have been implicated in atherogenesis. oxLDL/beta 2GPI complexes were measured in 339 patients with suspected acute coronary syndromes. Approximately 68% had angiographically documented coronary artery disease (CAD) and significantly higher mean +/- SD levels of oxLDL/beta 2GPI (3.75 +/- 6.31 U/mL) than patients with normal coronary arteries (2.21 +/- 3.03 U/mL; P = .0026). Patients with severe CAD had significantly higher mean SD levels of oxLDL/beta 2GPI (8.71 +/- 12.87 U/mL) compared with the overall mean of 3.25 U/mL (P &lt; .05) and a significantly higher rate (28.9%) of adverse events than the overall rate of 11.2% (P &lt; .05). Patients with adverse events had higher mean SD levels of oxLDL/beta 2GPI (4.05 +/- 5.38 U/mL) than patients without adverse events (3.15 +/- 5.53; P = .029). The relative risk for adverse events in higher oxLDL/beta 2GPI quartiles was 3.1 (95% confidence interval, 1.0-9.1; P = .06) for quartile 3 and 3.5 (95% confidence interval, 1.2-10.4; P = .02) for quartile 4. Our results support the concept that oxLDL/beta 2GPI complexes are associated with severity of CAD and a 3.5-fold increased risk for adverse outcomes.

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  • High-density lipoprotein inversely relates to its specific autoantibody favoring oxidation in thrombotic primary antiphospholipid syndrome Reviewed

    P. R. J. Ames, E. Matsuura, J. R. Batuca, A. Ciampa, L. L. Lopez, F. Ferrara, L. Iannaccone, J. Delgado Alves

    LUPUS   19 ( 6 )   711 - 716   2010.5

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    Abnormalities of the lipid profile partly explain the atherogenic tendency of systemic lupus erythematosus but the picture is unclear in thrombotic primary antiphospholipid syndrome (PAPS). Herein we compare the lipid profile, high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (CHO), apolipoprotein A (ApoA-I), apolipoprotein B (ApoB), tryglicerides (TRY)), anti-lipoprotein antibodies, beta-2-glycoprotein I complexed to oxidized low-density lipoprotein (oxLDL-beta(2)GPI) and C-reactive protein (CRP) from thrombotic PAPS (n = 34), thrombotic patients with inherited thrombophilia (IT; n = 36), subjects persistently positive for antiphospholipid antibodies (aPL, n = 18) with no underlying autoimmune or non-autoimmune disorders and healthy controls (n 28) and determined the reciprocal effects of anti-lipoprotein antibodies, the lipid profile, oxLDL-beta(2)GPI and CRP. Average concentrations of HDL (p &lt; 0.0001), LDL (p &lt; 0.0001), CHO (p = 0.0002), ApoA-I (p = 0.002) were lower in PAPS whereas average TRY was higher (p = 0.01) than other groups. Moreover, the aPL and PAPS group showed higher levels of IgG anti-HDL (p 0.01) and IgG anti-ApoA-I (p &lt; 0.0001) whereas the PAPS group showed greater average oxLDL-beta(2)GPI (p = 0.001) and CRP (p = 0.003). Within the PAPS group, IgG anti-HDL correlated negatively to HDL (p = 0.004) and was an independent predictor of oxLDL-beta(2)GPI (p = 0.009). HDL and ApoA-I correlated negatively with CRP (p 0.001 and p = 0.007, respectively). IgG anti-HDL may hamper the antioxidant and anti-inflammatory effect of HDL favoring low-grade inflammation and enhanced oxidation in thrombotic PAPS. Lupus (2010) 19, 711-716.

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  • 7-Ketocholesterol Induces Cell Apoptosis by Activation of Nuclear Factor kappa B in Mouse Macrophages Reviewed

    Zhenyu Huang, Qingping Liu, Wenzhe Li, Renjun Wang, Dan Wang, Yingbiao Zhang, Fan Zhang, Yan Chi, Zhe Liu, Eiji Matsuura, Zibo Liu, Qiming Zhang

    ACTA MEDICA OKAYAMA   64 ( 2 )   85 - 93   2010.4

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    We investigated the molecular mechanisms responsible for the induction of apoptosis in mouse monocytic macrophage cell line J774A.1 stimulated by 7-ketocholesterol (7-KC). Cell apoptosis was detected by Annexin V-propidium iodide (PI) staining. The DNA-binding activity of nuclear factor kappa B (NF-kappa B) was assessed by electrophoretic mobility shift assay (EMSA). Results showed that 7-KC-stimulation in J774A.1 cells activated NF-kappa B, which is involved in cell apoptosis, in a time- and dose-dependent manners. 7-KC was also found to increase the binding activity of NF-kappa B to specific DNA binding sites, a possible mechanism for the induction of the cell apoptosis. Moreover, these effects were partially inhibited by pyrrolidine dithiocarbamate (PDTC), an NF-kappa B inhibitor. Taken together, 7-KC may be an important factor in atherosclerosis due to the ability of 7-KC to induce cell apoptosis, which is at least partially mediated through the activation of NF-kappa B.

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  • Pathophysiology of beta(2)-glycoprotein I in antiphospholipid syndrome Reviewed

    E. Matsuura, L. Shen, Y. Matsunami, N. Quan, M. Makarova, F. J. Geske, M. Boisen, S. Yasuda, K. Kobayashi, L. R. Lopez

    LUPUS   19 ( 4 )   379 - 384   2010.4

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    Since beta(2)-glycoprotein I (beta(2)GPI) was described as the major antigenic target for antiphospholipid antibodies, many studies have focused their attention to the physiological role of beta(2)GPI and anti-beta(2)GPI antibodies on autoimmune-mediated thrombosis. Studies reporting the physiological role of beta(2)GPI have been numerous, but the exact mechanism of action(s) has yet to be completely determined. beta(2)GPI&apos;s epitopes for anti-beta(2)GPI autoantibodies have been characterized, however, not all of the heterogeneous anti-beta(2)GPI antibodies are pathogenic. The pathophysiologic role of beta(2)GPI has been reported in the fields of coagulation, fibrinolysis, angiogenesis, and atherosclerosis. Our understanding of the impact of beta(2)GPI, its metabolites and autoantibodies to beta(2)GPI on these physiological functions may contribute to the development of better therapeutic strategies to treat and prevent autoimmune-mediated atherothrombotic vascular disease. Lupus (2010) 19, 379-384.

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  • The role of oxidized low-density lipoprotein/β2-glycoprotein I complexes in autoimmune-mediated atherothrombosis. Reviewed

    Lopez LR, Geske FJ, Boisen M, Kobayashi K, Matsunami Y, Matsuura E

    International Atherosclerosis Society – published online (www.athero.org),   May, 2010   2010

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  • High Expression of CD244 and SAP Regulated CD8(+) T Cell Responses of Patients with HTLV-I Associated Neurologic Disease Reviewed

    Yoshimi Enose-Akahata, Eiji Matsuura, Unsong Oh, Steven Jacobson

    PLOS PATHOGENS   5 ( 12 )   2009.12

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    HTLV-I-specific CD8(+) T cells have been characterized with high frequencies in peripheral blood and cerebrospinal fluid and production of proinflammatory cytokines, which contribute to central nervous system inflammation in HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, little is known about the differences in CD8+ T cell activation status between asymptomatic carrier (ACs) and patients with HAM/TSP. The expression of CD244, a signaling lymphocyte activation molecule (SLAM) family receptor, was significantly higher on CD8(+) T cells in HTLV-I-infected patients, both ACs and patients with HAM/TSP, than those on healthy normal donors (NDs). Blockade of CD244 inhibited degranulation and IFN-gamma production in CD8(+) T cells of patients with HAM/TSP, suggesting that CD244 is associated with effector functions of CD8(+) T cells in patients with HAM/TSP. Moreover, SLAM-associated protein (SAP) was overexpressed in patients with HAM/TSP compared to ACs and NDs. SAP expression in Tax-specific CTLs was correlated in the HTLV-I proviral DNA loads and the frequency of the cells in HTLV-I-infected patients. SAP knockdown by siRNA also inhibited IFN-gamma production in CD8(+) T cells of patients with HAM/TSP. Thus, the CD244/SAP pathway was involved in the active regulation of CD8(+) T cells of patients with HAM/TSP, and may play roles in promoting inflammatory neurological disease.

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  • Regulation of cellular immunity prevents Helicobacter pylori-induced atherosclerosis Reviewed

    K. Ayada, K. Yokota, K. Hirai, K. Fujimoto, K. Kobayashi, H. Ogawa, K. Hatanaka, S. Hirohata, T. Yoshino, Y. Shoenfeld, E. Matsuura, K. Oguma

    LUPUS   18 ( 13 )   1154 - 1168   2009.11

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    Helicobacter pylori (H. pylori) is a predominant pathogen that causes not only gastroduodenal diseases but also extra-alimentary tract diseases. In this study, we demonstrated that H. pylori infection promoted atherogenesis in heterozygous apoe(+/-) ldlr(+/-) mice. The male mice were fed with high fat diet from the age of 6 weeks. At the age of 16 weeks, development of atherosclerotic lesions was observed in the H. pylori-infected mice, and it seemed to be associated with an elevation of Th1-immune response against H. pylori origin-heat shock protein 60 (Hp-HSP60) and an increment of transendothelial migration of T cells. Subcutaneous immunisation with Hp-HSP60 or H. pylori eradication with antibiotics significantly reduced the progression of atherosclerosis, accompanied by a decline of Th1 differentiation and reduction of their chemotaxis beyond the endothelium. Thus, oral infection with H. pylori accelerates atherosclerosis in mice and the active immunisation with Hp-HSP60 or the eradication of H. pylori with antibiotics can moderate/prevent cellular immunity, resulting in a reduction of atherosclerosis. Lupus (2009) 18, 1154-1168.

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  • Autoimmunity, Infectious Immunity, and Atherosclerosis Reviewed

    Eiji Matsuura, Kazuko Kobayashi, Yukana Matsunami, Lianhua Shen, Nanhu Quan, Marina Makarova, Sergey V. Suchkov, Kiyoshi Ayada, Keiji Oguma, Luis R. Lopez

    JOURNAL OF CLINICAL IMMUNOLOGY   29 ( 6 )   714 - 721   2009.11

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    Vascular inflammation is common in certain systemic autoimmune diseases and contributes to the oxidation of low-density lipoprotein (oxLDL) and oxLDL/beta 2-glycoprotein I (beta 2GPI) complex formation. These complexes have been implicated as proatherogenic autoantigens that participate in the development of atherosclerotic disease.
    We have demonstrated that the in vitro macrophage uptake of oxLDL/beta 2GPI complexes increases in the presence of IgG anti-beta 2GPI antibodies and that IgG immune complexes containing oxLDL/beta 2GPI upregulate the expression of both scavenger and Fc gamma receptors to activate beta 2GPI-specific T cells. Some persistent infections may cause immune responses that promote atherogenesis. Cellular immunity (Th1) against Helicobacter pylori (H. pylori) derived heat shock protein 60 (Hp-HSP60) cross-reacts with endogenous HSP60 to cause cardiovascular disease likely by molecular mimicry.
    Infectious cellular response may be proatherogenic, while the humoral response (antibody production) may be protective. We review the recent progress in our understanding of autoimmunity and infectious immunity that promote atherosclerosis.

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  • Newer Antiphospholipid Antibodies Predict Adverse Outcomes in Patients With Acute Coronary Syndrome Reviewed

    Thomas P. Greco, Ann Marie Conti-Kelly, Thomas Greco, Robin Doyle, Eiji Matsuura, J. Robert Anthony, Luis R. Lopez

    AMERICAN JOURNAL OF CLINICAL PATHOLOGY   132 ( 4 )   613 - 620   2009.10

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    Antiphospholipid antibodies (aPLs) have been implicated in atherogenesis. We studied 344 patients with acute coronary syndromes; approximately 40% were aPL+ in I or more tests and 60% aPL-. In 215 patients, coronary artery disease (CAD) was angiographically documented, with 43.7% positive for aft vs 34.9% of patients without CAD positive for aPLs. Anti-beta(2)-glycoprotein I (B2GPI; 54%) and anti-oxidized low-density; lipoprotein (oxLDL)/beta 2GPI (48%) were most frequent, accounting for 87% of all aPL+ CAD cases. aPLs correlated with severity of CAD (P=.012). Adverse events occurred in 16 7% of patients with CAD, more frequently in patients who were aPL+ (P=.0006; relative risk, 2.9; 95% confidence interval, 1.5-5.6). Patients who were aPL + with severe CAD had more adverse events than patients who were aPL- with severe CAD (P=.005) and aPL+patients undergoing revascularization procedures (P=.001). Vascular events occurred in 21.7% of aPL + patients compared with 7.1% of aPL-patients (P=.005). Anti-beta 2GPI and anti-oxLDL/beta 2GPI were associated with CAD severity and adverse outcomes.

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  • Nicked beta 2-glycoprotein I binds angiostatin 4.5 (plasminogen kringle 1-5) and attenuates its antiangiogenic property Reviewed

    Hisako Nakagawa, Shinsuke Yasuda, Eiji Matsuura, Kazuko Kobayashi, Masahiro Ieko, Hiroshi Kataoka, Tetsuya Horita, Tatsuya Atsumi, Takao Koike

    BLOOD   114 ( 12 )   2553 - 2559   2009.9

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    Angiostatin was first discovered as a plasminogen fragment with antitumor/antiangiogenic property. One of the angiostatin isoforms, that is, angiostatin 4.5 (AS4.5), consisting of plasminogen kringle 1 to 4 and a most part of kringle 5, is produced by autoproteolysis and present in human plasma. beta 2-glycoprotein I (beta 2GPI) is proteolytically cleaved by plasmin in its domain V (nicked beta 2GPI), resulting in binding to plasminogen. Antiangiogenic properties have been recently reported in nicked beta 2GPI as well as in intact beta 2GPI at higher concentrations. In the present study, we found significant binding of nicked beta 2GPI to AS4.5 (K(D) = 3.27 x 10(6) M(-1)). Via this binding, nicked beta 2GPI attenuates the antiangiogenic functions of AS4.5 in the proliferation of arterial/venous endothelial cells, in the extracellular matrix invasion and the tube formation of venous endothelial cells, and in vivo angiogenesis. In contrast, intact beta 2GPI does not bind to AS4.5 or inhibit its antiangiogenic activity. Thus, nicked beta 2GPI exerts dual effects on angiogenesis, that is, nicked beta 2GPI promotes angiogenesis in the presence of AS4.5, whereas nicked beta 2GPI inhibits angiogenesis at concentrations high enough to neutralize AS4.5. Our data suggest that plasmin-nicked beta 2GPI promotes angiogenesis by interacting with plasmin-generated AS4.5 in sites of increased fibrinolysis such as thrombus. (Blood. 2009; 114: 2553-2559)

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  • Atherosclerosis and Autoimmunity Reviewed

    Eiji Matsuura

    CLINICAL REVIEWS IN ALLERGY & IMMUNOLOGY   37 ( 1 )   1 - 3   2009.8

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  • Immunogenic Oxidized Low-density Lipoprotein/beta 2-glycoprotein I Complexes in the Diagnostic Management of Atherosclerosis Reviewed

    Luis R. Lopez, Kazuko Kobayashi, Yukana Matsunami, Eiji Matsuura

    CLINICAL REVIEWS IN ALLERGY & IMMUNOLOGY   37 ( 1 )   12 - 19   2009.8

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    Oxidized low-density lipoprotein (oxLDL) promotes atherosclerosis through a complex interaction of inflammatory and immunologic factors that lead to macrophage lipid uptake and foam cell formation. OxLDL interacts with beta 2-glycoprotein I (beta 2GPI) forming oxLDL/beta 2GPI complexes. These complexes may be formed in the arterial intima during atherogenesis and released into the circulation. Autoantibodies against oxLDL/beta 2GPI complexes have been demonstrated in patients with systemic lupus erythematosus and/or antiphospholipid syndrome, and shown to be significantly associated with arterial thrombosis. The observation that monoclonal autoantibodies against oxLDL/beta 2GPI complexes significantly increased the oxLDL uptake by macrophages strongly suggests that such IgG autoantibodies are pro-atherogenic. In this article, we review the recent progress in our understanding of LDL oxidation, oxLDL/beta 2GPI complex formation, and immune regulation of atherogenesis.

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  • Chronic Infections and Atherosclerosis Reviewed

    Kiyoshi Ayada, Kenji Yokota, Kazuko Kobayashi, Yehuda Shoenfeld, Eiji Matsuura, Keiji Oguma

    CLINICAL REVIEWS IN ALLERGY & IMMUNOLOGY   37 ( 1 )   44 - 48   2009.8

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    The immune response against heat shock protein 60 (HSP60) derived from pathogens causing chronic infections is thought to be an important pro-atherogenic mechanism because high serum levels of antibodies against HSP60 have been associated with atherosclerotic diseases, such as coronary artery diseases, or cerebro-vascular events. Furthermore, the presence of HSP60-specific T lymphocytes in circulation may increase the risk of atherosclerosis. Our recent in vitro and in vivo studies have also shown an association of Helicobacter pylori-HSP60 (Hp-HSP60) specific Th1 immune responses elicited by H. pylori infection with the progression of atherosclerosis in a hyperlipidemic mouse model. These Th1 dominant immune responses may cross-react with endogenous HSP60 expressed on stressed cells of the vascular endothelium, likely due to molecular mimicry. However, the exact mechanisms by which endothelial cells display their HSP60 molecule or present HSP60 antigenic epitopes on the surface are still unclear.

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  • The immunology of atherothrombosis in the antiphospholipid syndrome: Antigen presentation and lipid intracellular accumulation Reviewed

    Eiji Matsuura, Kazuko Kobayashi, Yukana Matsunami, Luis R. Lopez

    AUTOIMMUNITY REVIEWS   8 ( 6 )   500 - 505   2009.5

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    The antiphospholipid syndrome (APS), characterized by elevated serum levels of anti phospholipid antibodies (aPL) and thromboembolic complications, is a common cause of acquired hypercoagulability. The plasma protein beta 2-glycoprotein I (beta 2GPI) is the most clinically relevant antigenic target for aPL. Recent experimental evidence from our laboratory substantiated the concept that IgG anti-beta 2GPI immune complexes containing oxidized LDL (oxLDL) not only facilitated the intracellular accumulation of oxLDL in macrophages but also allowed the presentation of beta 2GPI epitopes to pathogenic autoreactive T cells. Both mechanisms required Fc gamma RI-mediated uptake by macrophages/monocytes. Furthermore, several clinical studies demonstrated that the presence of circulating oxLDL/beta 2GPI complexes and IgG autoantibodies to these complexes was significantly associated with vascular inflammation (i.e. autoimmune-mediated atherothrombosis) in autoimmune patients. In this article, we review recent findings concerning the biochemical and immunologic mechanisms involved in autoimmune-mediated atherothrombosis in patients with APS. (C) 2009 Elsevier B.V. All rights reserved.

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  • Atherosclerosis in autoimmune diseases Reviewed

    Eiji Matsuura, Kazuko Kobayashi, Luis R. Lopez

    Current Rheumatology Reports   11 ( 1 )   61 - 69   2009

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    Lipid peroxidation occurs frequently in patients with systemic autoimmune diseases and contributes to autoimmune vascular inflammation. Oxidized low-density lipoprotein (oxLDL) interacts with β2-glycoprotein I (β2GPI), forming oxLDL/β2GPI complexes. Circulating oxLDL/β2GPI complexes and autoantibodies to these complexes have been demonstrated in patients with systemic lupus erythematosus and antiphospholipid syndrome. These findings suggest an immunogenic nature of the complexes and an active proatherogenic role in autoimmunity. Biochemical characterization of the complexes and immunohistochemical studies of atherosclerotic lesions suggest that most of the complexes originate in the arterial wall and are released into circulation. The in vitro macrophage uptake of oxLDL/β2GPI complexes increased significantly in the presence of antiphospholipid antibodies (anti-β2GPI), suggesting that macrophage Fcγ receptors are involved in the lipid intracellular inflthat leads to foam cell formation. These findings provide an immunologic explanation for the accelerated development of atherosclerosis seen in systemic lupus erythematosus and antiphospholipid syndrome. © Springer Science+Business Media, LLC 2009.

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  • New impacts of cutaneous lupus erythematosus for global standard concepts. Reviewed

    Furukawa F, Matsuura E

    Autoimmun Rev   8   439 - 440   2009

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  • POST-INFECTIOUS CLINICAL-IMMUNOLOGICAL SYNDROME AND ITS PLACE IN CLINICAL PRACTICE Reviewed

    N. E. Cherepakhina, Z. S. Shogenov, T. Elbeik, K. A. Akhmedilova, M. M. Agirov, Zh. A. Tabaksoyeva, E. A. Ogneva, E. Matsuura, N. A. Mukhin, Y. Shoenfeld, M. A. Paltsev, S. V. Suchkov

    TERAPEVTICHESKII ARKHIV   81 ( 12 )   71 - 78   2009

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    The progression of chronic-relapsing infectious disease (CRID) depends on a combination of cumulative immune-mediated responses of the human body, which, in turn, are united by a number of the common mechanisms. The mechanisms are called as the post-infectious clinical-immunological syndrome (PICIS) to demonstrate the features and scale of imbalances of immune homeostasis. PICIS usually accompanies most of the known CRID to define the type of the disease, to predict the progression of, and risks for the complications to be risen as well. PIFIS is generally provoked by either infectious pathogens of various nature or by the atypical immune responses from the infected patient, or by the onset of the disease itself, or by the inadequate antimicrobial therapy.
    Three forms of PICIS which depend on two key factors have been described These included (i) the spectrum of a microbial colonization landscape; (ii) the antimicrobial immunity itself to generate, for instance., either (if three alternative PICIS, namely, (1) postinfectious secondary immunodeficiency syndrome (PISIS); (2) postinfectious autoimmune syndrome (PIAIS), and (3) PISIS combined with PINS, i.e. PISIDAS.
    The dominant monosyndrome-like form of associated immune imbalances in CRID patients is PISIS. PISIS occurs in more than a third of the clinical cases to stress the autoaggression (PIFAS), or combininative form ojthe immune-mediated imbalances, i.e. PISIDAS. In the process of the development of CRID, PISIS can give a way to either PIAIS or PISIDAS.
    Besides the immune-mediated imbalances, an essential role in the pathogenesis of CRID and PICIS is also attributed to the infectious factors capable of forming microbial associates in the pathogenesis of PICIS. Therefore, treatment of such patients should be directed not only at the elimination of the infectious pathogen(s), but also at the restoration of the physiological level of the immune homeostasis impaired by PICIS.

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  • oxLDL/beta 2GPI complex and anti-oxLDL/beta 2GPI in SLE: Prevalence and correlates Reviewed

    N. Bassi, S. Zampieri, A. Ghirardello, M. Tonon, M. Zen, S. Beggio, E. Matsuura, A. Doria

    AUTOIMMUNITY   42 ( 4 )   289 - 291   2009

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    High levels of oxidized low-density liprotein/beta2 glycoprotein 1 (oxLDL/beta 2GPI) complexes and anti-complex IgG as well as IgM have been reported in SLE. We analysed this complex and Ab against the complex in SLE patients and evaluated their relationship with clinical and serological findings, traditional risk factors for atherosclerosis, and subclinical atherosclerosis. The prevalence and the levels of the complex and of anti-complex Ab were significantly higher in systemic lupus erythematosus (SLE) patients than in normal healthy donors (NHD). The titers of oxLDL/beta 2GPI were significantly higher in patients with renal involvement and previous thromboembolic episodes and were correlated with the number of risk factors for atherosclerosis, whereas they were significantly lower in patients with neurological involvement. Both IgG and IgM anticomplex Ab were associated with antiphospholipid (APL). In conclusion, the oxLDL/beta 2GPI complex as well as Ab against the complex are prevalent in SLE where they seem to be involved in organ damage.

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  • 感染と動脈血栓 Invited

    松浦栄次, 小林和子, 申 蓮花, 松並由香菜, 綾田 潔, 小熊惠二

    日本血栓止血学会誌   20   534 - 538   2009

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  • 自己免疫・感染免疫と動脈硬化 Invited

    松浦栄次, 小林和子

    基礎老化研究   33   3 - 9   2009

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  • Primary antiphospholipid syndrome: a low-grade auto-inflammatory disease Reviewed

    P. R. J. Ames, I. Antinolfi, A. Ciampa, J. Batuca, G. Scenna, L. R. Lopez, J. Delgado Alves, L. Iannaccone, E. Matsuura

    RHEUMATOLOGY   47 ( 12 )   1832 - 1837   2008.12

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    Objective. To test the inflammation and immune activation hypothesis in primary thrombotic APS (PAPS) and to identify clinical and laboratory factors related to inflammation and immune activation.
    Methods. PAPS (n 41) patients were compared with patients with inherited thrombophilia (IT, n 44) and controls (CTR, n 39). IgG aCL, IgG anti-2-glycoprotein I ((2)GPI), high-sensitivity CRP (hs-CRP), serum amyloid A (SAA), CRP bound to oxidized low-density lipoprotein(2)GPI complex (CRPoxLDL(2)GPI) (as inflammatory markers) neopterin (NPT), soluble CD14 (sCD14) (as immune activation markers) were measured by ELISA.
    Results. After correction for confounders, PAPS showed higher plasma levels of hs-CRP (P 0.0004), SAA (P 0.01), CRPoxLDL(2)GPI (P 0.0004), NPT (P 0.0001) and sCD14 (P 0.007) than IT and CTR. Two regression models were applied to the PAPS group: in the first, IgG aCL and IgG (2)GPI were included amongst the independent variables and in the second they were excluded. In the first model, SAA (as the dependent variable) independently related to thrombosis number (P 0.003); NPT (as the dependent variable) independently related to thrombosis type (arterial, P 0.03) and number (P 0.04); sCD14 (as the dependent variable) independently related to IgG (2)GPI (P 0.0001), age (0.001) and arterial thrombosis (P 0.01); CRPoxLDL(2)GPI (as the dependent variable) independently related to IgG (2)GPI (P 0.0001). In the second model, sCD14 and NPT independently related to each other (P 0.002) (this was noted also in the IT group, P 0.0001) and CRPoxLDL(2)GPI independently predicted SAA (P 0.002).
    Conclusion. Low-grade inflammation and immune activation occur in thrombotic PAPS and relate to clinical features and aPL levels.

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  • Self-interaction of soluble and surface-bound beta 2-glycoprotein I and its enhancement by lupus anticoagulants Reviewed

    Akira Hayashi, Ayumi Hayashi, Eiji Matsuura, Koji Suzuki, Takao Koike, Eikichi Hashimoto, Hiroyuki Takeya

    FEBS LETTERS   582 ( 23-24 )   3308 - 3312   2008.10

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    Antiphospholipid antibodies found in antiphospholipid syndrome are autoantibodies to phospholipid-binding proteins, such as beta 2-glycoprotein I (beta 2GPI). We have previously reported that among these antibodies, the so-called lupus anticoagulants (LAs) augment beta 2GPI binding to the phospholipid membrane surface, which is associated with the pathological action of LAs. However, the molecular mechanisms underlying this augmentation are uncertain. Here we show that beta 2GPI, which is monomeric in solution, self-interacts at the interface of soluble and surface-bound molecules. In addition, this self-interaction is enhanced by LA-positive, but not LA-negative, anti-beta 2GPI monoclonal antibodies. This study suggests that beta 2GPI self-interaction upon surface binding could be involved in the LA-induced potentiation of b2GPI binding to the phospholipid surface.

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  • Self-interaction of soluble and surface-bound beta 2-glycoprotein I and its enhancement by lupus anticoagulants Reviewed

    Akira Hayashi, Ayumi Hayashi, Eiji Matsuura, Koji Suzuki, Takao Koike, Eikichi Hashimoto, Hiroyuki Takeya

    FEBS LETTERS   582 ( 23-24 )   3308 - 3312   2008.10

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    Antiphospholipid antibodies found in antiphospholipid syndrome are autoantibodies to phospholipid-binding proteins, such as beta 2-glycoprotein I (beta 2GPI). We have previously reported that among these antibodies, the so-called lupus anticoagulants (LAs) augment beta 2GPI binding to the phospholipid membrane surface, which is associated with the pathological action of LAs. However, the molecular mechanisms underlying this augmentation are uncertain. Here we show that beta 2GPI, which is monomeric in solution, self-interacts at the interface of soluble and surface-bound molecules. In addition, this self-interaction is enhanced by LA-positive, but not LA-negative, anti-beta 2GPI monoclonal antibodies. This study suggests that beta 2GPI self-interaction upon surface binding could be involved in the LA-induced potentiation of b2GPI binding to the phospholipid surface.

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  • Oxidation of LDL and its clinical implication Reviewed

    Eiji Matsuura, Graham R. V. Hughes, Munther A. Khamashta

    AUTOIMMUNITY REVIEWS   7 ( 7 )   558 - 566   2008.7

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    Oxidative modification of low-density lipoprotein (LDL) is one of the earliest events in atherosclerosis. Oxidized LDL (oxLDL) represents a variety of modification of both lipid and apolipoprotein B (apoB) components by lipid peroxidation. This promotes atherosclerosis through inflammatory and immunologic mechanisms that lead to the formation of macrophage foam cells. Recent findings also suggest that oxLDL forms complexes with beta(2)-glycoprotein I (beta(2)GPI) and/or C-reactive protein (CRP) within atherosclerotic lesions and that these complexes appear in the circulation. Autoantibodies (auto-Abs) against oxLDL/beta(2)GPI complexes occur in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). These autoantibodies significantly correlate with arterial thrombosis. IgG auto-Abs having similar specificity emerge spontaneously in NZW x BXSB F1 mice, which generally are considered to be an animal model of APS, and these mice produce a monoclonal IgG auto-Ab (WB-CAL-1) against oxLDL/beta(2)GPI complexes. WB-CAL-1 significantly increased the in vitro uptake of oxLDL/beta(2)GPI complexes by macrophages, which suggests that such IgG auto-Abs are pro-atherogenic. In contrast, IgM anti-oxLDL natural Abs found in the atherosclerosis-prone mice have been proposed to be protective. The presence of such Abs in humans has been documented in many publications but their exact pathophysiological significance remains unclear. In this article, we review recent progress in our understanding of the clinical significance of oxidation of LDL, formation of oxLDL complexes, and Abs in atherosclerotic and/or autoimmune disease. (C) 2008 Elsevier B.V. All rights reserved.

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  • Anti-cardiolipin antibodies and endothelial function in patients with coronary artery disease Reviewed

    Ibrahim Marai, Michael Shechter, Pnina Langevitz, Boris Gilburd, Ardon Rubenstein, Eiji Matsuura, Yaniv Sherer, Yehuda Shoenfeld

    AMERICAN JOURNAL OF CARDIOLOGY   101 ( 8 )   1094 - 1097   2008.4

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    Endothelial dysfunction is considered an important marker in atherosclerosis, having a prognostic value. Antiphospholipid antibodies are considered prothrombotic and have recently been reported to be associated also with atherosclerosis. This study was conducted to investigate a possible association of endothelial dysfunction with various antiphospholipid autoantibodies in healthy subjects and patients with cardiovascular disease. In a single-center, prospective study, 2 groups were included. The study group included patients with cardiovascular diseases (coronary disease and/or cerebrovascular disease) and healthy subjects without apparent heart disease who were referred to the endothelial function laboratory for the assessment of endothelial function. Flow-mediated dilatation, which indicates endothelial function, and nitroglycerin-mediated vasodilatation, which indicates smooth-muscle function, were measured. The 2 groups were evaluated for autoantibodies, including anticardiolipin (aCL; immunoglobulin G [IgG], immunoglobulin M [IgM], and immunoglobulin A [IgA]), antinuclear antibody, anti-beta 2-glycoprotein I (IgG, IgM, and IgA), and oxidized low-density lipoprotein. One hundred seven subjects were included in the study: 45 patients (42%) and 62 healthy controls (58%). Flow-mediated dilatation was significantly lower in patients compared with healthy controls (8.0 +/- 9.5% vs 8.0 +/- 13.5%, p = 0.012). In addition, nitroglycerin-mediated vasodilatation was nonsignificantly lower in patients than in healthy controls (8.0 +/- 13.4% vs 11.0 +/- 16.7%, p = 0.084). The mean levels of anti-beta 2-glycoprotein I (IgG, IgM, and IgA), aCL (IgM and IgA), antinuclear antibody, and oxidized low-density lipoprotein were not different between groups. However, the mean level of IgG aCL was significantly higher in patients than in healthy controls. In conclusion, in accordance with previous reports of an association between aCL and atherosclerosis, patients with cardiovascular disease had endothelial dysfunction and elevated levels of aCL. (C) 2008 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.amjcard.2007.12.010

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  • Low grade inflammation and in vivo immune activation in primary antiphospholipid syndrome

    Paul R. Ames, Antonio Ciampa, Eiji Matsuura, Luis Lopez, Giovanna Scenna, Iolanda Antinolfi, Luigi Iannaccone, Felicetto Ferrara

    RHEUMATOLOGY   47   II93 - II94   2008.4

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  • Atherosclerosis in primary antiphospholipid syndrome Reviewed

    Paul R. J. Ames, Giovanna Scenna, Iolanda Antinolfi, Luis Lopez, Luigi Iannaccone, Eiji Matsuura, Annamaria Margarita

    EXPERT REVIEW OF CLINICAL IMMUNOLOGY   4 ( 1 )   53 - 60   2008.1

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    Antiphospholipid syndrome (APS) is the most common cause of acquired thrombophilia, but experimental and clinical evidence accumulated over the years suggest that the clinical manifestations of APS go beyond those of a simple hypercoagulable state. Although still a controversial topic, the elevated risk of atherosclerosis in systemic lupus erythematosus seems little accounted for by the presence of antiphospholipid antibodies, whereas premature atherosclerosis has been addressed in few series of patients with primary APS. The available data in primary APS suggest that traditional risk factors for atherosclerosis are less involved in arterial disease, rather antiphospholipid antibodies appear as major players. Their effect on the coagulation system, the vessel wall and on the antioxidant/oxidant balance impairs vascular homeostasis, leading to premature arterial thickening.

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  • Preventing autoimmune and infection triggered atherosclerosis for an enduring healthful lifestyle Reviewed

    Eiji Matsuura, Kazuko Kobayashi, Luis R. Lopez

    AUTOIMMUNITY REVIEWS   7 ( 3 )   214 - 222   2008.1

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    Atherosclerosis is a chronic inflammatory disease of the arteries associated with various risk factors that promote lipid abnormalities (i.e., dyslipidemia), development and progression of atherosclerotic lesions, plaque rupture, and vascular thrombosis. Experimental evidence from biochemical and clinical studies support the idea that arterial thrombosis is an autoimmune process resulting from 'autoantibody'-mediated pro-atherogenic mechanisms now seen in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). In addition, it has been shown that persistent infections of Clamydia pneumoniae (C. pneumoniae), Porphyromonas gingivalis (P. gingivalis), and Helicobacter pylori (H. pylori) cause immune responses (infectious immunity) in their hosts that promote atherogenesis. In this article, we review recent progress in our understanding of immune- and infection-mediated atherosclerosis. (C) 2007 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.autrev.2007.11.008

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  • Autoimmune diseases and infections: controversial issues Reviewed

    Pierangelo Baio, Antonio Brucato, Dan Buskila, M. Eric Gershwin, Donatella Giacomazzi, Luis R. Lopez, Roberto Luzzati, Eiji Matsuura, Carlo Selmi, Piercarlo Sarzi-Puttini, Fabiola Atzeni

    CLINICAL AND EXPERIMENTAL RHEUMATOLOGY   26 ( 1 )   S74 - S80   2008.1

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    The etiology and pathogenesis of certain types of disease remain controversial and stand like a bridge that crosses infectious, autoimmune and autoinflammatory pathways. Infection, for example, may initiate a disease, although it is the genetic regulation in the host, the interplay between virus or bacteria persistence and autoimmunity that produces the later phases of disease, the antigenic determinants responsible for inducing autoimmune disease, and the pathogenetic effector mechanisms. Infections agents cause pericarditis, but in 85% of cases it is "idiopathic". It has also been shown that persistent Clamydia pneumoniae, Porphyromonas gingivalis, and Helicobacter pylori infections cause host immunity and promote atherogenesis. A number of infectious agents have been suggested as potential triggers for primary biliary cirrhosis. Infections and vaccinations have also been linked to the pathogenesis of fibromyalgia syndrome, a common, chronic syndrome of widespread pain. Many factors are also responsible for fever of unknown origin such as: infections, autoimmunity disease, etc. However, it is difficult to determine a direct correlation between the infections, agents in such a large group of diseases. The aim of this review is to analyze some of the controversies about the role of infections in autoimmune diseases.

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  • Distinguished effects of antiphospholipid antibodies and anti-oxidized LDL antibodies on oxidized LDL uptake by macrophages (vol 16, pg 929, 2007)

    K. Kobayashi, K. Tada, H. Itabe, T. Ueno, P-H Liu, A. Tsutsumi, M. Kuwana, T. Yasuda, Y. Shoenfeld, P. G. de Groot, E. Matsuura

    LUPUS   17 ( 1 )   75 - 75   2008.1

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    DOI: 10.1177/0961203307087668

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  • The role of anti-oxLDL/β2GPI antibodies (anti-AtherOx) in autoimmune-mediated atherosclerosis. Reviewed

    Lopez LR, Matsuura E

    FOL (AACC–Lipids and Cardiovascular Disease Newsletter   published online, June 2008   2008

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  • Autoimmune-mediated atherothrombosis Reviewed

    E. Matsuura, L. R. Lopez

    LUPUS   17 ( 10 )   878 - 887   2008

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    Autoimmune vascular inflammation and oxidative stress (lipid peroxidation) are common in systemic autoimmune diseases and contribute to the oxidative modification of low-density lipoprotein (oxLDL) and oxLDL/beta 2GPI complex formation. Circulating oxLDL/beta 2GPI complexes have been detected in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). The presence of antibodies to oxLDL/beta 2GPI complexes indicates that these complexes are immunogenic, and the coexistence of complexes and antibodies has pointed to an active proatherogenic role in the development of autoimmune vascular complications. Immunohistochemical staining of atherosclerotic lesions suggest that these complexes are formed in the arterial wall and released into circulation. The in vitro macrophage uptake of oxLDL/beta 2GPI complexes was significantly increased in the presence of antiphospholipid antibodies, either beta 2GPI-dependent anticardiolipin or anti-beta 2GPI antibodies, suggesting that macrophage Fe gamma receptors are involved in lipid intracellular influx and foam cell formation. These findings provide an explanation for the accelerated development of atherosclerosis seen in SLE and APS. The presence of circulation oxLDL/beta 2GPI complexes and IgG antibodies to these complexes indicate significant vascular injury and oxidative stress as well as an active role in autoimmune-mediated atherothrombosis. Lupus (2008) 17, 878 887.

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  • ARCHITECTONICS OF CELL SUBPOPULATIONS OF PERIPHERAL BLOOD IN PATIENTS WITH AUTOIMMUNE MYOCARDITIS: CLINICAL AND PATHOGENETIC ASPECTS Reviewed

    Z. S. Shogenov, N. N. Kekenadze, Se. Vorobyeva, M. P. Usik, T. Elbeik, K. A. Akhmedilova, E. E. Mamonova, E. Matsuura, M. A. Paltsev, S. V. Suchkov

    TERAPEVTICHESKII ARKHIV   80 ( 12 )   23 - 28   2008

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    Aim. To compare the most significant architectonic parameters of peripheral blood cell subpopulations in patients with different variants of an autoimmune myocarditis (AIM) course and their clinical value in therapeutic practice.
    Material and methods. Blood cell subpopulations were studied with flow cytometry in 99 blood samples from patients having different AIM variants and myocardiosclerosis as well as in 40 healthy donors.
    Results. Severe (malignant) AIM was characterized by growing indices of T-/B lymphocyte activation, expression of activation markers on the cells of both differentiation lines, disproportions in composition of subpopulations of the immunoregulatory cells, parallel rise in specific weight of dendritic cells, reduced intensity of apoptosis of autoreactive T-lymphocytes. In benign AIM marked immunopathology was not found. This group can be considered as a separate variant of AIM course necessitating an individual approach to planning pathogenetically sound therapeutic and rehabilitation measures.
    Conclusion. The study of activation markers expression on peripheral blood cells is superior to the study of endomyocardial biopsies providing a non-invasive method of immunodiagnosis.

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  • 自己免疫・感染免疫が惹起する動脈硬化 Invited

    松浦栄次

    Priming Biomedicine   3   1 - 11   2008

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  • Excessive exposure to anionic surfaces maintains autoantibody response to beta(2)-glycoprotein I in patients with antiphospholipid syndrome Reviewed

    Yukie Yamaguchi, Noriyuki Seta, Junichi Kaburaki, Kazuko Kobayashi, Eiji Matsuura, Masataka Kuwana

    BLOOD   110 ( 13 )   4312 - 4318   2007.12

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    Anti phospholipid syndrome (APS) is an autoimmune prothrombotic disorder associated with autoantibodies to phospholipid (PL)-binding proteins, such as beta(2)-glycoprotein I (beta(2)GPI). We have recently reported that binding of beta(2)GPI to anionic PL facilitates processing and presentation of the cryptic B(2)GPI epitope that activates pathogenic autoreactive T cells. To clarify mechanisms that induce sustained presentation of the dominant antigenic beta(2)GPI determinant in patients with APS, T-cell proliferation induced by beta(2)GPI-treated phosphatidylserine liposome (beta(2)GPI/PS) was evaluated in bulk peripheral blood mononuclear cell cultures. T cells from patients with APS responded to beta(2)GPI/PS in the presence of immunoglobulin G (IgG) anti-beta(2)GPI antibodies derived from APS plasma, and this response was completely inhibited either by the depletion of monocytes or by the addition of anti-Fc gamma RI antibody. These findings indicate that efficient presentation of the cryptic determinants can be Fc gamma RI-mediated uptake of beta(2)GPI-bound anionic surfaces in the presence of IgG anti-beta(2)GPI antibodies. Finally, beta(2)GPI-bound oxidized LDL or activated platelets also induced the specific T-cell response. Continuous exposure to these anionic surfaces may play a critical role in maintaining the pathogenic anti-beta(2)GPI antibody response in patients with APS.

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  • Excessive exposure to anionic surfaces maintains autoantibody response to beta(2)-glycoprotein I in patients with antiphospholipid syndrome Reviewed

    Yukie Yamaguchi, Noriyuki Seta, Junichi Kaburaki, Kazuko Kobayashi, Eiji Matsuura, Masataka Kuwana

    BLOOD   110 ( 13 )   4312 - 4318   2007.12

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    Anti phospholipid syndrome (APS) is an autoimmune prothrombotic disorder associated with autoantibodies to phospholipid (PL)-binding proteins, such as beta(2)-glycoprotein I (beta(2)GPI). We have recently reported that binding of beta(2)GPI to anionic PL facilitates processing and presentation of the cryptic B(2)GPI epitope that activates pathogenic autoreactive T cells. To clarify mechanisms that induce sustained presentation of the dominant antigenic beta(2)GPI determinant in patients with APS, T-cell proliferation induced by beta(2)GPI-treated phosphatidylserine liposome (beta(2)GPI/PS) was evaluated in bulk peripheral blood mononuclear cell cultures. T cells from patients with APS responded to beta(2)GPI/PS in the presence of immunoglobulin G (IgG) anti-beta(2)GPI antibodies derived from APS plasma, and this response was completely inhibited either by the depletion of monocytes or by the addition of anti-Fc gamma RI antibody. These findings indicate that efficient presentation of the cryptic determinants can be Fc gamma RI-mediated uptake of beta(2)GPI-bound anionic surfaces in the presence of IgG anti-beta(2)GPI antibodies. Finally, beta(2)GPI-bound oxidized LDL or activated platelets also induced the specific T-cell response. Continuous exposure to these anionic surfaces may play a critical role in maintaining the pathogenic anti-beta(2)GPI antibody response in patients with APS.

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  • Antibodies against heat shock protein 60 derived from Helicobacter pylori: Diagnostic implications in cardiovascular disease Reviewed

    Tomoyuki Okada, Kiyoshi Ayada, Shinichi Usui, Kenji Yokata, Jinhua Cui, Yoshiro Kawahara, Tomoki Inaba, Satoshi Hirohata, Motowo Mizuno, Daisuke Yamamoto, Shozo Kusachi, Eiji Matsuura, Keiji Oguma

    JOURNAL OF AUTOIMMUNITY   29 ( 2-3 )   106 - 115   2007.9

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    Immune responses against heat shock protein 60 (HSP60) of pathogen-origin are thought to be defensive events which, due to molecular mimicry, misdirect to a human counterpart. Therefore, atherosclerosis may be serologically predicted by anti-HSP60 antibodies (Abs). In the present study, we analyzed the clinical prevalence of the serum IgG Abs against Helicobacter pylori (Hp)-derived HSP60 (Hp-HSP60) or its peptide fragments in patients with cardiovascular disease (CVD; n = 250), as compared to those in age- and gender-matched non-CVD patients (n = 293). Anti-Hp cell lysate Abs frequently appeared in Hp-infected patients who were not associated with CVD. In contrast, Abs against the particular amino acid sequence Hp-HSP60(II3) (II3 region, Glu(141)-Leu(160), in Hp-HSP60) predominantly appeared in CVD patients, as well as IgG anti-human HSP60 (Hu-HSP60(w)). Furthermore, neither titer of anti-Hp-HSP60(113) nor anti-Hu-HSP60(w) Abs was correlated with the levels of high sensitivity C-reactive protein (hsCRP). This data strongly suggested that IgG anti-Hp-HSP60(II3) Abs cross-reacted with Hu-HSP60(w) were independent diagnostic markers relevant to CVD. Further, the 20 amino acid residues (Glu(141)-Leu(160)) might be predominant CVD-associated epitopes that induce anti-Hu-HSP60 auto-Abs, whose location was predicted in the tertiary structure of Hu-HSP60. (c) 2007 Elsevier Ltd. All rights reserved.

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  • Intracellular trafficking of beta(2)-glycoprotein I complexes with lipid vesicles in macrophages: Implications on the development of antiphospholipid syndrome Reviewed

    Toshimitsu Kajiwara, Tatsuji Yasuda, Eiji Matsuura

    JOURNAL OF AUTOIMMUNITY   29 ( 2-3 )   164 - 173   2007.9

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    beta(2)-Glycoprotein I (beta(2)GPI) is known as a major autoantigen for antiphospholipid antibodies. Our recent data show that binding Of beta(2)GPI to oxidized low-density lipoprotein (oxLDL) or to liposomes containing anionic phospholipid(s) may facilitate the presentation Of beta(2)GPI's epitope by macrophages/dendritic cells to autoreactive T cells. In the present study, we investigated intracellular trafficking Of beta(2)GPI and its complexes with oxLDL or liposomes containing phosphatidylserine (PS-liposomes) in mouse macrophage-like J774 cells. A relatively small amount of non-complexed beta(2)GPI was taken up and stagnated in the late endosome after incubating for 16 h. In contrast, beta(2)GPI complexes with oxLDL or PS-liposomes were transported into the lysosome. In the presence of the IgG anti-beta(2)GPI autoantibody, WB-CAL-1, beta(2)GPI/oxLDL complexes were rapidly incorporated into intracellular space and were finally localized in the lysosome. Interestingly, in vitro pulses by beta(2)GPI/oxLDL complexes together with WB-CAL-I led to the expression of membranous CD36 as well as Fey type I receptors (FcyRI). These observations suggest that IgG immune complexes Of beta(2)GPI/oxLDL provide not only FcyRI- but also scavenger receptor-mediated uptake Of beta(2)GPI/oxLDL complexes by macrophages. Thus, beta(2)GPI/oxLDL complexes as a major atherogenic autoantigen and IgG anti-beta(2)GPI autoantibodies may facilitate antigen presentation and foam cell formation in antiphospholipid syndrome. (c) 2007 Elsevier Ltd. All rights reserved.

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  • Cancer-associated immune-mediated syndromes: Pathogenic values. and clinical implementation Reviewed

    S. V. Suchkov, D. D. Petrunin, A. V. Kostalevskaya, I. A. Kachkov, T. Elbeik, E. Matsuura, M. A. Paltsev

    BIOMEDICINE & PHARMACOTHERAPY   61 ( 6 )   323 - 337   2007.7

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    The ability of tumors to provoke formation of cancer-associated secondary immunodeficiency (CASID) with predominant suppression of CMI and cancer-associated secondary immunodeficiency with clinical autoimmunity syndrome (CASICAS) with triggering of a set of the auto-immune deviations is appearing to be a key event in the restriction of hosts' anti-tumor immunity. Earlier the existence of the above-mentioned syndromes was demonstrated in BCC and GBM patients. In order to reach a point where immunological phenotypes in GBM and BCC can be clarified clinically and, partly, pathogenically, we have conducted a series of studies of typical and atypical types of immune responsiveness in patients with GBM and BCC. For GBM and BCC three scenarios of the involvement of the immune responsiveness have been established in a series of our studies, i.e., (i) malignancy with no immunopathology, (ii) malignancy as CASID, and (iii) malignancy as CASICAS. All of those scenarios demonstrated significant differences in their immune-mediated manifestations which, in turn, were proven to reveal close associative relationships with a specific clinicopathologic type and clinical manifestations of the tumor. CASID and CASICAS share two common features, i.e., (i) signs of immunodeficiency and (ii) a tandem of the deviations within the adaptive and innate links of the host immune responsiveness. At the same time, CASID and CASICAS are distinct pathogenically and clinically, and in terms of depth of the immune deviations observed, CASID patients manifest a breakage in both links, whereas in CASICAS patients, a breakage in the adaptive link would dominate. To get these differences clarified, we summarized major types of the immune imbalances and sets of clinical and clinicopathologic manifestations to illustrate the above-mentioned features in CASID and CASICAS patients. There are distinct close correlations between clinicopathologic features of the disease course and sets of the immune-mediated imbalances in patients harboring the tumors. The latter implicates a panel of the new immuno-diagnostic and immuno-prognostic criteria for patients with solid tumors, i.e., BCC, MCC and GB, which is of great value for clinical practice. In particular, the blood levels of some of the immunocompetent cells, state of their functional activity, serum titers of the antigenic markers and auto-antibodies, apoptotic parameters, and others may be accepted as additional and clinically informative criteria to be implemented for immunological monitoring and immunotherapy of patients with solid tumors. (C) 2007 Elsevier Masson SAS. All rights reserved.

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  • Postinfectious immunodeficiency and autoimmunity: Pathogenic and clinical values and implications Reviewed

    Alexander N. Khitrov, Zaur S. Shogenov, Eugenia B. Tretyak, Anatoly I. Ischenko, Eiji Matsuura, Oliver Neuhaus, Mikhail A. Paltsev, Sergey V. Suchkov

    Expert Review of Clinical Immunology   3 ( 3 )   323 - 331   2007.5

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    Autoimmunity is still a mystery of clinical immunology and medicine as a whole. The etiology and pathogenesis of autoimmune disorders remain unclear and, thus, are assessed as a balance between hereditary predisposition, triggering factors and the appearance of autoantibodies and/or self-reactive T cells. Among the immunological armamentarium, molecular mimicry, based on self-reactive T- and B-cell activation by cross-reactive epitopes of infectious agents, is of special value. Hypotheses regarding the possible involvement of molecular mimicry in the development of postinfectious autoimmunity are currently very intriguing. They provide new approaches for identifying etiological agents that are associated with postinfectious autoimmunity, paired microbial- and tissue-linked epitopes targeted for autoimmune reaction determination, postinfectious autoimmunity pathogenesis recognition and specific prevention, and therapy for autoimmune disorder development. © 2007 Future Drugs Ltd.

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  • The association of C-reactive protein with an oxidative metabolite of LDL and its implication in atherosclerosis Reviewed

    Masako Tabuchi, Katsumi Inoue, Hitomi Usui-Kataoka, Kazuko Kobayashi, Misako Teramoto, Koji Takasugi, Kenichi Shikata, Masahiro Yamamura, Kenji Ando, Keiichiro Nishida, Junko Kasahara, Noriaki Kume, Luis R. Lopez, Kazuaki Mitsudo, Masakiyo Nobuyoshi, Tatsuji Yasuda, Toru Kita, Hirofumi Makino, Eiji Matsuura

    JOURNAL OF LIPID RESEARCH   48 ( 4 )   768 - 781   2007.4

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    C-reactive protein (CRP) is one of the strongest independent predictors of cardiovascular disease. We have previously reported that oxidized LDL (oxLDL) interacts with beta 2-glycoprotein I (beta 2GPI), implicating oxLDL/P2GPI complexes as putative autoantigens in autoimmune-mediated atherosclerotic vascular disease. In this study, we investigated the interaction of CRP with oxLDL/beta 2GPI complexes and its association with atherosclerosis in patients with diabetes mellitus (DM). CRP/oxLDL/R2GPI complexes were predominantly found in sera of DM patients with atherosclerosis. In contrast, noncomplexed CRP isoforms were present in sera of patients with acute/chronic inflammation, i.e., various pyrogenic diseases, rheumatoid arthritis (RA), and DM. Immunohistochemistry staining colocalized CRP and beta 2GPI together with oxLDL in carotid artery plaques but not in synovial tissue from RA patients, strongly suggesting that complex formation occurs during the development of adierosclerosis. Serum levels of CRP correlated with soluble forms of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and oxLDL/beta 2GPI complexes correlated with total cholesterol and hemoglobin Al c. Thus, the generation of CRP/oxLDL/beta 2GPI complexes seems to be associated with arterial inflammation, hyperglycemia, and hypercholesterolemia. CRP/oxLDL/R2GPI complexes can be distinguished from pyrogenic noncomplexed CRP isoforms and may represent a more specific and predictive marker for atherosclerosis.

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  • C-reactive protein in primary antiphospholipid syndrome

    P. R. J. Ames, A. Ciampa, G. Scenna, I. Antinolfi, L. Lopez, E. Matsuura

    CLINICAL AND EXPERIMENTAL RHEUMATOLOGY   25 ( 2 )   132 - 132   2007.3

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  • Atherosclerosis in primary antiphospholipid syndrome

    P. R. J. Ames, A. Margarita, L. Lopez, E. Matsuura, I. Antinolfi, G. Scenna

    CLINICAL AND EXPERIMENTAL RHEUMATOLOGY   25 ( 2 )   132 - 132   2007.3

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  • Antiphospholipid antibodies in patients with coronary artery disease: New cardiac risk factors?

    T. P. Greco, A. M. Cont-Kelly, T. P. Greco, K. Dier, E. Matsuura, L. R. Lopez

    CLINICAL AND EXPERIMENTAL RHEUMATOLOGY   25 ( 2 )   133 - 133   2007.3

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  • β2-Glycoprotein I autoantibodies Reviewed

    Eiji Matsuura, Ken J. Dier, Luis R. Lopez

    Autoantibodies   687 - 693   2007

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    Elevated serum levels of antiphospholipid antibodies, thrombosis and/or pregnancy morbidity (miscarriages, recurrent fetal loss) are the major features of the antiphospholipid syndrome (APS). Antiphospholipid antibodies are a heterogeneous family of autoantibodies thought itplays an active role in the development of thrombosis in patients with APS. These antibodies react with negatively charged phospholipids, phospholipid/protein complexes, and certain plasma proteins presented on suitable surfaces (that is, activated cell membranes, oxygenated polystyrene). Most antiphospholipid antibodies from APS patients require the presence of certain plasma proteins for optimal phospholipid binding activity. β2-glycoprotein I (β2GPI), a phospholipid-binding protein, is now recognized as the most clinically relevant antigenic target for antiphospholipid antibodies. Antiβ2GPI antibodies are more specific for thrombosis (and APS) than anticardiolipin (aCL) antibodies. Recent prospective studies have shown that β2GPI-dependent aCL and antiβ2GPI antibodies were significant predictors of arterial thrombosis (myocardial infarction and stroke) in men. β2GPI has natural anticoagulant properties but it may also bind to oxidized low-density lipoprotein (oxLDL) to neutralize its pro-inflammatory effects and possibly to promote its clearance. Circulating oxLDL/β2GPI complexes are immunogenic and anti-oxLDL/β2GPI antibodies accelerate the development of autoimmune-mediated thrombosis and atherosclerosis. © 2007 Elsevier Inc. All rights reserved.

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  • Distinguished effects of antiphospholipid antibodies and anti-oxidized LDL antibodies on oxidized LDL uptake by macrophages Reviewed

    K. Kobayashi, K. Tada, H. Itabe, T. Ueno, P-H Liu, A. Tsutsumi, M. Kuwana, T. Yasuda, Y. Shoenfeld, P. G. de Groot, E. Matsuura

    LUPUS   16 ( 12 )   929 - 938   2007

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    Several interpretations have been made regarding the specificity of antiphospholipid antibodies and antibodies against oxidized low-density lipoprotein (oxLDL), but these are still controversial. In the present study, we delineated specificity of these two types of antibodies and analyzed their regulatory effect on oxLDL and/or beta(2)-glycoprotein I (beta(2)GPI) binding to macrophages. Scavenger receptormediated binding of oxLDL (or its beta(2)GPI complexes) to macrophages was observed and the binding was partly prevented by beta(2)GPI. The IgG monoclonal anti-beta(2)GPI antibody (WB-CAL-1), which was derived from NZW X BXSB F1 mouse (a model of antiphospholipid syndrome), significantly increased the oxLDL/beta(2)GPI binding to macrophages. In contrast, IgM anti-oxLDL natural antibody, EO6 (derived from apoe(-1-) mouse), prevented the binding. Different antigenic specificity of these antibodies to oxLDL and its beta(2)GPI complexes was also confirmed in TLC-ligand blot and ELISA. Thus, IgG anti-beta(2)GPI autoantibodies contribute to lipid metabolism (housekeeping of oxLDL by macrophages) whereas IgM natural anti-oxLDL antibodies may protect against atherogenesis. In addition, in vitro data suggest that relatively high dose of intravenous immunoglobulin preparations (mainly contain IgG anti-oxLDL antibodies) might also prevent atherogenesis by inhibiting the oxLDL binding to macrophages.

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  • Chronic infections and atherosclerosis Reviewed

    Kiyoshi Ayada, Kenji Yokata, Kazuko Kobayashi, Yehuda Shoenfeld, Eiji Matsuura, Keiji Oguma

    AUTOIMMUNITY, PT D   1108   594 - 602   2007

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    Immunoinflammatory processes due to chronic infection are thought to be one of the definitive atherogenetic processes. Especially, anti-heat shock protein antibodies have been related to the prevalence of disease such as coronary artery disease or cerebral infarction, etc., resulted from atherosclerosis. Furthermore, the presence of HSP60specific T lymphocytes in circulation may increase the risk of atherosclerosis. We have recently demonstrated the evidences that Helicobacter pylori infection induced atherosclerosis in apoe(+/-)Idlr(+/-) mice and that Hp-anti-heat-shock protein specific Th1-dominant immune responses had a major involvement in the progression of atherosclerosis. These cellular immune responses caused autoimmunity against endogenous HSP60 (expressed on the stressed cells of vascular endothelium), due to the molecular mimicry. Therefore, an appropriate treatment with antibiotics or with anti-HSP60 antibodies, which regulates the Th1 induction, could sufficiently reduce the progression of atherosclerosis.

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  • Determination of oxidized low-density lipoproteins (ox-LDL) versus ox-LDL/beta 2GPI complexes for the assessment of autoimmune-mediated atherosclerosis Reviewed

    Luis R. Lopez, Tammy R. Ruckner, Beth L. Hurley, Kazuko Kobayashi, Eiji Matsuura

    AUTOIMMUNITY, PART A: BASIC PRINCIPLES AND NEW DIAGNOSTIC TOOLS   1109   303 - 310   2007

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    The immunolocalization of oxidized low-density lipoproteins (ox-LDL), beta 2-glycoprotein I (beta(2)GPI), CD4(+)/CD8(+) immunoreactive lymphocytes, and immunoglobulins in atherosclerotic lesions strongly suggested an active participation of the immune system in atherogenesis. Oxidative stress leading to ox-LDL production is thought to play a central role in both the initiation and progression of atherosclerosis. ox-LDL is highly proinflammatory and chemotactic for macrophage/monocyte and immune cells. Enzyme-linked immunosorbent assays (ELISAs) to measure circulating ox-LDL have been developed and are being currently used to assess oxidative stress as risk factor or marker of atherosclerotic disease. ox-LDL interacts with beta(2)GPI and circulating ox-LDL/beta(2)GPI complexes have been demonstrated in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). It has been postulated that beta(2)GPI binds ox-LDL to neutralize its proinflammatory and proatherosclerotic effects. Because beta(2)GPI is ubiquitous in plasma, its interaction with ox-LDL may mask oxidized epitopes recognized by capture antibodies potentially interfering with immunoassays results. The measurement of ox-LDL/beta(2)GPI complexes may circumvent this interference representing a more physiological and accurate way of measuring ox-LDL.

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  • Oxidation of LDL and its clinical implication.

    Matsuura E, Hughes GRV, Khamashta MA

    Autoimmun Rev   7   558 - 566   2007

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  • Antiphospholipid antibodies patients with coronary artery disease - New cardiac risk factors? Reviewed

    Tom P. Greco, Ann Marie Conti-Kelly, Eiji Matsuura, Tom Greco, Ken J. Dier, Gregory Svanas, Robin Doyle, Luis R. Lopez

    AUTOIMMUNITY, PT D   1108   466 - 474   2007

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    Antiphospholipid antibodies (aPL) have been implicated in the pathogenesis of coronary artery disease (CAD). We evaluated the presence of aPL in patients with chest pain/acute coronary syndromes (ACS) to determine if aPL were associated with the presence and severity of CAD, adverse outcomes, and other coronary risk factors. Patients with chest pain/ACS were evaluated for aPL prior to diagnostic and therapeutic investigations. Coronary angiograms were graded according to the severity of disease. Risk factors, including family histories, were assessed and patients were followed for adverse outcomes. To date, 232 patients (116 M, 116 F, mean age 63 years) with a mean follow-up of 9 months were studied. Thirty-seven percent (86/232) were positive for one or more aPL. More women, 49/86 (57%), were aPL positive versus men, 37/86 (43%). The presence of aPL appeared associated with both presence and severity of CAD (P = 0.176 women; P = 0.163 men). In patients undergoing procedures (angioplasty, stent, bypass), aPL was significantly associated with both an increase in adverse cardiac outcomes (P = 0.045) and extracardiac thrombotic events (P = 0.033). Anti-beta 2 glycoprotein-1 (a beta 2GP1) was the most frequent aPL, occurring in 68.5% of aPL-positive patients with CAD. Anticardiolipin antibody (aCL) occurred in only 7.4%. IgM isotypes were the most frequent for all categories of aPL (range 55-90%). Family history of antiphospholipid syndrome (APS)-related events was more significant in aPL-positive than aPL-negative individuals (P = 0.027).

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  • Subclinical atherosclerosis in primary antiphospholipid syndrome Reviewed

    Annamaria Margarita, Joana Batuca, Giovanna Scenna, Jose' Delgado Alves, Louis Lopez, Luigi Iannaccone, Eiji Matsuura, Paul R. J. Ames

    AUTOIMMUNITY, PT D   1108   475 - 480   2007

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    To test the atherosclerosis hypothesis in primary antiphospholipid syndrome (PAPS) we measured intima media thickness (IMT) of carotid arteries and other cardiovascular risk factors in 44 patients with PAPS (mean age 35 +/- 12 years), in 25 patients with inherited thrombophilia (mean age 40 +/- 10 years), and in 34 normal controls (mean age 38 +/- 11 years). The frequency of smoking, hypertension, and dyslipidemia was similar across groups. IMT was almost similar across groups at age groups below 40 years but IMT was greater in PAPS than controls at the common carotid (P = 0.01), at the bifurcation (P = 0.003), and at the internal carotid (P = 0.005) in the age group over 40 years. Atherosclerosis is a possibility in PAPS patients in their fourth decade of life or older.

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  • Atherogenic Antiphospholipid antibodies in Antiphospholipid syndrome Reviewed

    Kazuko Kobayashi, Luis R. Lopez, Eiji Matsuura

    AUTOIMMUNITY, PT D   1108   489 - 496   2007

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    Macrophage uptake of oxidized LDL (oxLDL) plays a critical role in early stages of atherosclerosis. We previously reported that oxLDL forms stable complexes with beta(2)-glycoprotein I (beta(2)GPI), and that these complexes were frequently present in the sera of patients with systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). oxLDL/beta(2)GPI complexes were shown to be antigenic targets for autoantibodies present in APS. To understand the role of autoantibodics in accelerated atherosclerosis of SLE and APS, we investigated the binding characteristics of beta(2)GPI and oxLDL to mouse macrophages, and the effect of anti-p2GPI and anti-oxLDL autoantibodies on this macrophage binding. IgM anti-oxLDL antibody (derived from Apoe(-/-) mouse) showed inhibitory effect on oxLDL binding to macrophages. Although beta(2)GPI partly inhibited oxLDL binding to macrophages, IgG anti-beta(2)GPI antoantibody (derived from APS model mouse) showed pro-atherogenic property by promoting the binding of oxLDL/beta(2)GPI to macrophages.

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  • Elevated serum sFlt-1/Ang-2 ratio in women with preeclampsia Reviewed

    Kumiko Hirokoshi, Yohei Maeshima, Kazuko Kobayashi, Eiji Matsuura, Hitoshi Sugiyama, Yasushi Yamasaki, Hisashi Masuyama, Yuji Hiramatsu, Hirofumi Makino

    NEPHRON CLINICAL PRACTICE   106 ( 1 )   C43 - C50   2007

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    Background: An imbalance of angiogenesis-associated factors may predispose to preeclampsia. Here, we determined the ratio of serum concentration of soluble fms-like tyrosine kinase 1 (sFlt-1), a natural inhibitor of pro-angiogenic vascular endothelial growth factor (VEGF) relative to angiopoietin-2 (Ang-2), a natural antagonist of angiopoietin-1 (Ang-1) involved in promoting angiogenesis in the presence of VEGF, in women with preeclampsia. Methods: The levels of serum sFlt-1 and Ang-2 were measured by enzyme-linked immunosorbent assay. Results: Significant decrease of serum Ang-2 and the increase of sFlt-1 were observed in women with preeclampsia as compared to healthy pregnant women. The serum sFlt-1/Ang-2 ratio was strikingly increased in preeclamptic women in contrast to healthy pregnant women exhibiting lower value similar to non-pregnant women. The serum sFlt1 concentrations tended to positively correlate with mean blood pressure (BP) in preeclamptic women, but not in healthy pregnant women. A cut-off value &gt; 0.25 in the serum sFlt-1/Ang-2 ratio showed 87.1% sensitivity and 82.8% specificity in differentiating preeclamptic women from healthy pregnant women. Conclusion: The serum sFlt-1/Ang-2 ratio is significantly elevated in preeclamptic women as compared to healthy pregnant women. Remarkable difference of sFlt-1/Ang-2 ratio between these two groups with excellent specificity and sensitivity suggests the clinical usefulness of the serum sFlt-1/Ang-2 ratio in diagnosing and potentially predicting the onset of preeclampsia. Copyright (c) 2007 S. Karger AG, Basel.

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  • Oxidative modification of low-density lipoprotein and immune regulation of atherosclerosis

    Eiji Matsuura, Kazuko Kobayashi, Masako Tabuchi, Luis R. Lopez

    PROGRESS IN LIPID RESEARCH   45 ( 6 )   466 - 486   2006.11

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    Oxidized low-density lipoprotein (oxLDL) is thought to promote atherosclerosis through complex inflammatory and immunologic mechanisms that lead to lipid dysregulation and foam cell formation. Recent findings suggested that oxLDL forms complexes with beta(2)-glycoprotein I (beta(2)GPI) and/or C-reactive protein (CRP) in the intima of atherosclerotic lesions. Autoantibodies against oxLDL/beta 2GPI complexes occur in patients with systemic lupus erythematosus (SLE) and/or anti-phospholipid syndrome (APS) and significantly correlate with arterial thrombosis. IgG autoantibodies having similar specificity emerged spontaneously in non-immunized NZW x BXSB F1 mice, an animal model of APS, and a monoclonal autoantibody (WB-CAL-1; IgG2a) against complexed beta(2)GPI (oxLDL/beta 2GPI complexes) was derived from the same mice. WB-CAL-1 significantly increased the in vitro uptake of oxLDL/P2GPI complexes by macrophages. This observation strongly suggests that such IgG autoantibodies are pro-atherogenic. In contrast, IgM anti-oxLDL natural antibodies found in the atherosclerosis-prone mice (ApoE(-/-) and LDL-R-/- mice) have been proposed to be anti-atherogenic (protective). The presence of IgG anti-oxLDL antibodies in humans has been documented in many publications but their exact clinical significance remains unclear. In this article, we review recent progress in our understanding of the mechanisms involved in oxidation of LDL, formation of oxLDL complexes, and antibody mediated-immune regulation of atherogenesis. (c) 2006 Elsevier Ltd. All rights reserved.

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  • Excessive exposure to anionic surfaces maintains autoimmune response to ss 2-glycoprotein I in patients with antiphospholipid syndrome.

    Yukie Yamaguchi, Noriyuki Seta, Yuka Okazaki, Junichi Kaburaki, Eiji Matsuura, Masataka Kuwana

    ARTHRITIS AND RHEUMATISM   54 ( 9 )   S561 - S562   2006.9

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  • Accelerated atheroma in the antiphospholipid syndrome Reviewed

    Eiji Matsuura, Kazuko Kobayashi, Masako Tabuchi, Luis R. Lopez

    RHEUMATIC DISEASE CLINICS OF NORTH AMERICA   32 ( 3 )   537 - +   2006.8

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    Increased cardiovascular morbidity and mortality due to the premature or accelerated development of atherosclerosis has been reported in patients with systemic autoimmune diseases such as a systemic lupus erythematosus (SLE) [1-3]. These findings motivated a great deal of research into the role of autoimmunity in atherogenesis. The relationship of cholesterol metabolism to atherosclerosis has been well established. However, the participation of newer inflammatory and immunologic mechanisms are emerging as relevant factors for the initiation and progression of atherosclerotic lesions. The oxidative modification of low-density lipoprotein (oxLDL) with the development of autoantiboclies to oxLDL have been identified as key proatherogenic events that accelerate the formation of macro phage-derived foam cells and atherosclerotic lesions [4-7]. Many of the life-threatening clinical complications presented by patients with antiphospholipid syndrome (APS) involve both the venous and arterial blood vessels. Since the original description of APS, much attention has been directed toward the basic and clinical mechanisms of vascular injury and thrombosis. The venous and arterial thromboembolic events of APS are associated with elevated serum levels of antiphospholipid antibodies, and frequently observed in the context of an autoimmune disorder [8,9]. The exact mechanism by which antiphospholipid antibodies promote thrombosis is not yet completely understood. However, it is widely accepted that these antibodies play a direct pathogenic role in the development of thrombosis. Venous thrombosis is the most common vascular event; however, one of three APS patients presents arterial thrombosis (myocardial infarction, cerobrovascular accident, angina, and suggest that beta 2-glycoprotein I (beta 2GPI) is the major antigenic target for antiphospholipid antibodies, and thought to play a central role in the development of the clinical complications of APS [13-16]. Further, anti-beta 2GPI antibodies have been associated with the history of arterial thrombosis [17-19]. OxLDL is the principal lipoprotein found in atherosclerotic lesions by immunohistochemical analysis, and it colocalizes with beta 2GPI, immunoreactive CD4 and CD8 lymphocytes and immunoglobulins [20,21]. These findings further suggested an active role of antiphospholipid antibodies in atherogenesis. OxLDL binds to beta 2GPI in vitro, and circulating OxLDL/ beta 2GPI complexes were demonstrated in patients with various systemic autoimmune and chronic inflammatory diseases, such as SLE, APS, chronic renal disease, diabetes mellitus, and in some patients with acute myocardial infarction [22-25]. IgG antibodies to OxLDL/beta 2GPI complexes were only detected in patients with SLE and APS, and were strongly associated with arterial thrombosis [26]. In vitro experiments have shown that OxLDL/beta 2GPI complexes were more rapidly internalized by macrophages when anti-beta 2GPI antibodies were present, suggesting the participation of Fey receptors [23-25]. Thus, circulating IgG immune complexes containing oxLDL and beta 2GPI may be atherogenic.

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  • Antibodies against beta(2)-glycoprotein I complexed with an oxidised lipoprotein relate to intima thickening of carotid arteries in primary antiphospholipid syndrome Reviewed

    P. R. J. Ames, J. Delgado Alves, L. R. Lopez, F. Gentile, A. Margarita, L. Pizzella, J. Batuca, G. Scenna, V. Brancaccio, E. Matsuura

    CLINICAL & DEVELOPMENTAL IMMUNOLOGY   13 ( 1 )   1 - 9   2006.3

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    To explore whether antibodies against beta(2)-glycoprotein I (beta(2)GPI) complexed to 7-ketocholesteryl-9-carboxynonanoate (oxLig-1) and to oxidised low-density lipoproteins (oxLDL) relate to paraoxonase activity (PONa) and/or intima media thickness (IMT) of carotid arteries in primary antiphospholipid syndrome (PAPS). As many as 29 thrombotic patients with PAPS, 10 subjects with idiopathic antiphospholipid antibodies (aPL) without thrombosis, 17 thrombotic patients with inherited thrombophilia and 23 healthy controls were investigated. The following were measured in all participants: b2GPI oxLDL complexes, IgG anti-beta(2)GPI-oxLig-1, IgG anti-beta(2)GPI-oxLDL antibodies (ELISA), PONa, (para-nitrophenol method), IMT of common carotid (CC) artery, carotid bifurcation (B), internal carotid (IC) by high resolution sonography. beta(2)GPI-oxLDL complex was highest in the control group (p &lt; 0.01), whereas, IgG anti-beta(2)GPI-oxLig-1 and IgG anti-beta(2)GPI-oxLDL were highest in PAPS (p &lt; 0.0001). In healthy controls, beta(2)GPI-oxLDL complexes positively correlated to IMT of the IC (p = 0.007) and negatively to PONa after correction for age (p &lt; 0.03). PONa inversely correlated with age (p = 0.008). In PAPS, IgG anti-beta(2)GPI-oxLig-1 independently predicted PONa (p = 0.02) and IMT of B (p = 0.003), CC, (p 0.03) and of IC (p = 0.04). In PAPS, PONa inversely correlated to the IMT of B, CC and IC (p = 0.01, 0.02 and 0.003, respectively). IgG anti-beta(2)GPI-oxLig-1 may be involved in PAPS related atherogenesis via decreased PON activity.

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  • Roles of interaction between β2-glycoprotein I and plasma lipoproteins in atherosclerosis. Reviewed

    Matsuura E, Kobayashi K, Tabuchi M, Lopez LR

    Prog Lipid Res   45   466 - 486   2006

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  • IVIG and atherosclerosis. Reviewed

    Matsuura E, Kobayashi K, Inoue K, Shoenfeld Y

    Clin Rev Allergy Immunol   29   311 - 319   2006

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  • Oxidized low-density lipoprotein and beta 2-glycoprotein I in patients with systemic lupus erythematosus and increased carotid intima-media thickness: implications in autoimmune-mediated atherosclerosis Reviewed

    LR Lopez, M Salazar-Paramo, C Palafox-Sanchez, BL Hurley, E Matsuura, Garcia-De La Torre, I

    LUPUS   15 ( 2 )   80 - 86   2006

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    Oxidative stress and LDL modification (oxLDL) are early pro- atherogenic events. OxLDL binds beta 2GPI producing immunogenic oxLDL/beta 2GPI complexes. Antibodies to these complexes have been associated with arterial thrombosis in patients with systemic lupus erythematosus ( SLE) and antiphospholipid syndrome (APS). Circulating oxLDL/beta 2GPI complexes, IgG and IgM antibodies to these complexes were measured by ELISA in 30 SLE patients asymptomatic for cardiovascular disease (mean age 31 years) and 27 age/ sex matched healthy controls. Carotid intima-media thickness (IMT) was measured by ultrasound in all patients and controls. Forty- seven percent of SLE presented plaques (median IMT of 0.65 +/- 0.12 mm) while only 7% of the controls had plaques (median IMT of 0.50 +/- 0.04 mm, P &lt; 0.001). Median optical density (OD450nm) for oxLDL/beta 2GPI complexes in SLE was 0.244 +/- 0.07, higher than controls (0.174 +/- 0.09, P &lt; 0.001). Median OD for IgG anti-oxLDL/beta 2GPI antibodies was also higher in SLE (0.297 +/- 0.26) compared to controls (0.194 +/- 0.07, P &lt; 0.001) while the median OD for IgM antibodies in SLE ( 0.444 +/- 0.46) was not different than controls (0.326 +/- 0.22, P = 0.267). There was no correlation between IMT and oxLDL/beta 2GPI complexes, IgG or IgM antibodies, possibly reflecting the complex interrelationship between these serologic elements and tissue factors in the arterial wall. These results support the hypothesis that oxLDL/beta 2GPI complexes and IgG (not IgM) anti-oxLDL/beta 2GPI antibodies contribute to the development of autoimmune-mediated atherosclerosis.

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  • Atherogenic oxidized low-density lipoprotein/beta(2)-glycoprotein I (oxLDL/beta(2)GPI) complexes in patients with systemic lupus erythematosus and antiphospholipid syndrome Reviewed

    E. Matsuura, K. Kobayashi, B. L. Hurley, L. R. Lopez

    LUPUS   15 ( 7 )   478 - 483   2006

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    Oxidized low-density lipoprotein (oxLDL) interacts in vitro with ss(2)-glycoprotein I(ss(2)GPI) via LDL-derived specific ligands forming oxLDL/ss(2)GPI complexes. Circulating oxLDL/ss(2)GPI complexes have been demonstrated in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Autoimmune vascular inflammation and oxidative stress contribute to oxLDL/ss(2)GPI complex formation. Immunohistochemical staining of atherosclerotic lesions suggest that these complexes are formed in the arterial wall and released into circulation. The demonstration of antibodies to oxLDL/ss(2)GPI complexes indicates that these complexes are immunogenic, and the coexistence of complexes and antibodies suggest an active pro-thrombotic/pro-atherogenic role in the development of autoimmune vascular complications. Circulating oxLDL/ss(2)GPI complexes can be measured by ELISA using a monoclonal antibody specific to complexed human ss(2)GPI to capture ss(2)GPI bound to oxLDL. An enzyme-conjugated monoclonal antibody to human Apo B 100 allows the specific detection of oxLDL/ss(2)GPI complexes. OxLDL/ss(2)GPI complexes were common in SLE and APS patients suggesting an underlying process of inflammation and oxidation. Using oxLDL/ss(2)GPI complexes as capture antigen, antibodies to oxLDL/ss(2)GPI can be measured by ELISA. Serum levels of IgG anti-oxLDL/ss(2)GPI antibodies were significantly higher in SLE patients with APS compared to SLE controls without APS. Further, high titers of these IgG antibodies were observed in APS patients with a history of arterial thrombosis. The presence of circulating oxLDL/ss(2)GPI complexes and IgG antibodies to these complexes indicates significant vascular injury and oxidative stress as well as an active role in autoimmune-mediated atherothrombosis.

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  • Intravenous immunoglobulin and atherosclerosis Reviewed

    E Matsuura, K Kobayashi, K Inoue, Y Shoenfeld

    CLINICAL REVIEWS IN ALLERGY & IMMUNOLOGY   29 ( 3 )   311 - 319   2005.12

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    Several inflammatory and immunological factors have been established as important contributors to atherogenesis. Among these, oxidized low-density lipoprotein (oxLDL) play a central role in the initiation and progression of atherosclerotic lesions. In atherosclerotic lesions, oxLDL was also found to co-localize with beta(2)-glycoprotein I (beta(2)-GPI). Immunoglobulin (Ig)G autoantibodies against beta(2)-GPI complexes with oxLDL are pro-atherogenic because they increase uptake of the complexes by macrophages. In contrast, IgM natural anti-oxLDL antibodies derived from atherosclerosis-prone apolipoprotein E (ApoE) deficient mice reduced incidence of atherosclerosis. Such anti-oxLDL antibodies have been found in humans, and the accumulating evidences seem to support the idea that anti-oxLDL antibodies have a protective role for atherogenesis. Intravenous immunoglobulins (IVIgs) contain natural anti-oxLDL antibodies and infusion of IVIg into ApoE-deficient mice has been reported to decrease atherosclerosis. The anti-atherogenic property of IVIg may be derived from non-antigen-specific antibody binding to FC gamma receptors, which blocks foam cell formation of macrophages. Several other possible mechanisms are also discussed.

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  • Antigenic structures recognized by anti-beta 2-glycoprotein I auto-antibodies Reviewed

    H Kasahara, E Matsuura, K Kaihara, D Yamamoto, K Kobayashi, J Inagaki, K Ichikawa, A Tsutsumi, S Yasuda, T Atsumi, T Yasuda, T Koike

    INTERNATIONAL IMMUNOLOGY   17 ( 12 )   1533 - 1542   2005.12

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    beta 2-Glycoprotein I (beta 2-GPI) is a major antigen for anti-cardiolipin antibodies and their epitopes are cryptic. Conformation of each domain of beta 2-GPI was optimized from its crystal structure by energy minimization and by molecular dynamics simulation. Three electrostatic interactions, i.e. D-193-K-246, D-222-K-317 and E-228-K-308, were observed between domains IV and V in the optimized structure that was constructed based on the consensus sequences obtained by the phage-displayed random peptide library. Antigenic structures determined by the epitope mapping mainly consisted of hydrophobic amino acids located on two discontinuous sequences in domain IV. These amino acid clusters, as an epitope, were covered by domain V and were of a hidden nature. A similar but incomplete counterpart to the epitopic clusters was found in domain I but was not in domains II or III. Binding of anti-beta 2-GPI auto-antibodies to solid-phase beta 2-GPI was significantly reduced either by L replacement for W-235, a common amino acid component for the epitopes, or by V replacement for all of D-193, D-222 and E-228. Structural analysis indicated a hypothesis that these electrostatic interactions between domains IV and V retained exposure to W-235 and that epitope spreading occurred in the region surrounding W-235. Thus, epitopic structures recognized by anti-beta 2-GPI auto-antibodies are cryptic and inter-domain electrostatic interactions are involved in their in exposure.

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  • Accelerated atherosclerosis in autoimmune rheumatic diseases Reviewed

    Y Shoenfeld, R Gerli, A Doria, E Matsuura, MM Cerinic, N Ronda, LJ Jara, M Abu-Shakra, PL Meroni, Y Sherer

    CIRCULATION   112 ( 21 )   3337 - 3347   2005.11

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  • Increase of serum angiopoietin-2 during pregnancy is suppressed in women with preeclampsia Reviewed

    K Hirokoshi, Y Maeshima, K Kobayashi, E Matsuura, H Sugiyama, Y Yamasaki, H Masuyama, Y Hiramatsu, H Makino

    AMERICAN JOURNAL OF HYPERTENSION   18 ( 9 )   1181 - 1188   2005.9

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    Background: Numerous recent reports demonstrated that changes in serum levels of angiogenesis-related factors were associated with preeclampsia. Here, we determined the serum concentration of angiopoietin-2 (Ang-2), a natural antagonist of angiopoietin-1 (Ang-1) involved in promoting angiogenesis in the presence of angiogenic stimuli such as vascular endothelial growth factor (VEGF), in women with preeclampsia.
    Methods: The levels of serum Ang-2 and Tie-2, a receptor for Ang-1 expressed on endothelial cells, were determined by enzyme-linked immunosorbent assay.
    Results: The concentrations of serum Ang-2 were significantly elevated in healthy pregnant women (18.9 ng/ mL) as compared to nonpregnant women or women in postpartum period. Increase in the levels of serum Ang-2 was significantly suppressed in preeclamptic women (4.5 ng/mL). The serum Ang-2 concentrations inversely correlated with gestational age in healthy pregnant women, but not in preeclamptic women. The serum Ang-2 concentrations positively correlated with placental weight or mean blood pressure (BP) in healthy pregnant women,but not in preeclamptic women. The serum Ang-2 concentrations inversely correlated with proteinuria in preeclamptic women. The serum concentrations of Tie-2 were riot significantly different between preeclamptic and nonpreeclamptic women.
    Conclusions: These results suggest the potential requirement of circulating Ang-2 in proper formation of placental vasculatures during pregnancy. Although we cannot exclude the possibility that suppression in the increase of serum Ang-2 levels during pregnancy in preeclampsia as a consequence rather than a cause, measurement of serum Ang-2 concentration in pregnant women may serve as a useful marker in the diagnosis and potentially in predicting subsequent development of preeclampsia.

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  • Research around beta 2-glycoprotein I: A major target for antiphospholipid antibodies Reviewed

    T Atsumi, O Amengual, S Yasuda, E Matsuura, T Koike

    AUTOIMMUNITY   38 ( 5 )   377 - 381   2005.8

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    beta 2-Glycoprotein I (beta 2GPI), a phospholipid-binding protein, is one of the major target antigens for antiphospholipid antibodies (aPL) found in patients with antiphospholipid syndrome (APS). Thrombophilic disorders in APS patients are strongly associated with aPL, and their pathogenic properties depend on the presence of beta 2GPI. Procoagulant cell stimulation by aPL, via beta 2GPI, is one of the most plausible mechanisms of thrombosis in APS, and p38 mitogen activated protein kinase (MAPK) pathway plays a crucial role in such activation. beta 2GPI is proteolytically cleaved in domain V by activated factor X or plasmin, leading to the generation of the nicked form of beta 2GPI. Recently, increasing attention is focused on the role of nicked-beta 2GPI as a regulator of extrinsic fibrinolysis pathway.

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  • INCREASE OF SERUM ANGIOPOIETIN-2 DURING PREGNANCY IS AMELIORATED IN WOMEN WITH PREECLAMPSIA

    Kumiko Hirokoshi, Yohei Maeshima, Hitoshi Sugiyama, Yasushi Yamasaki, Hirofumi Makino, Kazuko Kobayashi, Eiji Matsuura, Hisashi Masuyama, Yuji Hiramatsu

    NEPHROLOGY   10   A103 - A103   2005.6

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  • Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis: Identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid Reviewed

    K Amano, PSC Leung, R Rieger, C Quan, XB Wang, J Marik, YF Suen, MJ Kurth, MH Nantz, AA Ansari, KS Lam, M Zeniya, E Matsuura, RL Coppel, ME Gershwin

    JOURNAL OF IMMUNOLOGY   174 ( 9 )   5874 - 5883   2005.5

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    Emerging evidence has suggested environmental factors as causative agents in the pathogenesis of primary biliary cirrhosis (PBC). We have hypothesized that in PBC the lipoyl domain of the immunodominant E2 component of pyruvate dehydrogenase (PDC-E2) is replaced by a chemical xenobiotic mimic, which is sufficient to break self-tolerance. To address this hypothesis, based upon our quantitative structure-activity relationship data, a total of 107 potential xenobiotic mimics were coupled to the lysine residue of the immunodominant 15 amino acid peptide of the PDC-E2 inner lipoyl domain and spotted on microarray slides. Sera from patients with PBC (n = 47), primary sclerosing cholangitis (n = 15), and healthy volunteers (n = 20) were assayed for Ig reactivity. PBC sera were subsequently absorbed with native lipoylated PDC-E2 peptide or a xenobiotically modified PDC-E2 peptide, and the remaining reactivity analyzed. Of the 107 xenobiotics, 33 had a significantly higher IgG reactivity against PBC sera compared with control sera. In addition, 9 of those 33 compounds were more reactive than the native lipoylated peptide. Following absorption, 8 of the 9 compounds demonstrated cross-reactivity with lipoic acid. One compound, 2-octynoic acid, was unique in both its quantitative structure-activity relationship analysis and reactivity. PBC patient sera demonstrated high Ig reactivity against 2-octynoic acid-PDC-E2 peptide. Not only does 2-octynoic acid have the potential to modify PDC-E2 in vivo but importantly it was/is widely used in the environment including perfumes, lipstick, and many common food flavorings.

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  • Characterization of a murine anti-laminin-1 monoclonal antibody (AK8) produced by immunization with mouse-derived laminin-1 Reviewed

    Akane Kondo, Junko Inagaki, Kazuko Kobayashi, Hideo Tsukamoto, Daisuke Yamamoto, Mikiya Nakatsuka, Nobuharu Suzuki, Motoyoshi Nomizu, Satoshi Amano, Hidehiko Matsubayashi, Tatsuji Yasuda, Luis R. Lopez, Yehuda Shoenfeld, Tsunehisa Makino, Eiji Matsuura

    Clinical and Developmental Immunology   12 ( 1 )   67 - 73   2005.3

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    Laminin-1 is a structural glycoprotein that forms an integral part of the scaffolding of basement membranes, and plays an important role during embryonic development. We have recently demonstrated a significant association between anti-laminin-1 antibodies (Abs) and reproductive failure, such as recurrent spontaneous abortions and infertility-associated endometriosis in both human and mouse studies. In the present study, we established an IgM (μ, κ) monoclonal anti-laminin-1 Ab (AK8) by immunizing mice with mouse Engelbreth-Holm-Swarm sarcoma (EHS)-derived laminin-1. The AK8 monoclonal antibody (mAb) reacted with particular peptide sequences from the globular G domain of mouse laminin-α1 chain of using ELISA and Western blot techniques. The peptide tertiary structure of the epitope recognized by AK8 mAb was predicted using eight synthesized domain peptide sequences and three consensus sequences obtained by phage displayed random peptide library. Basement membranes of endometrium of pregnant mice and humans were immunostained with AK8 mAb. Thus, AK8 mAb recognized a common structure present in the G domain of the laminin-α1 chain in both mice and humans. The passive immunization of mice with AK8 mAb may represent a suitable animal model for anti-laminin-1 Ab-mediated reproductive failure. © 2005 Taylor &amp
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  • Binding of beta(2)-glycoprotein I to anionic phospholipids facilitates processing and presentation of a cryptic epitope that activates pathogenic autoreactive T cells Reviewed

    M Kuwana, E Matsuura, K Kobayashi, Y Okazaki, J Kaburaki, Y Ikeda, Y Kawakami

    BLOOD   105 ( 4 )   1552 - 1557   2005.2

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    Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder in association with autoantibodies to phospholipid (PL)-binding plasma proteins, such as beta(2)-glycoprotein I (PAPI). We have recently found that CD4(+) T cells autoreactive to beta(2)GPI in patients with APS preferentially recognize a cryptic peptide encompassing amino acid residues 276-290 (p276-290), which contains the major PL-binding site, in the context of DR53. However, it is not clear how previously cryptic p276-290 becomes visible to the immune system and elicits a pathogenics autoimmune response to beta(2)GPI. Here we show that presentation of a disease-relevant cryptic T-cell determinant in PAN is induced as a direct consequence of antigen processing from beta(2)GPI bound to anionic PL. Dendritic cells or macrophages pulsed with PL-bound beta(2)GPI induced a response of p276-290-specific CD4(+) T-cell lines generated from the patients in an HLA-DR-restricted and antigen-processing-dependent manner but those with beta(2)GPI or PL alone did not. in addition, the p276-290-reactive T-cell response was primed by stimulating peripheral blood T cells from DR53-carrying healthy individuals with dendritic cells bearing PL-bound beta(2)GPI in vitro. Our finding is the first demonstration of an in vitro mechanism eliciting pathogenic autoreactive T-cell responses to beta(2)GPI and should be useful in clarifying the pathogenesis of APS. (C) 2005 by The American Society of Hematology.

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  • Significance of valine/leucine(247) polymorphism of beta(2)-glycoprotein I in antiphospholipid syndrome - Increased reactivity of anti-beta(2)-glycoprotein I autoantibodies to the valine(247) gamma(2)-glycoprotein I variant

    S Yasuda, T Atsumi, E Matsuura, K Kaihara, D Yamamoto, K Ichikawa, T Koike

    ARTHRITIS AND RHEUMATISM   52 ( 1 )   212 - 218   2005.1

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    Objective. To clarify the consequences of the valise/leucine polymorphism at position 247 of the beta(2)-glycoprotein I (beta(2)GPI) gene in patients with antiphospholipid syndrome (APS), by investigating the correlation between genotypes and the presence of anti-beta(2)GPI antibody. The reactivity of anti-beta(2)GPI antibodies was characterized using recombinant Val(247) and Leu(247) beta(2)GPI.
    Methods. Sixty-five Japanese patients with APS and/or systemic lupus erythematosus who were positive for antiphospholipid antibodies and 61 controls were analyzed for the presence of the Val/Leu(247) polymorphism of beta(2)GPI. Polymorphism assignment was determined by polymerase chain reaction followed by restriction enzyme digestion. Recombinant Val(247) and Leu(247) beta(2)GPI were established to compare the reactivity of anti-beta(2)GPI antibodies to beta(2)GPI between these variants. The variants were prepared on polyoxygenated plates or cardiolipin-coated plates, and the reactivity of a series of anti-beta(2)GPI antibodies (immunized anti-human beta(2)GPI monoclonal antibodies [Cof-19-21] and autoimmune anti-beta(2)GPI monoclonal antibodies [EYIC8, EY2C9, and TMIG2]) and IgGs purified from patient sera was investigated.
    Results. A positive correlation between the Val(247) allele and the presence of anti-beta(2)GPI antibodies was observed in the patient group. Human monoclonal/polyclonal anti-beta(2)GPI autoantibodies showed higher binding to recombinant Val(247) beta(2)GPI than to Leu(247) beta(2)GPI, although no difference in the reactivity of the immunized anti-beta(2)GPI between these variants was observed. Conformational optimization showed that the replacement of Leu(247) by Val(247) led to a significant alteration in the tertiary structure of domain V and/or the domain IV-V interaction. Conclusion. The Val(247) beta(2)GPI allele was associated with both a high frequency of anti-beta(2)GPI antibodies and stronger reactivity with anti-beta(2)GPI antibodies compared with the Leu(247) beta(2)GPI allele, suggesting that the Val(247) beta(2)GPI allele may be one of the genetic risk factors for development of APS.

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  • Lymphocyte subpopulations and intima media thickness in primary antiphospholipd syndrome Reviewed

    PRJ Ames, C Tommasino, G Fossati, E Matsuura, A Margarita, A Saulino, L Lopez, G Scenna, Brancaccio, V

    LUPUS   14 ( 10 )   809 - 813   2005

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    The aim of this study was to evaluate a possible association between lymphocyte subsets and intima media thickness (IMT) of carotid arteries in primary antiphospholipid syndrome (PAPS). We used a cross-sectional study on PAPS patients (n = 18) and healthy controls (n = 16). IgG anti-cardiolipin antibody (aCL), IgG anti-beta(2)glycoprotein-I (anti-beta(2)GPI), IgG anti-beta(2)glycoprotein-I complexed to oxidized low-density lipoprotein (oxLDL) and to a specific oxidized moiety of LDL (oxLig1), and beta(2)GPI-oxLDL were measured by ELISA. Lymphocyte immunophenotyping was performed using pairs of monoclonal antibodies directly labelled with fluorescein isothiocyanate, or phycoerythrin or phycoerythrin-Texas-red-X. Intima media thickness (IMT) of carotid arteries was determined by high-resolution sonography. Total peripheral blood lymphocytes did not differ between PAPS and controls. Memory CD4+/CD45RO + T cells were lower in PAPS than controls (P = 0.0007) as well as CD 16+ 56+ natural killer cells (P = 0.02), In PAPS memory T CD45RO + cells positively correlated with IgG anti-beta(2)GPI-oxLig1 (P = 0.002) and to IMT of carotid arteries (common carotid P = 0.02, bifurcation P = 0.007). Naive CD4+ /CD45RA+ T cells inversely correlated with beta 2GPI-oxLDL (P = 0.009). The relation between IgG anti-beta 2GPI-oxLig1 and IMT of carotid arteries with memory CD45RO + T lymphocytes suggests a role for the latter in PAPS related atherogenesis. Lupus (2005) 14, 809-813.

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  • The role of innate and adaptive immunity to oxidized low-density lipoprotein in the development of atherosclerosis

    K Kobayashi, LR Lopez, Y Shoenfeld, E Matsuura

    AUTOIMMUNE DISEASES AND TREATMENT: ORGAN-SPECIFIC AND SYSTEMIC DISORDERS   1051   442 - 454   2005

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    Atherosclerosis is a chronic inflammatory process of the arterial wall associated with systemic and local immune responses to various antigens, oxidized low-density lipoprotein (oxLDL) being the most significant. Both IgM and IgG antibodies to oxLDL are produced during atherosclerosis. Some studies have shown that elevated levels of antibody to oxLDL correlate with the degree of atherosclerosis. Other studies reported that immunization of experimental animals with oxLDL induces high levels of antibodies to oxLDL, with decreased atherosclerosis, suggesting that the immune response to oxLDL may be antiatherogenic. The accelerated development of atherosclerosis has been observed in patients with systemic autoimmune diseases. In patients with antiphospholipid syndrome (APS), beta 2-glycoprotein I (beta 2GPI) is a major antigenic target for anticardiolipin antibodies (aCLs). We recently reported that oxLDL interacts with beta 2GPI via oxLDL-derived specific ligands, such as 7-ketocholesteryl-9-caboxynonanoate (oxLig-1) to form complexes. In vitro, anti-beta 2GPI autoantibodies bind to oxLDL/beta 2GPI complexes that are actively taken up by macrophages via Fc gamma receptors. Circulating oxLDL/beta 2GPI complexes were detected in patients with systemic lupus erythematosus (SLE) and APS, at higher levels than in healthy individuals. Autoantibodies against these complexes were also present; however, IgG anti-oxLig-1/beta 2GPI antibody levels in SLE patients with APS were significantly higher than those in SLE patients without APS and those in healthy individuals.

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  • Oxidized LDL/β2-glycoprotein I complexes: New aspects in atherosclerosis Reviewed

    Eiji Matsuura, K. Kobayashi, K. Inoue, L. R. Lopez, Y. Shoenfeld

    Lupus   14 ( 9 )   736 - 741   2005

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    β2-glycoprotein I (β2GPI) is a major antigenic target for antiphospholipid antibodies. Oxidized low-density lipoprotein (oxLDL) is the principal lipoprotein found in atherosclerotic lesions, and it colocalizes with β2GPI and immunoreactive lymphocytes. oxLDL/β2GPI complexes appeared in the blood circulation of patients with diseases, such as systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), systemic sclerosis, diabetes mellitus and chronic renal diseases. Thus, the complexes may be associated with systemic and chronic inflammation of the vasculature. IgG anti- oxLDL/β2GPI complexes autoantibodies and their immune complexes were detected only in SLE/APS patients and in its animal model and were strongly associated with arterial thrombosis. The oxLDL/β2GPI complexes were internalized by macrophages via IgG anti-β2GPI antibody-mediated phagocytosis. In contrast, IgM anti-oxLDL antibodies derived from hyperlipidemic mice reduced the incidence of atherosclerosis. The distribution patterns of IgG and IgM anti-oxLDL antibodies in patients suggest the different roles of these antibodies. © 2005 Edward Arnold (Publishers) Ltd.

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  • From animal models to human genetics: Research on the induction and pathogenicity of autoantibodies Reviewed

    Karsten Conrad, Michael P. Bachmann, Eiji Matsuura, Yehuda Shoenfeld

    Autoimmunity Reviews   4 ( 3 )   178 - 187   2005

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    The revolutionary techniques of modern molecular and cellular biology enhance almost daily our knowledge of immunity and autoimmunity in men and experimental animals. Our fragmentary puzzle of the immune system is going to form a fascinating picture of a masterpiece of evolution. Although many of these aspects were achieved by analysis of human body fluids and tissues, the etiopathogenesis of autoimmune diseases cannot readily be analyzed without appropriate animal models. Therefore, the 7th Dresden Symposium on Autoantibodies has focused on experimental autoimmune models. The 295 attendants of the symposium listened to and discussed about the pathogenesis and therapy of autoimmunity in experimental mouse models, natural and pathogenic autoantibodies, molecular mechanisms of xenobiotic-induced autoimmunity, the genetic background of autoimmune diseases, novel autoantibodies and their pathogenic and/or clinical relevance, autoantibodies in systemic and neurological diseases, the occurrence and measurement of therapy-induced antibodies and methodical aspects as well as novel diagnostic strategies including multiplex assays for autoantibody profiling. Those who are interested to read the full length articles are referred to the book published in parallel to this meeting ([Conrad K, Bachmann MP, Chan EKL, Fritzler MJ, Humbel RL, Sack U, Shoenfeld Y, editors. From animal models to human genetics: research on the induction and pathogenicity of autoantibodies, Report on the 7th Dresden Symposium on Autoantibodies held in Dresden on September 1-4, 2004. Germany: Pabst Science Publishers
    2004.]
    www.pabst-publishers.de). © 2004 Elsevier B.V. All rights reserved.

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  • Oxidized low-density lipoprotein/beta(2)-glycoprotein I complexes and autoantibodies in patients with type 2 diabetes mellitus Reviewed

    LR Lopez, BL Hurley, DF Simpson, E Matsuura

    AUTOIMMUNE DISEASES AND TREATMENT: ORGAN-SPECIFIC AND SYSTEMIC DISORDERS   1051   97 - 103   2005

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    Diabetes mellitus (DM) is associated with a high incidence of atherosclerotic cardiovascular complications that result from chronic metabolic abnormalities such as hyperglycemia-induced oxidative stress. The oxidative-modification of low-density lipoproteins (oxLDL) and oxLDL/beta(2)-GPI complex formation have been reported in patients with autoimmune disorders. OxLDL/ beta(2)-GPI complexes and autoantibodies to these complexes were measured by ELISA in serum samples from 50 type 2 DM patients and 50 age/sex-matched healthy controls. Mean OD for oxLDL/beta(2)-GPI complexes in DM was 0.099 +/- 0.065 with 50% of patients reacting above the assay cutoff (P &lt; 0.001 vs. controls). Mean OD for controls was 0.037 +/- 0.015 with 2% positives. Thirty-six (72%) DM patients were taking cholesterol-lowering statins and had a significantly lower mean OD complex level (0.092 +/- 0.071, P=0.05) compared to patients not taking statins (0.112 +/- 0.05). Mean OD for IgG anti-oxLDL/beta(2)-GPI antibodies in DM was 0.157 +/- 0.112, similar to the controls (0.146 +/- 0.098, P= 0.328). Increased serum levels of oxLDL/beta(2)-GPI complexes may be a consequence of oxidative stress and LDL modification in DM. Lower levels of oxLDL/beta(2)GPI complexes in DM patients taking statins are in agreement with the antioxidant and antithrombotic properties of these drugs. No significant IgG autoantibody production was observed in this group of DM patients. The interaction of oxLDL with beta(2)-GPI in circulation suggests the intriguing possibility that oxLDL/beta(2)-GPI complexes may also play a role in the development of atherosclerosis and/or cardiovascular complications in DM.

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  • OxLDL/beta 2GPI complexes and autoantibodies in patients with systemic lupus erythematosus, systemic sclerosis, and antiphospholipid syndrome - Pathogenic implications for vascular involvement Reviewed

    LR Lopez, DF Simpson, BL Hurley, E Matsuura

    AUTOIMMUNE DISEASES AND TREATMENT: ORGAN-SPECIFIC AND SYSTEMIC DISORDERS   1051   313 - 322   2005

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    Oxidized low-density lipoprotein (oxLDL) interacts with beta 2GPI, forming oxLDL/beta 2GPI complexes. Autoimmune vascular inflammation (and oxidative stress) may promote the formation of these complexes. The coexistence of oxLDL/beta 2GPI complexes with autoantibodies to these complexes suggests an active pro-atherogenic role in vascular thrombosis and atherosclerosis. Immunoglobulin G (IgG) anti-oxLDL/beta 2GPI antibodies have been regarded as pro-atherogenic, whereas IgM antibodies are thought to be anti-atherogenic. For this study, oxLDL/beta 2GPI complexes, IgG, and IgM anti-oxLDL/beta 2GPI antibodies were measured using enzyme-linked immunosorbent assay (ELISA). Measurements were taken in two patient groups: (1) those with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and rheumatoid arthritis (RA); and (2) those with primary and secondary antiphospholipid syndrome (APS). For oxLDL/beta 2GPI complexes, SLE and SSc patients had the highest mean optical densities (ODs) (P &lt;.001), followed by RA (P = .139) and healthy controls. IgG anti-oxLDL/beta 2GPI antibody distribution followed the same pattern observed with oxLDL/beta 2GPI complexes, SLE and SSc (P &lt;.001), RA (P = .08), and controls. IgM antibodies showed a reverse pattern, with the highest mean OD in RA (P &lt;.001), followed by SSc (P = .007) and SLE (P = 143). Both IgG and IgM anti-oxLDL/beta 2GPI antibodies were significantly higher in secondary APS patients compared with SLE controls without APS. In addition, the highest mean OD and prevalence of IgG anti-oxLDL/beta 2GPI antibodies were observed in APS patients with a history of arterial thrombosis. These results may reflect the widespread vascular involvement seen in SLE and SSc, in contrast to the relatively low vascular involvement in RA. In SLE and SSc, high serum levels and prevalence of circulating oxLDL/beta 2GPI complexes and IgG anti-oxLDL/beta 2GPI antibodies indicate significant vascular oxidative stress as well as a possible pathogenic role in autoimmune-mediated atherosclerosis.

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  • Pregnancy loss and endometriosis - Pathogenic role of anti-laminin-1 autoantibodies Reviewed

    J Inagaki, A Kondo, LR Lopez, Y Shoenfeld, E Matsuura

    AUTOIMMUNE DISEASES AND TREATMENT: ORGAN-SPECIFIC AND SYSTEMIC DISORDERS   1051   174 - 184   2005

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    Laminin-1 is a major multifunctional glycoprotein that forms an integral part of the scaffolding network of basement membranes, and is the earliest synthesized component during embryogenesis. This protein (alpha 1 beta 1 gamma 1) plays an important role in basement membrane assembly and epiblast differentiation during embryonic development. Anti-laminin-1 autoantibodies are known to cause infertility and recurrent spontaneous abortion in animals. Recently, we reported that the presence of IgG anti-laminin-1 antibodies (Abs) in the blood is significantly associated with recurrent first-trimester miscarriages and subsequent negative pregnancy outcomes. Interestingly, these antibodies are also strongly associated with infertility, especially infertility caused by endometriosis. Laminin-alpha 1, laminin-beta 1, and laminin-gamma 1 mRNAs were also detected in 90% of endometriotic lesions, and all laminin-alpha 1, laminin-beta 1, and laminin-gamma 1 chains were localized to the basement membranes of glandular epithelium in endometriotic peritoneal lesions. ELISA showed specific reactivity of the autoantibodies to a particular region of the laminin-1 molecule, that is, the alpha 1 chain G domain. IgM monoclonal anti-laminin-1 Abs, which we recently established, also recognized the G domain and cross-reacted with human alpha 1 chain located in the basement membrane of the glandular epithelium of human endometrium. We also established an animal model that produced high titers of anti-laminin-1 Abs after immunization with mouse laminin-1. Anti-laminin-1 Abs from the immunized mice caused a higher fetal resorption rate with lower embryonic and placental weights. Thus, anti-laminin-1 Abs may be important in the development of autoimmune-mediated reproductive failures, and the assessment of the such antibodies may provide a novel means for noninvasive diagnosis of endometriosis.

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  • Are anti-oxidized low-density lipoprotein antibodies pathogenic or protective? Reviewed

    Y Shoenfeld, RH Wu, LD Dearing, E Matsuura

    CIRCULATION   110 ( 17 )   2552 - 2558   2004.10

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  • Anti-laminin-1 autoantibodies, pregnancy loss and endometriosis Reviewed

    Junko Inagaki, Akane Kondo, Luis R. Lopez, Yehuda Shoenfeld, Eiji Matsuura

    Clinical and Developmental Immunology   11 ( 3-4 )   261 - 266   2004.9

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    Laminin-1 is a major component and multifunctional glycoprotein of basement membranes that consists of three different subunits, α1, β1 and γ1 chains. It is the earliest synthesized network-forming protein during embryogenesis and plays an important role in embryonic development, embryonic implantation and placentation. We have recently shown that IgG anti-laminin-1 antibodies were significantly associated with recurrent first-trimester miscarriages and with subsequent pregnancy outcome. Interestingly, these antibodies were also observed in patients with endometriosis-associated infertility but not in patients with other causes of infertility, including tubal factors, hormonal and uterine abnormalities. Laminin-α1, -β1 and -γ1 mRNAs have been detected in 90% of endometriotic lesions and all laminin-α1, -β1 and -γ1 chains were localized in the basement membranes of glandular epithelium in endometriotic peritoneal lesions. Western blot analysis showed that anti-laminin-1 antibodies from those patients reacted with all laminin-1's chains. ELISA also confirmed that one of the target epitopes for these antibodies was located in a particular region of the laminin-1 molecule, i.e. the carboxyl-terminal globular G domain of α1 chain. IgM monoclonal anti-laminin-1 autoantibody, that we recently established, also recognized the G domain. Anti-laminin-1 antibodies from mice immunized with "mouse" laminin-1, caused a higher fetal resorption rate with lower embryonic and placental weights. Thus, anti-laminin-1 antibodies may be important in development of autoimmune-mediated reproductive failures and the assessment of the antibodies may provide a novel non-invasive diagnosis of endometriosis.

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  • Nicked beta2-glycoprotein I binds to plasminogen and plays a role in extrinsic fibrinolysis via negative feedback mechanism

    S Yasuda, T Atsumi, M Ieko, E Matsuura, Y Amasaki, T Koike

    ARTHRITIS AND RHEUMATISM   50 ( 9 )   S640 - S640   2004.9

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  • Are oxidized LDL/β2-glycoprotein I complexes pathogenic antigens in autoimmune-mediated atherosclerosis? Reviewed

    Eiji Matsuura, Luis R. Lopez

    Clinical and Developmental Immunology   11 ( 2 )   103 - 111   2004.6

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    The oxidative modification of low-density lipoprotein (LDL) in the intima of arteries contributes to the initiation and progression of atherosclerotic lesions. We have previously reported that oxidized LDL (oxLDL) interacts with an endogenous plasma protein, β2-glycoprotein I (β2GPI), to form complexes and that the interaction is mediated by oxLDL specific ligands. We have also demonstrated the presence of oxLDL/β2GPI complexes in the blood stream of patients with systemic inflammatory and autoimmune diseases. These findings implicate that oxLDL/β2GPI complexes are possible atherogenic autoantigens. Autoantibodies to oxLDL/β2GPI complexes have been associated with arterial thrombosis. Further, circulating IgG immune complexes containing oxLDL and β2GPI were also detected in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). Although many unanswered questions remain about the exact pathogenic mechanism(s) involved, oxLDL/β2GPI complexes may be described as metabolic products relevant in atherogenesis and as significant participants in autoimmune-mediated atherosclerosis.

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  • Nicked beta(2)-glycoprotein I: a marker of cerebral infarct and a novel role in the negative feedback pathway of extrinsic fibrinolysis Reviewed

    S Yasuda, T Atsumi, M Ieko, E Matsuura, K Kobayashi, J Inagaki, H Kato, H Tanaka, M Yamakado, M Akino, H Saitou, Y Amasaki, S Jodo, O Amengual, T Koike

    BLOOD   103 ( 10 )   3766 - 3772   2004.5

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    beta(2)-Glycoprotein I (beta(2)-GPI) is proteolytically cleaved by plasmin in domain V (nicked beta(2)-GPI), being unable to bind to phospholipids. This cleavage may occur in vivo and elevated plasma levels of nicked P2-GPI were detected in patients with massive plasmin generation and fibrinolysis turnover. In this study, we report higher prevalence of elevated ratio of nicked P2-GPI against total beta(2)-GPI in patients with ischemic stroke (63%) and healthy subjects with lacunar infarct (27%) when compared to healthy subjects with normal findings on magnetic resonance imaging (8%), suggesting that nicked beta(2)-GPI might have a physiologic role beyond that of its parent molecule in patients with thrombosis. Several inhibitors of extrinsic fibrinolysis are known, but a negative feedback regulator has not been yet documented. We demonstrate that nicked beta(2)-GPI binds to Glu-plasminogen with K-D Of 0.37 x 10(-6) M, presumably mediated by the interaction between the fifth domain of nicked beta2-GPI and the fifth kringle domain of Glu-plasminogen. Nicked beta(2-)GPI also suppressed plasmin generation up to 70% in the presence of tissue plasminogen activator, plasminogen, and fibrin. Intact beta2-GPI lacks these properties. These data suggest that beta(2)-GPI/plasmin-nicked beta(2)-GPI controls extrinsic fibrinolysis via a negative feedback pathway loop. (C) 2004 by The American Society of Hematology.

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  • ANTIBODIES AGAINST OXIDISED THE COMPLEX LOW DENSITY LIPOPROTEIN-BETA-2-GLYCOPROTEIN-I MAY HAVE A PRO-ATHEROGENIC ROLE IN PRIMARY ANTIPHOSPHOLIPID SYNDROME

    P. R. J. Ames, J. Delgado-Alves, D. Lopez, L. Lopez, E. Matsuura, A. Margarita, L. Iannaccone, V. Brancaccio

    RHEUMATOLOGY   43   109 - 109   2004.4

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  • Oxidized low-density lipoprotein beta(2)-glycoprotein I complexes and autoantibodies to oxLig-1 beta(2)-glycoprotein I in patients with systemic lupus erythematosus and antiphospholipid syndrome Reviewed

    D Lopez, Garcia-Valladares, I, CA Palafox-Sanchez, IG De La Torre, K Kobayashi, E Matsuura, LR Lopez

    AMERICAN JOURNAL OF CLINICAL PATHOLOGY   121 ( 3 )   426 - 436   2004.3

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    Oxidized low-density lipoprotein (oxLDL) interacts with beta(2)-glycoprotein I (beta(2)-GPI) via oxLDL-derived specific ligands (oxLig-1)forming complexes. The prevalence and significance of oxLDL/beta(2)-GPI complexes and antibodies to oxLig-Ybeta(2)-GPI were evaluated in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). The oxLDL/beta(2)-GPI complex was 69% positive (above mean + 3 SD of control subjects) in 97 consecutive patients with SLE, % in 40 patients with SLE with secondary APS, and 60% in 50 control patients with SLE without APS. IgG anti-oxLig-1/beta(2)-GPI antibody was positive in 31 (32%) of 97 consecutive patients with SLE, in 26 (65%) of 40 patients with SLE with secondary APS, and in 6 (19%) of 32 control patients with SLE. Anti-oxLig1/beta(P)2-GPI antibodies were 93.7% specific with a positive predictive value of 90.0% for APS, better than anticardiolipin antibodies (80.0% specific, 71.4% predictive value). These results confirm that oxLDL/beta(2)GPI complexes are common in SLE and suggest a possible immunogenic role in APS. In contrast, IgG anti-oxLig-1/beta(2)-GPI antibodies not only are associated with but also are clinically useful risk factors for APS.

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  • Immunology of anti-phospholipid antibodies and cofactors Reviewed

    Tatsuya Atsumi, Eiji Matsuura, Takao Koike

    Systemic Lupus Erythematosus: Fourth Edition   1081 - 1105   2004

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    Anti-phospholipid antibodies (aPLs) are present in a wide range of infectious and autoimmune diseases. aPLs, in particular anti-cardiolipin antibodies (aCL) and lupus anticoagulants (LA), are of considerable clinical importance because of the close association with predominant clinical features of venous, arterial thrombosis, and pregnancy morbidity. The term "antiphospholipid syndrome (APS)" has been used to define this set of pathologic features. Numerous studies have elucidated the specificity of anti-phospholipid antibodies (aPLs). It is clear that the nomenclature of aPLs is a misnomer and that these autoantibodies react with phospholipid-binding plasma proteins (cofactors), such as β2-glycoprotein, prothrombin, annexin V, high-molecular-weight kininogen, protein S, and protein C. Many varieties of pathophysiologic mechanisms have been explored in order to understand the wide spectrum of antigenic specificities of aPLs. Numerous observations are reviewed in this discussion concerning putative mechanisms related to anti-β2-GPI antibodies or other aPLs predisposing to thrombosis and to atherosclerosis. © 2004 Elsevier Inc. All rights reserved.

    DOI: 10.1016/B978-012433901-9/50042-9

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  • Anti-laminin-1 autoantibodies in endometriosis Reviewed

    J Inagaki, M Nakatsuka, M Nomizu, K Aoki, E Matsuura

    PROCEEDINGS OF THE IX INTERNATIONAL CONGRESS OF REPRODUCTIVE IMMUNOLOGY - ISIR   77 - 80   2004

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    Laminin-1, an extracellular matrix glycoprotein located in the basement membrane (BM), is important in embryogenesis and placentation. We showed that serum IgG anti-laminin-1 autoantibodies (autoAbs) are associated with recurrent first-trimester miscarriages and endometriosis-associated infertility. The Abs were significantly associated with endometriosis, but not with adenomyosis. The Abs recognized the G domain of laminin-a1 chain and several peptides in the domain. The assessment of the Abs may be useful for the diagnosis and medical treatment of endometriosis.

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  • Clinical significance of serum oxidized low-density lipoprotein/beta(2)-glycoprotein I complexes in patients with chronic renal diseases Reviewed

    J Kasahara, K Kobayashi, Y Maeshima, Y Yamasaki, T Yasuda, E Matsuura, H Makino

    NEPHRON CLINICAL PRACTICE   98 ( 1 )   C15 - C24   2004

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    Background: Peroxidation of low-density lipoprotein (LDL) plays an important role in the development of dyslipidemias associated with the progression of chronic renal disorders. We recently reported [J Lipid Res 2001; 42: 697, 2002; 43: 1486, 2003; 44: 716] that oxidized LDL (oxLDL) interacts with an endogenous plasma protein, beta(2)-glycoprotein I (beta(2)GPI), via specific ligands. In the present study, the prevalence and clinical significance of oxLDL/beta(2)GPI complexes were evaluated in patients with chronic renal disorders. Methods: Serum levels of oxLDL/beta(2)GPI complexes were measured by ELISA in patients with chronic renal disease and their association with clinical manifestations was assessed. Results: The serum levels of oxLDL/beta(2)GPI complexes were significantly higher in patients with chronic renal failure (CRF), chronic nephritis (CN) and diabetes mellitus than those in healthy individuals. The presence of complexes in patients with CN was significantly associated with high dietary protein and sodium chloride intake, but not with lipid metabolic parameters. Malondialdehyde-modified LDL was significantly associated with total cholesterol and LDL cholesterol in all patient groups, but did not correlate with renal function parameters. Conclusions: Serum oxLDL/beta(2)GPI complexes, generated by oxidative stress and associated with high dietary protein and salt intake, might be a novel risk factor and a diagnostic marker for the development of chronic renal diseases, especially IgA nephropathy. Copyright (C) 2004 S. Karger AG, Basel.

    DOI: 10.1159/000079923

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  • 自己免疫と動脈硬化 Invited

    松浦栄次, 小林和子, 小池隆夫

    日本アフェレシス学会学会誌   23   167 - 175   2004

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  • The relationship of oxLDL, beta(2)GPI and beta(2)GPI-oxLDL complexes in patients with APS

    A Ambrozic, T Kveder, B Rozman, E Matsuura

    THROMBOSIS RESEARCH   114 ( 5-6 )   646 - 647   2004

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  • T lymphocyte subsets in primary antiphospholipid syndrome

    C Tommasino, G Fossati, LR Lopez, E Matsuura, A Margarita, G Scenna, Brancaccio, V, PRJ Ames

    THROMBOSIS RESEARCH   114 ( 5-6 )   612 - 612   2004

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  • Circulating oxLDL/beta(2)GPI complexes in autoimmune diseases: Pathogenic implications for systemic lupus erythematosus and systemic sclerosis

    LR Lopez, K Dier, B Hurley, J Kuca, C Fink, E Matsuura

    THROMBOSIS RESEARCH   114 ( 5-6 )   653 - 653   2004

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  • Hybridomas expressing gamma delta T-cell receptors respond to cardiolipin and beta(2)-glycoprotein 1 (apolipoprotein H) Reviewed

    WK Born, M Vollmer, C Reardon, E Matsuura, DR Voelker, PC Giclas, RL O'Brien

    SCANDINAVIAN JOURNAL OF IMMUNOLOGY   58 ( 3 )   374 - 381   2003.9

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    Hybridomas expressing murine gammadelta T-cell receptors were found to produce cytokines in response to cardiolipin (CL) and structurally related anionic phospholipids. This response required serum at concentrations related to the amount of CL in cultures. The purified serum factor, beta(2)-glycoprotein I (beta(2)-GP1) (apolipoprotein H), supported the CL response alone, whereas several other serum proteins and ovalbumin did not. beta(2)-GP1 is known to form complexes with anionic phospholipids, particularly CL, which are often recognized by pathological autoantibodies. We speculate that gammadelta T cells also recognize such complexes and that the hybridoma response reported here reflects this specificity.

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  • Binding of beta 2-glycoprotein I to anionic phospholipids facilitates processing and presentation of a cryptic epitope that activates pathogenic autoreactive T cells.

    M Kuwana, Y Okazaki, J Kaburaki, Y Kawakami, E Matsuura

    ARTHRITIS AND RHEUMATISM   48 ( 9 )   S446 - S446   2003.9

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  • Immunization of naive mice with mouse laminin-1 affected pregnancy outcome in a mouse model Reviewed

    ST Matalon, M Blank, E Matsuura, J Iganaki, M Nomizu, Y Levi, T Koike, Y Shere, A Ornoy, Y Shoenfeld

    AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY   50 ( 2 )   159 - 165   2003.8

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    PROBLEM: Laminins have important roles during placental and embryonic development. The aim of our study was to determine if active immunization of mice with laminin-1 could elicit an autoimmune response, and induce features of reproductive failure.
    METHOD OF STUDY: BALB/c mice were immunized with mouse laminin-1. Autoantibodies to laminin-1 were measured by enzyme-linked immunosorbent assay. Pregnant mice were killed on day 14 of pregnancy and examined for pregnancy outcome.
    RESULTS: Mice immunized with laminin-1 developed elevated levels of anti-laminin-1 auto-antibodies contrary to the control group. A higher fetal resorption rate was found in the laminin-1 immunized group (23.8%) compared with that of the control group (12.2%), and was even higher in the subgroup of those animals with very high levels of anti-laminin-1 (P &lt; 0.01). Laminin-1 immunized mice also had lower fetal and placental weights.
    CONCLUSIONS: Active immunization with laminin-1 followed by elevated circulating anti-laminin-1 antibodies results in reproductive failure manifested by a higher fetal resorption rate.

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  • Anti-idiotypes against oxidized LDL antibodies intravenious immunoglobulin preparations explanation for its immunomodulatory effects in atherosclerosis

    Y Sherer, R Wu, E Matsuura, B Gilburd, T Koike, JB Peter, Y Shoenfeld

    ANNALS OF THE RHEUMATIC DISEASES   62   125 - 126   2003.7

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  • IgG Autoantibodies against β2-Glycoprotein I Complexed with a Lipid Ligand Derived from Oxidized Low-Density Lipoprotein are Associated with Arterial Thrombosis in Antiphospholipid Syndrome Reviewed

    Daniel Lopez, Kazuko Kobayashi, Joan T. Merrill, E. Matsuura, Luis R. Lopez

    Clinical and Developmental Immunology   10 ( 2-4 )   203 - 211   2003.6

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    We recently reported [J. Lipid Res. 42 (2001), 697
    43 (2002), 1486
    44 (2003), 716] that β2-glycoprotein I (β2GPI) forms complexes with oxidized LDL (oxLDL) and autoantibodies against these complexes are present in patients with SLE and antiphospholipid syndrome (APS). The relationship of β2GPI/oxLDL complexes and IgG autoantibodies against β2GPI complexed with oxLig-1 I (an oxLDL-derived defived ligand) with clinical manifestations of APS was studied in 150 APS and SLE patients. The β2GPI/oxLDL levels of APS patients were similar to those of SLE patients without APS, but they were significantly higher than healthy individuals. There was no difference in the complex levels among the patients with arterial, venous thrombosis, or pregnancy morbidity. IgG anti-β2GPI/oxLig-1 levels of APS were significantly higher than those of SLE without APS and healthy individuals. Further, antibody levels of APS patients with arterial thrombosis were significantly higher than those patients with venous thrombosis and pregnancy morbidity. Thus, oxidation of LDL leads the complex formation with β 2GPI in SLE and APS patients. In contrast, anti-β 2GPI/oxLig-1 autoantibodies were generated only in APS and were strongly associated with arterial thrombosis. These results suggest that autoantibodies against β2GPI/oxLDL complexes are etiologically important in the development of atherosclerosis in APS.

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  • Circulating oxidized LDL forms complexes with beta(2)-glycoprotein I: implication as an atherogenic autoantigen Reviewed

    K Kobayashi, M Kishi, T Atsumi, ML Bertolaccini, H Makino, N Sakairi, Yamamoto, I, T Yasuda, MA Khamashta, GRV Hughes, T Koike, DR Voelker, E Matsuura

    JOURNAL OF LIPID RESEARCH   44 ( 4 )   716 - 726   2003.4

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    beta(2)-glycoprotein I (beta(2)-GPI) is a major antigen for antiphospholipid antibodies (Abs, aPL) present in patients with antiphospholipid syndrome (APS). We recently reported (I. Lipid Res., 42: 697, 200 1; J Lipid Res., 43: 1486, 2002) that beta(2)-GPI specifically binds to Cu2+-oxidized LDL (oxLDL) and that the beta(2)-GPI ligands are omega-carboxylated 7-ketocholesteryl esters. In the present study, we demonstrate that oxLDL forms stable and nondissociable complexes with beta(2)-GPI in serum, and that high serum levels of the complexes are associated with arterial thrombosis in APS. A conjugated ketone function at the 7-position of cholesterol as well as the omega-carboxyl function of the beta(2)-GPI ligands was necessary for beta(2)-GPI binding. The ligand-mediated noncovalent interaction of beta(2)-GPI and oxLDL undergoes a temperature- and time-dependent conversion to much more stable but readily dissociable complexes in vitro at neutral pH. In contrast, stable and nondissociable beta(2)-GPI-oxLDL complexes were frequently detected in sera from patients with APS and/or systemic lupus erythematodes. Both the presence Of beta(2)-GPI-oxLDL complexes and IgG Abs recognizing these complexes were strongly associated with arterial thrombosis. Further, these same Abs correlated with IgG immune complexes containing beta(2)-GPI or LDL.jlr Thus, the beta(2)-GPI-oxLDL complexes acting as an autoantigen are closely associated with autoimmune-mediated atherogenesis.

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  • Anti-idiotypes to oxidized LDL antibodies in intravenous immunoglobulin preparations - Possible immunomodulation of atherosclerosis Reviewed

    RH Wu, Y Shoenfeld, Y Sherer, M Patnaik, E Matsuura, B Gilburd, T Koike, JB Peter

    AUTOIMMUNITY   36 ( 2 )   91 - 97   2003.3

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    Objective: The aim of this study was to examine whether intravenous immunoglobulin (IVIg) preparations contain anti-oxLDL and anti-anti-oxLDL antibodies.
    Background: Oxidized low-density lipoprotein (oxLDL) is one of the major players in atherogenesis. IVIg can reduce atherosclerosis in experimental animal models.
    Methods: Six commercial IVIg preparations were tested for the presence of anti-oxLDL antibodies by EIA. Inhibition studies were performed with the different IVIg preparations and IgGs purified from a pool of sera from patients with high anti-oxLDL antibody levels. Absorption assays were carried out to evaluate the presence of anti-idiotypes against anti-oxLDL antibodies in IVIg preparations.
    Results: IVIg preparations tested had various degrees of reactivity towards oxLDL. Absorption experiments suggested that the reactivity was specific because it could be effectively absorbed by oxLDL and not by an irrelevant antigen PPD. The reactivity was smaller than that observed with the IgG from the pool with high anti-oxLDL antibody levels. Inhibition studies with IVIg demonstrated 20-45% inhibition of anti-oxLDL binding to oxLDL, compared to 76% inhibition by the pool with high anti-oxLDL levels. To investigate the presence of anti-idiotypes against anti-oxLDL antibodies within IVIg, F(ab')(2) fragments of IVIg IgG were used to absorb IgG F(ab')(2) fragments from the pool of sera with high anti-oxLDL levels. The decreased binding to oxLDL of the absorbed supernatants shows that IgG F(ab')(2) fragments of the IVIg preparations had high inhibitory capacities ranging from 65 to 90%.
    Conclusions: IVIg preparations contain both anti-oxLDL and anti-anti-oxLDL activity. This finding may explain the immunomodulating effect of IVIg in atherosclerosis.

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  • An association of IgG anti-laminin-1 autoantibodies with endometriosis in infertile patients Reviewed

    J Inagaki, M Sugiura-Ogasawara, M Nomizu, M Nakatsuka, K Ikuta, N Suzuki, K Kaihara, K Kobayashi, T Yasuda, Y Shoenfeld, K Aoki, E Matsuura

    HUMAN REPRODUCTION   18 ( 3 )   544 - 549   2003.3

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    BACKGROUND: Laminin-1, a multifunctional glycoprotein of the basement membrane, is thought to be important in embryogenesis, embryonic implantation, and placentation. We recently showed that serum IgG anti-laminin-1 autoantibodies (auto-Abs) are associated with recurrent first-trimester miscarriages. The present study assessed the clinical significance of anti-laminin-1 Abs with infertility, accompanied with or without endometriosis. METHODS: Sixty-eight infertile patients who underwent laparoscopy or laparotomy and 39 healthy non-pregnant women were tested for IgG anti-laminin-1 Abs. The association between the Abs and endometriosis was analysed. The presence of laminin-1 mRNA was detected in endometriotic lesions. RESULTS: Twenty infertile patients were positive for anti-laminin-1 Abs. The Ab levels in those patients were significantly higher than those in healthy non-pregnant women (P = 0.0005). The presence of the Abs was significantly associated with endometriosis in those patients (P = 0.0096). The Abs recognized a particular domain, i.e., the laminin-alpha1 chain G domain. mRNA encoding laminin-alpha1, -beta1, and -gamma1 chains was expressed in 90% of endometriotic lesions. CONCLUSIONS: IgG anti-laminin-1 Abs were significantly associated with endometriosis in infertile patients. The Abs might be clinically important in the development of autoimmune-mediated reproductive failures and the assessment of the Abs may provide a novel non-invasive diagnosis of endometriosis.

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  • Multiple autoantibodies associated with autoimmune reproductive failure Reviewed

    Y Sherer, S Tartakover-Matalon, M Blank, E Matsuura, Y Shoenfeld

    JOURNAL OF ASSISTED REPRODUCTION AND GENETICS   20 ( 2 )   53 - 57   2003.2

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    Purpose: Autoimmune factors are involved in some of the cases of reproductive failure. The aim of this paper is to discuss the association between autoantibodies and reproductive failure.
    Methods: Literature review of autoantibodies associated with reproductive failure.
    Results: Several autoantibodies were found in association with such clinical manifestations, mainly in patients having systemic lupus erythematosus or the antiphospholipid syndrome. These autoantibodies include "classical" antiphospholipid antibodies such as anticardiolipin, anti-beta2-glycoprotein-I, antiphosphatidylserine, and antiphosphatidylethanolamine. There are also some "nonclassical" antiphospholipid antibodies directed to prothrombin, thromboplastin, or mitochondrial antibodies of M5 type, which were also found in patients with reproductive failure. Moreover, animal models as well as some human studies support a role for other autoantibodies in these clinical manifestations including antithyroglobulin, antilaminin-1, anti-corpus luteum, antiprolactin, anti-poly(ADP-ribose), and lymphocytotoxic antibodies.
    Conclusions: Even though there is not enough data currently to support a firm association between some of these autoantibodies and reproductive failure, future studies are likely to help us determine and expand the number of autoantibodies screened in these patients.

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  • Atherogenic autoantigen: oxidized LDL complexes with beta 2-glycoprotein I Reviewed

    E Matsuura, K Kobayashi, T Koike, Y Shoenfeld, MA Khamashta, GRV Hughes

    IMMUNOBIOLOGY   207 ( 1 )   17 - 22   2003

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    beta2-Glycoprotein I (beta2-GPI) is a major antigen for antiphospholipid antibodies present in patients with antiphospholipid syndrome (APS). In 1997, we demonstrated that beta2-GPI specifically binds to Cu2+-oxidized low-density lipoprotein (oxLDL) and that the beta2-GPI-oxLDL complex is subsequently targeted by anti-beta2-GPI antibodies in vitro. Then ligands for beta2-GPI were purified from oxLDL and characterized as omega-carboxylated 7-ketocholesteryl esters, such as 7-ketocholesteryl-9-carboxynonanoate (oxLig-1) and 7-ketocholesteryl-12-carboxy (keto) dodecanoate (oxLig-2). These ligands mediate to form oxLDL-beta2-GPI complexes, and the complexes are taken up avidly by macrophages via anti-beta2-GPI autoantibody-mediated phagocytosis. We recently demonstrated that appearance of autoantibodies against a complex of beta2-GPI and oxLig-1 are highly associated with a history of arterial thrombosis. Serum oxLDL-beta2-GPI complex and their IgG immune complexes are also risk factors arterial thrombosis in APS patients. There is increasing circumstantial evidence of autoimmune mechanism involving beta2-GPI and oxLDL in the atherogenesis in APS.

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  • 子宮内膜症と抗ラミニン-1抗体 Invited Reviewed

    稲垣純子, 青木耕治, 松浦栄次

    臨床免疫   39   575 - 581   2003

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  • Oxidized low-density lipoprotein as a risk factor of thrombosis in antiphospholipid syndrome Reviewed

    E Matsuura, K Kobayashi, T Koike, Y Shoenfeld, MA Khamashta, GRV Hughes

    LUPUS   12 ( 7 )   550 - 554   2003

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    beta2-Glycoprotein I (beta2-GPI) is a major antigen for anticardiolipin antibodies (aCL, Abs) present in patients with antiphospholipid syndrome (APS). We recently reported that oxidized LDL (oxLDL) is subsequently targeted by beta2-GPI and anti-beta2-GPI auto-Abs and that -carboxyl variants of 7-ketocholesteryl esters, such as 7-ketocholesteryl-9-carboxynonanoate (oxLig-1) and 7-ketocholesteryl-12-carboxy (keto) octadodecanoate (oxLig-2), are ligands for beta2-GPI (J Lipid Res 2001; 42: 697; J Lipid Res 2002; 43: 1486). These beta2-GPI ligands provide an electrostatic interaction between oxLDL and beta2-GPI followed by forming stable complexes (such as Schiff base adducts). The -carboxyl function in these ligands is responsible for beta2-GPI binding to oxLDL and the oxLDL-beta2-GPI complexes are anti-beta2-GPI auto-Ab-dependently taken up by macrophages (i.e., by phagocytosis). Our recent observations are consistent with the evidence that beta2-GPI co-localizes with lymphocytes and mononuclear cells in human athero-plaques. Thus, autoimmune thrombogenesis (atherogenesis) is linked to interaction of anti-beta2-GPI Abs with the beta2-GPI-oxLDL complexes. We propose an alternative idea, that an immune response against the beta2-GPI-oxLDL complexes may be involved in mechanisms in the development of atherosclerosis, which has been explained by the theory of 'the response to injury'.

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  • Autoantibody-mediated atherosclerosis Invited Reviewed

    Eiji Matsuura, Kazuko Kobayashi, Takao Koike, Yehuda Shoenfeld

    Autoimmunity Reviews   1 ( 6 )   348 - 353   2002.12

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    β2-Glycoprotein I (β2-GPI) is a major antigen for antiphospholipid antibodies (aPL) present in patients with antiphospholipid syndrome (APS). Oxidized low-density lipoprotein (oxLDL) is subsequently targeted by β2-GPI and anti-β2-GPI autoantibodies. Ligands specific for β2-GPI derived from oxLDL have been characterized as oxidized forms of cholesteryl linoleate, such as 7-ketocholesterol-9-carboxynonanoate, i.e. 9-oxo-9-(7-ketocholest-5-en-3β- yloxy) nonanoic acid, (namely oxLig-1). The in vitro phenomenon that it is significantly increased in binding of oxLig-1 containing liposomes to macrophages via an interaction with β2-GPI and an anti-β2-GPI autoantibody (via the Fcγ receptor) may propose a novel mechanism on 'autoantibody-mediated athrosclerosis'. Furthermore, autoantibodies against a complex of β2-GPI and oxLig-1 are detected in sera of APS patients and appearance of the antibodies is associated with episodes of thrombosis, especially, arterial thrombosis. Thus, autoimmune atherogenesis linked to β2-GPI interaction with oxLDL and autoantibodies may be present in APS. © 2002 Elsevier Science B.V. All rights reserved.

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  • 抗リン脂質抗体症候群における血栓形成機序 酸化LDL-β2-グリコプロテインI複合体の自己抗原としての意義

    松浦 栄次, 小林 和子, 貴志 周, 渥美 達也, 稲垣 純子, 山本 格, 保田 立二, 小池 隆夫

    日本免疫学会総会・学術集会記録   32   208 - 208   2002.10

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  • omega-Carboxyl variants of 7-ketocholesteryl esters are ligands for beta 2-glycoprotein I and mediate antibody-dependent uptake of oxidized LDL by macrophages

    QP Liu, K Kobayashi, J Furukawa, J Inagaki, N Sakairi, A Iwado, T Yasuda, T Koike, DR Voelker, E Matsuura

    JOURNAL OF LIPID RESEARCH   43 ( 9 )   1486 - 1495   2002.9

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    beta(2)-Glycoprotein I (beta(2)-GPI) is a major antigen for anticardiolipin antibodies (aCL, Abs) present in patients with antiphospholipid syndrome. We recently reported that beta(2)-GPI specifically binds to oxidized LDL (oxLDL) and that the beta(2)-GPI's major ligand, oxLig-1 is 7-ketocholesteryl-9-carboxynonanoate (Kobayashi, K, E. Matsuura, Q. P. Liu, J. Furukawa, K. Kaihara, J. Inagaki, T. Atsumi, N. Sakairi, T. Yasuda, D. R. Welker, and T. Koike. 2001. A specific ligand for beta(2)-glycoprotein I mediates autoantibody-dependent uptake of oxidized low density lipoprotein by macrophages. J Lipid Res. 42: 697-709). In the present study, we demonstrate that omega-carboxylated 7-ketocholesteryl esters are critical for beta(2)-GPI binding. A positive ion mass spectrum of a novel ligand, designated oxLig-2, showed fragmented ions at m/z 383 and 441 in the presence of acetone, which share features of oxLig-1 and 7-ketocholesterol. In the negative ion mode, ions at m/z 627, 625, and 243 were observed. oxLig-2 was most likely 7-ketocholesteryl-12-carboxy (keto) dodecanoate. These ligands were recognized by beta(2)-GPI. Liposome binding to macrophages was significantly increased depending on the ligand's concentration, in the presence of beta(2)-GPI and an anti-beta(2)-GPI Ab. Synthesized variant, 7-ketocholesteryl-13-carboxytxidecanoate (13-COOH-7KC), also showed a significant interaction with beta(2)-GPI and a similar binding profile with macrophages. Methylation of the carboxyl function diminished all of the specific ligand interactions with beta(2)-GPI. Thus, omega-carboxyl variants of 7-ketocholesteryl esters can mediate anti-beta(2)-GPI Ab-dependent uptake of oxLDL by macrophages, and autoimmune atherogenesis linked to beta(2)-GPI interaction with oxLDL.

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  • Antigenic levels and autoantibodies to oxidized-LDL in patients with antiphospholipid syndrome.

    D Lopez, KJ Dier, CA Fink, LR Lopez, JT Merrill, E Matsuura

    ARTHRITIS AND RHEUMATISM   46 ( 9 )   S219 - S219   2002.9

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  • Oxidized LDL, not anti-oxidized LDL, predicts coronary calcification.

    M Petri, Y Shoenfeld, E Matsuura

    ARTHRITIS AND RHEUMATISM   46 ( 9 )   S54 - S54   2002.9

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  • Anti-beta(2)-glycoprotein I antibodies in children with atopic dermatitis Reviewed

    A Ambrozic, T Avicin, K Ichikawa, T Kveder, E Matsuura, M Hojnik, T Atsumi, B Rozman, T Koike

    INTERNATIONAL IMMUNOLOGY   14 ( 7 )   823 - 830   2002.7

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    beta(2)-Glycoprotein I (beta(2)GPI) appears to be the major antigen for antiphospholipid antibodies (aPL) in patients with antiphospholipid syndrome (APS). In early infancy, virtually all children initiate transient immune response to non-pathogenic nutritional antigens, which fails to terminate in children with atopic diseases. To examine the possibility that a prolonged immune response to beta(2)GPI could also spread to the human protein, antibodies against human beta(2)GPI (anti-beta(2)GPI) were determined in 93 randomly selected children with different allergic diseases. A high frequency (42%) of IgG anti-beta(2)GPI was found in children with atopic dermatitis (AD), but not in those with other allergic diseases. Anti-beta(2)GPI in children with AD were exclusively of the IgG1 subclass and bound to bovine beta(2)GPI as well, but not to either beta(2)GPI combined with the phospholipid cardiolipin. The epitopes were identified in domain V of beta(2)GPI and the antibody binding was abolished upon the specific proteolytic cleavage of the phospholipid-binding C-terminal loop in domain V of beta(2)GPI. These results indicated that the epitopes for anti-beta(2)GPI in children with AD most likely resided in close vicinity of the phospholipid-binding site of beta(2)GPI. The epitopic difference from anti-beta(2)GPI in APS may explain presumed non-thrombogenicity of anti-beta(2)GPI in children with AD.

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  • The orientation of beta 2GPI on the plate is important for the binding of anti-beta 2GPI autoantibodies by ELISA Reviewed

    GM Iverson, E Matsuura, EJ Victoria, KA Cockerill, MD Linnik

    JOURNAL OF AUTOIMMUNITY   18 ( 4 )   289 - 297   2002.6

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    (beta2-glycoprotein I (beta2GPI) is a plasma protein that plays an important role in the antigenic specificity of antiphospholipid autoantibodies (aPL). These antibodies are associated with an increased risk for thrombosis and recurrent foetal loss in humans. Crystallographic analysis of beta2GPI showed that its five complement control protein (CCP) or 'sushi' domains are arranged in an elongated, fish-hook shape; yet the domain-specific location of epitopes recognized by these autoantibodies has remained the subject of considerable controversy. Investigators have used different forms of recombinant beta2GPI and different ELISA methods to obtain conflicting results. One group mapped autoinumme epitopes to domain I using deletion mutants of beta2GPI in a competitive inhibition ELISA on NUNC Maxisorp(TM) microplates. Another group mapped epitopes to domain IV using beta2GPI with mutations in domain IV in a direct binding ELISA on polyoxygenated microplates. In an effort to resolve these discrepancies, a collaboration between the groups compared wildtype beta2GPI with domain IV mutants in both types of ELISA. Autoantibodies bound very poorly to domain IV mutants coated on polyoxygenated plates, yet they bound very well to the same mutants coated on NUNC Maxisorp(TM) plates. The amount of protein adsorbed on to both types of plates was similar. In the competitive inhibition ELISA, no difference could be detected between wildtype beta2GPI and domain IV mutants. These results strongly suggest that the orientation of beta2GPI on the microplate, and not necessarily the lateral density, plays the predominant role in the binding of autoantibodies. (C) 2002 Elsevier Science Ltd. All rights reserved.

    DOI: 10.1006/jaut.2002.0590

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  • β2-グリコプロテイン1に対する自己抗体の動脈血栓発症への関与

    小林 和子, 松浦 栄次, 劉 慶平, 笠原 順子, 稲垣 純子, 保田 立二, 小池 隆夫

    リウマチ   42 ( 2 )   271 - 271   2002.3

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  • Anti-β2-glycoprotein I autoantibodies and atherosclerosis. Reviewed

    Matsuura E, Kobayashi K, Kasahara J, Yasuda T, Makino H, Koike T, Shoenfeld Y

    Int Rev Immunol   21   51 - 66   2002

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  • 抗リン脂質抗体症候群 Invited

    松浦栄次

    岡山医学会雑誌   114   19 - 26   2002

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  • A chimeric antibody as a putative standard for assays to detect IgA anticardiolipin and anti-beta 2-glycoprotein 1 antibodies.

    K Ichikawa, T Atsumi, E Matsuura, Y Amasaki, T Koike

    ARTHRITIS AND RHEUMATISM   44 ( 9 )   S147 - S147   2001.9

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  • Analysis of epitopes of mouse monoclonal antibodies against human alpha-fetoprotein Reviewed

    Y Kang, E Matsuura, T Sakamoto, M Sakai, S Nishi

    TUMOR BIOLOGY   22 ( 4 )   254 - 261   2001.7

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    Thirty-six monoclonal antibodies (MAbs) against human alpha-fetoprotein (AFP) were analyzed for the location of their epitopes by reacting them with a set of yeast recombinant AFP proteins using ELISA. Recombinant AFP proteins containing either one, two or all three domains, i.e. domain I, domain III, domain I-II, domain II-III and domain I-II-III, were produced and secreted into the culture medium of yeast cells harboring the expression plasmids. Epitopes of 13 MAbs were localized on domain I and 17 others were on domain III. However, the exact location of the epitopes of the remaining 6 MAbs could not be defined. The epitope of an antibody, namely AFY6, which was located in domain I, was successfully mapped on an octapeptide, C(175)KAENAVE(182), using synthesized overlapping octapeptides. Copyright (C) 2001 S. Karger AG, Basel.

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  • A specific ligand for beta(2)-glycoprotein I mediates autoantibody-dependent uptake of oxidized low density lipoprotein by macrophages Reviewed

    K Kobayashi, E Matsuura, Q Liu, J Furukawa, K Kaihara, J Inagaki, T Atsumi, N Sakairi, T Yasuda, DR Voelker, T Koike

    JOURNAL OF LIPID RESEARCH   42 ( 5 )   697 - 709   2001.5

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    beta (2)-Glycoprotein I (beta (2)-GPI) is a major antigen for antiphospholipid antibodies (Abs) present in patients with the antiphospholipid syndrome (APS), We previously reported that beta (2)-GPI specifically binds to oxidized low density lipoprotein (oxLDL), but not to native low density lipoprotein (LDL), In the present study, a ligand specific for beta (2)- GPI, oxLig-1, was purified from the extracted lipids of oxLDL, The structure of oxLig-1 was sho cvn to be identical to that of synthesized 7-keto cholesteryl-9-carboxynonanoate by mass spectroscopy and nuclear magnetic resonance analyses. Both purified and synthesized oxLig-1 were recognized by beta (2)-GPI and subsequently by anti-BP-GPI auto-Abs, either in enzyme-linked immunosorbent assay (ELISA) or in ligand blot analysis. Binding of liposomes containing oxLig-1 (oxLig-1-liposomes) to mouse macrophages, J774A.1 cells, was relatively low, as compared with that of phosphatidylserine (PS)-liposomes. In contrast, binding of oxLig-1-liposomes was enhanced more than 10-fold in the presence of both beta2-GPI and an anti-beta (2)-GPI auto-Ab (WB-CAL-1), derived from (NZW x BXSB) F1 mouse, an animal APS model, Anti-PP-GPI auto-Abs derived from APS patients with episodes of arterial thrombosis were detected in ELISA, using a solid phase oxLig-1 complexed with beta (2)-GPI.j/r We suggest that autoimmune atherogenesis linked to PP-GPI interaction with oxLDL and Abs may be present in APS.-Kobayashi Ii, E. Matsuura, Q. Liu, J. Furukawa, It. Kaihara, J. Inagaki, T. Atsumi, N. Sakairi, T. Yasuda, D. R. Voelker, and T. Koike. A specific ligand for beta (2)-glycoprotein I mediates autoantibody-dependent uptake of oxidized low density lipoprotein by macrophages.

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  • IgG anti-laminin-1 autoantibody and recurrent miscarriages Reviewed

    J Inagaki, E Matsuura, M Nomizu, M Sugiura-Ogasawara, K Katano, K Kaihara, K Kobayashi, T Yasuda, K Aoki

    AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY   45 ( 4 )   232 - 238   2001.4

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    PROBLEM: The present study assesses the clinical significance of anti-lamillin-1 auto-antibodies (auto-Abs) in recurrent miscarriages.
    METHOD OF STUDY: A total of 207 recurrent aborters with a history of two or more consecutive first-trimester miscarriages were tested for the presence of anti-laminin-1 Abs, beta (2)-glycoprotein I-dependent anticardiolipin Abs, lupus anticoagulants, anti-DNA Abs, and anti-nuclear Abs, before they had conceived again. Recurrent aborters then were followed up during subsequent pregnancies and their outcomes were evaluated relative to their blood test results prior to pregnancy.
    RESULTS: Fifty-five (31.1%) women out of 177 recurrent aborters were positive for IgG anti-laminin-1 auto-Abs. The levels of IgG anti-laminin-1 auto-Abs in recurrent aborters were significantly higher than those in healthy pregnant women and in healthy non-pregnant women (P = 0.0043 and 0.0073, respectively). The live birth rate of subsequent pregnancies in IgG anti-laminin-1 auto-Abs-positive recurrent aborters was significantly lower than the IgG anti-laminin-1 auto-Abs-negative recurrent aborters (P = 0.0320). There were no specifically significant relationships observed between IgG anti-laminin-1 auto-Abs and other tested auto-Abs.
    CONCLUSION: IgG anti-laminin-1 auto-Abs are associated with recurrent miscarriages and the subsequent pregnancy outcome of recurrent aborters.

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  • 抗リン脂質抗体症候群における動脈硬化発症への酸化コレステロールエステルの関与

    小林 和子, 松浦 栄次, 劉 慶平, 貝原 恵子, 稲垣 純子, 保田 立二, 小池 隆夫

    リウマチ   41 ( 2 )   391 - 391   2001.4

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  • 抗リン脂質抗体症候群患者血清中に抗スルファチド抗体の特異性

    貝原 恵子, 松浦 栄次, 小林 和子, 稲垣 純子, 劉 慶平, 保田 立二, 宮脇 昌二, 小池 隆夫

    リウマチ   41 ( 2 )   392 - 392   2001.4

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  • 抗リン脂質抗体と動脈硬化 Invited

    松浦栄次

    臨床免疫   36   564 - 573   2001

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  • IgG抗ラミニン-1自己抗体:反復流産および子宮内膜症の危険因子 Invited

    稲垣純子

    第31回日本免疫学会総会・学術集会   2001

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  • beta2-グリコプロテインIに特異的な酸化脂質リガンドと自己抗体の動脈硬化進展への関与 Invited

    松浦栄次

    第31回日本免疫学会総会・学術集会   2001

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  • 抗リン脂質抗体とマクロファージによる酸化LDLの取り込み

    松浦栄次

    臨床免疫   36,1,116-122   2001

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  • 抗リン脂質抗体症候群における動脈血栓への抗β2-グリコプロテインI自己抗体の関与

    小林 和子, 松浦 栄次, 劉 慶平, 貝原 恵子, 稲垣 純子, 保田 立二, 小池 隆夫

    日本免疫学会総会・学術集会記録   30   107 - 107   2000.11

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  • 抗リン脂質抗体症候群における血中酸化LDLの臨床的意義

    笠原 順子, 松浦 栄次, 趙 丹丹, 小林 和子, 劉 慶平, 貝原 恵子, 稲垣 純子, 保田 立二, 槇野 博史

    日本免疫学会総会・学術集会記録   30   108 - 108   2000.11

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  • 自己免疫疾患患者おける抗スルファチド抗体の出現 SLE及び抗リン脂質抗体症候群における解析

    貝原 恵子, 松浦 栄次, 小林 和子, 稲垣 純子, 劉 慶平, 保田 立二, 宮脇 昌二, 小池 隆夫

    日本免疫学会総会・学術集会記録   30   107 - 107   2000.11

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  • beta(2)-glycoprotein I deficiency: prevalence, genetic background and effects on plasma lipoprotein metabolism and hemostasis Reviewed

    S Yasuda, A Tsutsumi, H Chiba, H Yanai, Y Miyoshi, R Takeuchi, T Horita, T Atsumi, K Ichikawa, E Matsuura, T Koike

    ATHEROSCLEROSIS   152 ( 2 )   337 - 346   2000.10

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    beta(2)-glycoprotein I (beta(2)-GPI = apolipoprotein H) is an important autoantigen in patients with the antiphospholipid syndrome. It also plays a role in lipoprotein metabolism, such as anti-atherogenic property, triglyceride removal, and enhancement of lipoprotein lipase. Serum beta(2)-GPI concentration of 812 apparently healthy Japanese individuals was measured by sandwich EIA. Two families with complete beta(2)-GPI deficiency were identified. In one family, all affected had increased serum LDL-cholesterol levels or smaller particle sizes of LDL, while the other had no apparent abnormality in lipid metabolism. Individuals investigated had no history of thrombosis or overt abnormalities in hemostatic tests. A thymine corresponding to position 379 of the beta(2)-GPI cDNA was deleted in every beta(2)-GPI deficient individual. The incidence of this heterozygous deficiency determined by RFLP was 6.3% in Japanese and none in Caucasians. Heterozygotes had significantly lower concentrations of serum beta(2)-GPI than did those without the mutation, yet no significantly different lipid profiles, such as total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol, apoA-I, apoB and Lp(a), were observed. A low concentration of beta(2)-GPI seemed not to be associated with apparent abnormality in lipoprotein metabolism. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.

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  • beta 2-glycoprotein I-anti-beta 2-glycoprotein I interaction Invited

    T Koike, K Ichikawa, T Atsumi, H Kasahara, E Matsuura

    JOURNAL OF AUTOIMMUNITY   15 ( 2 )   97 - 100   2000.9

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  • Association of autoantibodies against the phosphatidylserine-prothrombin complex with manifestations of the antiphospholipid syndrome and with the presence of lupus anticoagulant Reviewed

    T Atsumi, M Ieko, ML Bertolaccini, K Ichikawa, A Tsutsumi, E Matsuura, T Koike

    ARTHRITIS AND RHEUMATISM   43 ( 9 )   1982 - 1993   2000.9

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    Objective. To clarify the association of autoantibodies against prothrombin with the clinical manifestations of the antiphospholipid syndrome (APS) and with the presence of lupus anticoagulant (LAC).
    Methods. We examined 265 patients who visited our autoimmune disease clinic. IgG and IgM antiprothrombin antibodies were tested by enzyme-linked immunosorbent assay (ELISA) as either antiphosphatidylserine-prothrombin complex (aPS/PT) antibodies or as antibodies against prothrombin coated on irradiated ELISA plates (as antigen) (aPT). IgG, IgM, and IgA anticardiolipin (aCL) antibodies and their beta(2)-glycoprotein I (beta(2)GPI) dependency were also evaluated by ELISA. LAC was tested by 3 different methods.
    Results. The presence of aPS/PT, but not of aPT, significantly correlated with the clinical manifestations of APS (odds ratio [OR] 4.39, 95% confidence interval [95% CI] 2.06-9.38), and aPS/PT antibodies were as specific as beta(2)GPI-dependent aCL for APS (93.1% for both). IgG aPS/PT strongly correlated with the presence of LAC as detected using the dilute Russell viper venom time test (OR 38.2, 95% CI 13.4-109.1).
    Conclusion. Antiprothrombin antibodies are heterogeneous and their clinical relevance depends on the method of detection applied. Positive results on the aPS/PT test can serve as a marker of thrombotic events in patients with autoimmune diseases.

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  • Valine/leucine(247) polymorphism of beta 2-glycoprotein 1 affects the reactivity of anti-beta 2-glycoprotein 1 antibodies.

    S Yasuda, T Atsumi, K Ichikawa, E Matsuura, K Kaihara, T Yasuda, Y Amasaki, T Koike

    ARTHRITIS AND RHEUMATISM   43 ( 9 )   S404 - S404   2000.9

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  • Proteolytic cleavage of beta 2-glycoprotein I: reduction of antigenicity and the structural relationship Reviewed

    E Matsuura, J Inagaki, H Kasahara, D Yamamoto, T Atsumi, K Kobayashi, K Kaihara, DD Zhao, K Ichikawa, A Tsutsumi, T Yasuda, DA Triplett, T Koike

    INTERNATIONAL IMMUNOLOGY   12 ( 8 )   1183 - 1192   2000.8

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    Binding of beta(2)-glycoprotein I (beta(2)-GPI)-dependent anticardiolipin antibodies (aCL) derived from antiphospholipid syndrome (APS) is significantly reduced in aCL ELISA due to loss of the phospholipid (PL) binding property of beta(2)-GPI by plasmin treatment. In the present study, the treatment generated a nicked form of alpha(2)-GPI and resulted in loss of antigenicity for the autoantibodies detected in ELISA, using an PP-GPI directly adsorbed polyoxygenated carboxylated plate, the assay system of which was not related to PL binding. The nicked form bound to neither Cu2+-oxidized low-density lipoprotein (oxLDL) nor to beta(2)-GPI-specific lipid ligands isolated from oxLDL, the result being a complete loss of subsequent binding of anti-pg-GPI autoantibodies. The conformational change in the nicked domain V was predicted from its intact structure determined by an X-ray analysis (implemented in Protein Data Bank: 1C1Z), molecular modeling and epitope mapping of a monoclonal anti-beta(2)-GPI antibody, i.e. Cof-18, which recognizes the related structure. The analysis revealed that novel hydrophobic and electrostatic interactions appeared in domain V after the cleavage, thereby affecting the PL binding of beta(2)-GPI, Such a conformational change may have important implications for exposure of cryptic epitopes located in the domains such as domain IV.

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  • Proteolytic cleavage of beta 2-glycoprotein I: reduction of antigenicity and the structural relationship Reviewed

    E Matsuura, J Inagaki, H Kasahara, D Yamamoto, T Atsumi, K Kobayashi, K Kaihara, DD Zhao, K Ichikawa, A Tsutsumi, T Yasuda, DA Triplett, T Koike

    INTERNATIONAL IMMUNOLOGY   12 ( 8 )   1183 - 1192   2000.8

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    Binding of beta(2)-glycoprotein I (beta(2)-GPI)-dependent anticardiolipin antibodies (aCL) derived from antiphospholipid syndrome (APS) is significantly reduced in aCL ELISA due to loss of the phospholipid (PL) binding property of beta(2)-GPI by plasmin treatment. In the present study, the treatment generated a nicked form of alpha(2)-GPI and resulted in loss of antigenicity for the autoantibodies detected in ELISA, using an PP-GPI directly adsorbed polyoxygenated carboxylated plate, the assay system of which was not related to PL binding. The nicked form bound to neither Cu2+-oxidized low-density lipoprotein (oxLDL) nor to beta(2)-GPI-specific lipid ligands isolated from oxLDL, the result being a complete loss of subsequent binding of anti-pg-GPI autoantibodies. The conformational change in the nicked domain V was predicted from its intact structure determined by an X-ray analysis (implemented in Protein Data Bank: 1C1Z), molecular modeling and epitope mapping of a monoclonal anti-beta(2)-GPI antibody, i.e. Cof-18, which recognizes the related structure. The analysis revealed that novel hydrophobic and electrostatic interactions appeared in domain V after the cleavage, thereby affecting the PL binding of beta(2)-GPI, Such a conformational change may have important implications for exposure of cryptic epitopes located in the domains such as domain IV.

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  • 抗β2-グリコプロテインI・酸化LDL抗体による動脈硬化の発症機序

    小林 和子, 松浦 栄次, 劉 慶平, 貝原 恵子, 稲垣 純子, 保田 立二, 小池 隆夫

    リウマチ   40 ( 2 )   385 - 385   2000.4

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  • 自己抗原の発現に関与するβ2-グリコプロテインIのドメインIV-V間の相互作用

    貝原 恵子, 松浦 栄次, 山本 大助, 小林 和子, 稲垣 純子, 劉 慶平, 保田 立二, 小池 隆夫

    リウマチ   40 ( 2 )   387 - 387   2000.4

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  • Heterogeneous behavior of anti-beta(2)-glycoprotein I antibodies on various commercially available enzyme immunoassay plates coated with beta(2)-glycoprotein I

    A Tsutsumi, K Ichikawa, E Matsuura, KI Sawada, T Koike

    JOURNAL OF RHEUMATOLOGY   27 ( 2 )   391 - 396   2000.2

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    Objective. To evaluate commercially available enzyme immunoassay (EIA) plates for the measurement of anti-beta(2)-glycoprotein I autoantibody (anti-beta(2)-GPI).
    Methods. Sera from 10 patients with the antiphospholipid syndrome, and 3 monoclonal anti-beta(2)-GPI antibodies established from patients with antiphospholipid syndrome, were assayed for binding to solid phase beta(2)-GPI on 20 commercially available plates.
    Results. Several commercially available EIA plates were found to be of potential value for the measurement of anti-beta(2)-GPI autoantibody. Some plates were unsuitable for anti-beta(2)-GPI detection, possibly due to less beta(2)-GPI on the plates, or to differences in the nature of conformational changes of beta(2)-GPI induced by the plates.
    Conclusion. Differences among EIA plates need to be considered when measuring beta(2)-GPI antibodies.

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  • Heterogeneous behavior of anti-beta(2)-glycoprotein I antibodies on various commercially available enzyme immunoassay plates coated with beta(2)-glycoprotein I Reviewed

    A Tsutsumi, K Ichikawa, E Matsuura, KI Sawada, T Koike

    JOURNAL OF RHEUMATOLOGY   27 ( 2 )   391 - 396   2000.2

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    Objective. To evaluate commercially available enzyme immunoassay (EIA) plates for the measurement of anti-beta(2)-glycoprotein I autoantibody (anti-beta(2)-GPI).
    Methods. Sera from 10 patients with the antiphospholipid syndrome, and 3 monoclonal anti-beta(2)-GPI antibodies established from patients with antiphospholipid syndrome, were assayed for binding to solid phase beta(2)-GPI on 20 commercially available plates.
    Results. Several commercially available EIA plates were found to be of potential value for the measurement of anti-beta(2)-GPI autoantibody. Some plates were unsuitable for anti-beta(2)-GPI detection, possibly due to less beta(2)-GPI on the plates, or to differences in the nature of conformational changes of beta(2)-GPI induced by the plates.
    Conclusion. Differences among EIA plates need to be considered when measuring beta(2)-GPI antibodies.

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  • Accelerated atheroma and anti-beta 2-glycoprotein I antibodies Invited

    E Matsuura, T Koike

    LUPUS   9 ( 3 )   210 - 216   2000

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  • 抗リン脂質抗体の測定原理と多様性 Invited

    松浦栄次

    臨床病理   48   317 - 322   2000

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  • 抗リン脂質抗体の反応エピトープとその機能 Invited

    松浦栄次, 小池隆夫

    リウマチ科   23   422 - 428   2000

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  • 全身性エリテマトーデスの病態形成に関与する分子群・抗リン脂質抗体 Invited

    保田晋助, 渥美達也, 笠原英樹, 松浦栄次, 市川健司, 小池隆夫

    臨床免疫   34   470 - 474   2000

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  • 抗リン脂質抗体・ループスアンチコアグラント Invited

    松浦栄次

    血栓と循環   8   134 - 139   2000

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  • 抗リン脂質抗体と動脈硬化 Invited

    松浦栄次, 小林和子, 笠原順子, 貝原恵子, 小池隆夫

    リウマチ科   24   378 - 384   2000

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  • A chimeric antibody with the human gamma 1 constant region as a putative standard for assays to detect IgG beta(2)-glycoprotein I-dependent anticardiolipin and anti-beta(2)-glycoprotein I antibodies Reviewed

    K Ichikawa, A Tsutsumi, T Atsumi, E Matsuura, S Kobayashi, GRV Hughes, MA Khamashta, T Koike

    ARTHRITIS AND RHEUMATISM   42 ( 11 )   2461 - 2470   1999.11

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    Objective. Thromboembolic manifestations or thrombocytopenia in association with anticardiolipin antibodies (aCL) or lupus anticoagulant are known as the antiphospholipid syndrome (APS), Efforts have been made to elucidate precise clinical features and adequate therapeutic options for treating patients with APS, However, the lack of a proper international standard for measurement of aCL makes it difficult to compare data derived from different laboratories. We attempted to design a chimeric antibody with human gamma constant regions and variable regions of WBCAL-1, a monoclonal antibody established from an APS-prone mouse which has a specificity similar to that of aCL in sera from humans with APS,
    Methods. Variable-region genes of WBCAL-1, which were cloned using reverse transcription-polymerase chain reaction, were inserted into plasmids containing human gamma 1 and kappa constant-region genes. The construct was transfected to a mouse myeloma cell line. Stable transfectants that secreted a chimeric antibody, HCAL, into the culture supernatant were obtained. The reactivity of HCAL to cardiolipin and to beta(2)-glycoprotein I (beta(2)GPI) was studied using a solid-phase enzyme immunoassay, The binding of HCAL was compared with the binding of standards for IgG aCL and anti-beta(2)GPI antibody assays done in 18 independent laboratories.
    Results, In the presence of beta(2)GPI, HCAL bound to the wells of cardiolipin-coated microtiter plates in a dose-dependent manner and reacted with beta(2)GPI on oxygenated polystyrene plates. The aCL activity of HCAL can be converted into GPL units (IgG phospholipid units), which is widely used to quantify IgG aCL activity, using the following formula: 1 GPL unit 32.9 x (concentration of HCAL [in mu g/ml])(0.503). The reactivity of HCAL to cardiolipin or beta(2)GPI was similar to the reactivity of standards for IgG aCL or anti-beta(2)GPI antibody assays done in collaborative laboratories.
    Conclusion. Because the reactivity of HCAL is similar to that of aCL in sera from humans with APS, HCAL will be useful as a standard for human IgG aCL and anti-beta(2)GPI antibody assays.

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  • cryptic epitopeの発現に関与するβ2-グリコプロテインIのドメインIV-V間の相互作用

    貝原 恵子, 松浦 栄次, 山本 大助, 小林 和子, 稲垣 純子, 劉 慶平, 保田 立二, 小池 隆夫

    日本免疫学会総会・学術集会記録   29   35 - 35   1999.10

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  • 抗β2-グリコプロテインI抗体の動脈硬化への関与I.酸化LDL由来のリガンドの精製と自己抗体の反応性

    松浦 栄次, 小林 和子, 劉 慶平, 貝原 恵子, 稲垣 純子, 保田 立二, 小池 隆夫

    日本免疫学会総会・学術集会記録   29   35 - 35   1999.10

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  • A chimeric antibody with the human gamma 1 constant region as a putative standard for assays to detect IgG anticardiolipin and anti-beta 2-glycoprotein 1 antibodies.

    K Ichikawa, A Tsutsumi, T Atsumi, E Matsuura, S Kobayashi, T Koike

    ARTHRITIS AND RHEUMATISM   42 ( 9 )   S367 - S367   1999.9

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  • Modulation of T cell function by alpha-fetoprotein: An in vivo study on procine thyroid peroxidase-induced experimental autoimmune thyroiditis in transgenic mice producing human alpha-fetoprotein Reviewed

    E Matsuura, Y Kang, H Kitakawa, A Ogata, T Kotani, S Ohtaki, S Nishi

    TUMOR BIOLOGY   20 ( 3 )   162 - 171   1999.5

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    Experimental autoimmune thyroiditis was induced in transgenic mice (TG-3) producing human cl-fetoprotein (AFP) and in control mice by immunization of porcine thyroid peroxidase (TPO). Development of thyroiditis accompanied with mononuclear cell infiltration was observed in 6 out of 8 treated control mice. In contrast, the development was significantly suppressed in TG-3 mice and mild histologic change was observed in only 1 out of 8 TG-3 mice (p &lt; 0.05). Serum anti-TPO antibody titers gradually increased in TG-3 mice as well as in control mice and there were no significant differences. In vitro phytohemagglutinin response of splenocytes from TG-3 mice was lower than that from control mice. Significantly reduced numbers of CD4+ and CD8+ splenocytes, total thymocytes, and CD4+ thymocytes were found in the nontreated TG-3 mice as compared with those in control mice. These results suggest that ubiquitously produced AFP modulates in vivo T cell development and/or T cell-dependent immune responses.

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  • plasminによる限定分解 自己抗原であるβ2-グリコプロテイン1の抗原性の消失

    松浦 栄次, 稲垣 純子, 小林 和子, 貝原 恵子, 保田 立二, 笠原 英樹, 市川 健司, 堤 明人, 小池 隆夫

    リウマチ   39 ( 2 )   323 - 323   1999.4

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  • 抗リン脂質抗体の動脈硬化の進展への関与

    小林 和子, 松浦 栄次, 稲垣 純子, 貝原 恵子, 保田 立二, 小池 隆夫

    リウマチ   39 ( 2 )   322 - 322   1999.4

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  • Antiphospholipid syndrome Invited

    K Ichikawa, A Tsutsumi, E Matsuura, T Koike

    INTERNAL MEDICINE   38 ( 2 )   170 - 173   1999.2

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  • beta(2),-glycoprotein I is necessary to inhibit protein C activity by monoclonal anticardiolipin antibodies

    M Ieko, K Ichikawa, DA Triplett, E Matsuura, T Atsumi, K Sawada, T Koike

    ARTHRITIS AND RHEUMATISM   42 ( 1 )   167 - 174   1999.1

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    Objective, To clarify mechanisms of the thrombosis associated with anticardiolipin antibodies (aCL), we examined the effects on activated protein C (APC) of monoclonal aCL and beta(2)-glycoprotein I (beta(2)GPI), which is required for formation of the epitopes of aCL,
    Methods. We developed the chromogenic assay, in which the degradation of coagulation factor Va by APC is reflected in the reduced generation of thrombin from prothrombin, using soybean trypsin inhibitor to inhibit APC, APC activities were measured in the presence and absence of 3.4 mu M beta(2)GPI and/or 2.5 mu g/ml of IgM monoclonal aCL (EY2C9 and EY1C8) established from peripheral blood lymphocytes obtained from a patient with aCL.
    Results, Without APC, the formed thrombin activity decreased by the addition of 3.4 mu M beta(2)GPI, When 12.8 nM APC was added, beta(2)GPI partially reversed the APC-induced inhibition of thrombin generation in a concentration-dependent manner. With 3.4 mu M beta(2)GPI, the thrombin generation in monoclonal aCL (2.5 mu g/ml) decreased to 77.1-80.2% by the addition of 12.8 nM APC, but the values were above that in the control IgM (72.7%). Without beta(2)GPI, the APC activity was unaffected by the addition of monoclonal aCL.
    Conclusion, Beta(2)-glycoprotein I exhibits procoagulant activity by inhibiting APC activity and anticoagulant activity by inhibiting thrombin generation. Any further inhibition of APC activity was caused by monoclonal aCL and only in the presence of beta(2)GPI.

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  • beta(2),-glycoprotein I is necessary to inhibit protein C activity by monoclonal anticardiolipin antibodies Reviewed

    M Ieko, K Ichikawa, DA Triplett, E Matsuura, T Atsumi, K Sawada, T Koike

    ARTHRITIS AND RHEUMATISM   42 ( 1 )   167 - 174   1999.1

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    Objective, To clarify mechanisms of the thrombosis associated with anticardiolipin antibodies (aCL), we examined the effects on activated protein C (APC) of monoclonal aCL and beta(2)-glycoprotein I (beta(2)GPI), which is required for formation of the epitopes of aCL,
    Methods. We developed the chromogenic assay, in which the degradation of coagulation factor Va by APC is reflected in the reduced generation of thrombin from prothrombin, using soybean trypsin inhibitor to inhibit APC, APC activities were measured in the presence and absence of 3.4 mu M beta(2)GPI and/or 2.5 mu g/ml of IgM monoclonal aCL (EY2C9 and EY1C8) established from peripheral blood lymphocytes obtained from a patient with aCL.
    Results, Without APC, the formed thrombin activity decreased by the addition of 3.4 mu M beta(2)GPI, When 12.8 nM APC was added, beta(2)GPI partially reversed the APC-induced inhibition of thrombin generation in a concentration-dependent manner. With 3.4 mu M beta(2)GPI, the thrombin generation in monoclonal aCL (2.5 mu g/ml) decreased to 77.1-80.2% by the addition of 12.8 nM APC, but the values were above that in the control IgM (72.7%). Without beta(2)GPI, the APC activity was unaffected by the addition of monoclonal aCL.
    Conclusion, Beta(2)-glycoprotein I exhibits procoagulant activity by inhibiting APC activity and anticoagulant activity by inhibiting thrombin generation. Any further inhibition of APC activity was caused by monoclonal aCL and only in the presence of beta(2)GPI.

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  • A 50-kDa variant form of human surfactant protein D Reviewed

    RJ Mason, LD Nielsen, Y Kuroki, E Matsuura, JH Freed, JM Shannon

    EUROPEAN RESPIRATORY JOURNAL   12 ( 5 )   1147 - 1155   1998.11

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    The dominant form of human surfactant protein D (SP-D) is a multimeric collagenous glycoprotein composed of monomeric subunits that have a molecular mass of 43 kDa under reducing conditions, However, in evaluating monoclonal antibodies to human SP-D, an additional monomeric subunit was identified with a reduced molecular mass of 50 kDa.
    This 50-kDa variant was detected in approximately half of the samples evaluated and was found in lavage fluid from normal subjects, patients with alveolar proteinosis or idiopathic pulmonary fibrosis and in amniotic fluid. This 50-kDa variant had the same amino-terminal sequence, amino acid composition and apparent size of the carboxy-terminal collagenase-resistant fragment (20 kDa) as the 43-kDa subunit. The major difference was in the amino-terminal portion of the molecule and was due to altered glycosylation, as determined by carbohydrate staining, chemical deglycosylation, treatment with N-glycanase and neuraminidase and reduced signals for threonine at positions 5, 9 and 10 during amino-terminal sequencing.
    After gel filtration chromatography, the 50-kDa form was not present in the high molecular weight fraction, which is commonly used in purification of SP-P), but was found only in the smaller molecular weight fraction of monomers and trimers of SP-D.
    In conclusion, the 50 kDa-form of surfactant protein D is produced by post-translational glycosylation and does not form higher ordered oligomers, but its precise physiological function remains to be determined.

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  • IgA class anti-beta(2)-glycoprotein I in patients with systemic lupus erythematosus - Reply

    A Tsutsumi, E Matsuura, K Ichikawa, T Koike

    JOURNAL OF RHEUMATOLOGY   25 ( 11 )   2283 - 2284   1998.11

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  • 自己抗原であるβ2-グリコプロテインIの不活化:plasminによる酵素的開裂に伴う抗原性の消失

    松浦 栄次, 稲垣 純子, 小林 和子, 貝原 恵子, 保田 立二, 山本 大助, 笠原 英樹, 市川 健司, 堤 明人, 小池 隆夫

    日本臨床免疫学会会誌   ( 26回抄録集 )   242 - 242   1998.10

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  • 抗β2-グリコプロテインI抗体の反応特異性の解析:酸性リン脂質由来の脂肪酸の関与

    小林 和子, 松浦 栄次, 稲垣 純子, 貝原 恵子, 保田 立二, 小池 隆夫

    日本臨床免疫学会会誌   ( 26回抄録集 )   242 - 242   1998.10

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  • 自己抗原であるβ2-グリコプロテインIの三次構造

    山本 大助, 松浦 栄次, 貝原 恵子, 稲垣 純子, 小林 和子, 保田 立二, 小池 隆夫

    日本臨床免疫学会会誌   ( 26回抄録集 )   239 - 239   1998.10

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  • Identification of the epitopes of anticardiolipin antibodies on the tertial structure of beta 2-glycoprotein I.

    K Ichikawa, H Kasahara, E Matsuura, D Yamamoto, A Tsutsumi, H Kitakawa, T Atsumi, T Koike

    ARTHRITIS AND RHEUMATISM   41 ( 9 )   S135 - S135   1998.9

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  • Use of various methods for anticardiolipin detection in the updated American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus: comment on the letter by Hochberg Reviewed

    A Tsutsumi, K Ichikawa, T Atsumi, E Matsuura, T Koike, SA Krilis

    ARTHRITIS AND RHEUMATISM   41 ( 7 )   1326 - 1327   1998.7

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  • Target recognition of beta(2)-glycoprotein I (beta(2)GPI)-dependent anticardiolipin antibodies: Evidence for involvement of the fourth domain of beta(2)GPI in antibody binding Reviewed

    J George, B Gilburd, M Hojnik, Y Levy, P Langevitz, E Matsuura, T Koike, Y Shoenfeld

    JOURNAL OF IMMUNOLOGY   160 ( 8 )   3917 - 3923   1998.4

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    beta(2)-glycoprotein I (P(2)GPI) is an absolute requirement for the binding of autoimmune anticardiolipin Abs (aCL) to cardiolipin (CL), We evaluated the target recognition of human beta(2)GPI by IgG derived from two patients with primary and two with secondary antiphospholipid syndrome, The total IgG serum fractions and beta(2)GPI affinity-purified IgGs were assessed by using various domain-deleted mutants (DM) of human beta(2)GPI (DMs: I-III, I-IV, II-V, III-V, IV-V, and V) and mouse mAbs against individual beta(2)GPI domains, The four IgGs bound slightly to CL in the absence of beta(2)GPI and showed increased binding in the beta(2)GPI presence, Following affinity purification of the IgGs on a beta(2)GPI column, reactivity toward CL was absent. DMs containing domain V inhibited the binding of biotinylated beta(2)GPI to CL, The addition to CL-coated plates of DM V, but not the other DMs, reduced the binding of all four IgGs, The anti-beta(2)GPI IgGs bound only to complete beta(2)GPI and DM I-IV coated on the plates, The binding to plate-adsorbed beta(2)GPI could be inhibited by complete beta(2)GPI and DM I-IV, the latter being a more efficient inhibitor, Further, the human anti-beta(2)GPI IgGs could compete with the binding to beta(2)GPI of Cof-21 mouse mAb (directed at domain IV), but not with the two other mouse mAbs, The results suggest that some "autoimmune:" beta(2)GPI-dependent anticardiolipin Abs recognize a beta(2)GPI target that is distinct from the CL-binding site in domain V, The target site for some antiphospholipid syndrome IgGs appear to reside in domain TV of beta(2)GPI.

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  • IgA class anti-beta(2)-glycoprotein I in patients with systemic lupus erythematosus Reviewed

    A Tsutsumi, E Matsuura, K Ichikawa, A Fujisaku, M Mukai, T Koike

    JOURNAL OF RHEUMATOLOGY   25 ( 1 )   74 - 78   1998.1

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    Objective. To search for a possible relationship between the presence of IgA class anti-beta(2)-glycoprotein I antibody (alpha beta(2)-GPI) and clinical manifestations, including thrombotic episodes, in patients with systemic lupus erythematosus (SLE).
    Methods. Serum IgA alpha beta(2)-GPI levels in 124 Japanese patients with SLE were measured using a phospholipid independent enzyme immunoassay. Relationships to clinical histories and to various laboratory data including IgG and IgM class alpha beta(2)-GPI were examined.
    Results. Twenty-five percent of patients with SLE were positive for IgA alpha beta(2)-GPI. Patients with a history of thrombosis had significantly higher probabilities for positivity of IgA alpha beta(2)-GPI, compared to those without. The presence of IgA alpha beta(2)-GPI was correlated with presence of lupus anticoagulant and/or biological false positive result for serological syphilis test. Titer of IgA alpha beta(2)-GPI significantly correlated with values of IgG alpha beta(2)-GPI, IgM alpha beta(2)-GPI, and anti-DNA antibodies.
    Conclusion. The presence of IgA alpha beta(2)-GPI may be related to the occurrence of thrombosis in patients with SLE. Measurements of IgA alpha beta(2)-GPI may be of value for evaluating risk of thrombosis in patients with SLE.

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  • Antiphospholipid antibodies and atherosclerosis Invited

    E Matsuura, K Kobayashi, T Yasuda, T Koike

    LUPUS   7   S135 - S139   1998

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    B-2-Glycoprolein I (beta(2)-GPI) is a major antigen for anticardiolipin antibodies (aCL) induced in patients with antiphospholipid syndrome and their antigenic epitopes are cryptic. The epitopes appear on the surface of beta(2)-GPI molecule only when beta(2)-GPI interacts with lipid membranes containing negatively charged phospholipids or polyoxygenated polystyrene surface. Our data also indicated that CuSO4-oxidized low density lipoproteins (oxLDL) are subsequently targeted by beta(2)-GPI and aCL; however, malonedialdehyde (MDA)-modified LDL were recognized neither by beta(2)-GPI nor aCL. beta(2)-GPI binding to LDL was rapidly increased by incubation with CuSO4. Oxidation of lipoproteins was accompanied with the increment of thiobarbituric acid-reactive substances (TBARS) and denature of apolipoprotein. Ligands on LDL for beta(2)-GPI seemed to be intermediate oxidative derivatives which were extractable into the chloroform phase by Bligh and Dyer's extraction, but not MDA. Further, immune responses against beta(2)-GPI, as an anti-atherogenic protein, were demonstrated to induce atherogenic effect in in vitro oxLDL uptake by macrophages.

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  • Anti-beta(2)-glycoprotein I antibodies Invited

    A Tsutsumi, K Ichikawa, E Matsuura, T Koike

    LUPUS   7   S98 - S102   1998

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    The relationship between presence of anti-beta(2)-glycoprotein I autoantibodies (a beta(2)-GPI) and history of thrombosis is now widely known. However, differences in the methodology of a beta(2)-GPI detection have made the comparison of data from different laboratories extremely difficult. We discuss the significance of a beta(2)-GPI of the IgG, IgM and IgA isotypes, and our approach to developing an easier and mon reproducible method for the detection of this autoantibody. In addition, we present data that shows that commercially available enzyme immunoassay plates differ regarding detectability of a beta(2)-GPI. Since the clinical significance of this heterogeneity is presently unclear, the set-up of the detection systems and interpretation of data need great care.

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  • Epitopes on beta 2-GPI recognized by anticardiolipin antibodies

    T Koike, K Ichikawa, H Kasahara, T Atsumi, A Tsutsumi, E Matsuura

    LUPUS   7   S14 - S17   1998

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    Anticardiolipin antibodies (aCL) found in sera from patients with antiphospholipid syndrome recognize a cryptic epitope that appears on the beta 2-glycoprotein I (beta 2-GPI) molecule when beta 2-GPI interacts with a lipid membrane composed of negatively charged phospholipid or when beta 2-GPI is adsorbed on a polyoxygenated polystyrene plate. A homology based model of beta 2-GPI was constructed based on the NMR coordinates of sushi domains of human factor H. The conformation was like a cylinder consisting of five domains, its IV and V domains being glued by electrostatic interaction. We used phage-displayed random peptide libraries to search the epitopes of human aCL. Structures similar to consensus sequences selected by a biopanning method was found on domain IV of beta 2-GPI.

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  • 抗リン脂質抗体症候群における新展開 Invited

    松浦栄次, 小池隆夫

    炎症と免疫   6   76 - 82   1998

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  • 抗カルジオリピン抗体と血栓形成 Invited

    松浦栄次, 北川浩彦, 保田立二, 小池隆夫

    臨床免疫   30   239 - 245   1998

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  • 自己免疫疾患の病態と治療.1.自己免疫疾患の病態−最近の知見から−.3)抗リン脂質抗体症候群 Invited

    市川健司, 堤 明人, 渥美達也, 松浦栄次, 小池隆夫

    日本内科学会雑誌   87   1729 - 1734   1998

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  • Detection of peptides recognized by anticardiolipin antibodies using phage displayed random peptide library.

    H Kasahara, K Ichikawa, A Tsutsumi, E Matsuura, S Kobayashi, T Koike

    ARTHRITIS AND RHEUMATISM   40 ( 9 )   430 - 430   1997.9

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  • Antibodies to beta(2)-glycoprotein I in patients with systemic lupus erythematosus: Reply Reviewed

    A Tsutsumi, E Matsuura, K Ichikawa, T Koike

    ARTHRITIS AND RHEUMATISM   40 ( 7 )   1366 - 1367   1997.7

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  • Immunologic characterization and functional properties of murine antibodies raised against deleted mutants of human beta(2)-glycoprotein I Reviewed

    J George, M Blank, B Gilburd, M Hojnik, B Shenkman, Tamarin, I, D Varon, E Matsuura, T Koike, Y Shoenfeld

    INTERNATIONAL IMMUNOLOGY   9 ( 6 )   913 - 921   1997.6

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    beta(2)-Glycoprotein I (beta(2)GPI) is a 50 kDa molecule proposed as a principal target of 'autoimmune' antiphospholipid antibodies (aPL). We have used deleted mutants (DM) representing different domains of beta(2)GPI (I-IV, IV-V and V) for immunization of naive mice and studied the characteristics of the respective murine IgG preparations in comparison with affinity-purified IgG from two patients with primary antiphospholipid syndrome. Immunization with beta(2)GPI and with the DM produced anti-beta(2)GPI antibodies, part of which reacted with negatively charged phospholipids (PL), whereas reactivity with cardiolipin was evident only in the IgG from mice immunized with beta(2)GPI. These results are consistent with the presumption that aPL are induced following the in vivo association of beta(2)GPI (used for immunization) with resident negatively charged PL. Accordingly, DM which either lack the PL binding site or aPL attachment locus did not elicit, upon immunization, antibodies reactive with PL. Further, murine anti-beta(2)GPI IgG and human 'autoimmune' aPL were similar, albeit not identical, in terms of DM requirement for PL binding and charge dependency. Murine antibodies and human aPL, regardless of their binding characteristics, were found to bind significantly to platelets upon their activation with thrombin and to promote platelet activation, The results of the current study emphasize the dissimilarities between human 'autoimmune' aPL and murine anti-beta(2)GPI. Thus, anti-beta(2)GPI antibodies to different DM as well as human aPL are capable of binding and activating human platelets provided beta(2)GPI is present.

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  • Inhibitory effect of beta 2-glycoprotein I on the anticoagulant activity of activated protein C, and its modulation by anti-beta 2-glycoprotein I monoclonal antibodies

    H Urano, H Takeya, T Mori, EC Gabazza, E Matsuura, T Koike, K Suzuki

    THROMBOSIS AND HAEMOSTASIS   P2199 - P2199   1997.6

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  • Anti-beta 2-glycoprotein I antibody and lupus anticoagulant in patients with recurrent pregnancy loss

    M Ogasawara, T Aoyama, K Katano, E Matsuura, K Aoki

    THROMBOSIS AND HAEMOSTASIS   P1345 - P1345   1997.6

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  • Anti-beta 2-glycoprotein I monoclonal antibodies with lupus anticoagulant-like activity enhance the beta 2GPI binding to phospholipids

    H Takeya, EC Gabazza, E Matsuura, T Koike, K Suzuki

    THROMBOSIS AND HAEMOSTASIS   OC687 - OC687   1997.6

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  • Oxidized low-density lipoprotein (Ox-LDL) but not LDL aggravates the manifestations of experimental antiphospholipid syndrome (APS) Reviewed

    J George, M Blank, M Hojnik, E BarMeir, T Koike, E Matsuura, M Lorber, M Aviram, Y Shoenfeld

    CLINICAL AND EXPERIMENTAL IMMUNOLOGY   108 ( 2 )   227 - 233   1997.5

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    Ox-LDL is thought to play a major role in atherogenesis. The mechanisms mediating the deleterious influences of Ox-LDL include foam cell formation and cell cytotoxicity. The production of anti-Ox-LDL antibodies results in the formation of immune complexes which are taken up at enhanced rate by macrophages, leading to foam cell formation. APS is characterized by repeated venous and arterial thromboembolic phenomena, recurrent fetal loss and thrombocytopenia, associated with the presence of antibodies to negatively charged phospholipids (aPL) (i.e. cardiolipin, phosphatidylserine). Phospholipids bear structural resemblance to LDL, and several studies have indeed proved that aPL display cross-reactivity with anti-Ox-LDL antibodies. In this study we assessed the capacity of oxidized and native forms of LDL to aggravate the clinical picture of experimentally induced APS in naive mice. Mice were actively immunized intradermally with anticardiolipin antibodies and developed a clinical picture resembling APS in humans. Subsequently, the mice were infused with either Ox-LDL, native LDL or PBS, and similar regimens were applied to controls. APS mice infused with Ox-LDL were found to exhibit a significantly more severe form of the disease in comparison with native LDL- and PBS-infused mice, expressed by lower platelet counts (261 000/mm(3), 535 000/mm(3) and 455 000/mm(3), respectively), longer activated partial thromboplastin time (aPTT) (99 +/- 12 s, 63 +/- s s and 74 +/- 8 s respectively) and higher fetal resorption rates (72.7%, 34.4% and 32.6%, respectively). The results of this study show that Ox-LDL, compared with native LDL, aggravates the clinical manifestations of experimental APS and suggest that cross-reactivity of Ox-LDL with phospholipids may provide a pathogenic explanation for this effect.

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  • Anti-beta 2-glycoprotein I (beta 2GPI) monoclonal antibodies with lupus anticoagulant-like activity enhance the beta 2GPI binding to phospholipids Reviewed

    H Takeya, T Mori, EC Gabazza, K Kuroda, H Deguchi, E Matsuura, K Ichikawa, T Koike, K Suzuki

    JOURNAL OF CLINICAL INVESTIGATION   99 ( 9 )   2260 - 2268   1997.5

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    beta 2-Glycoprotein I (beta 2GPI), a plasma glycoprotein with phospholipid-binding property, is known to be the actual target antigen for autoimmune type anticardiolipin antibodies (aCLs), Certain groups of aCLs (anti-beta GPI antibodies) exert lupus anticoagulant (LA) activity and perturb the function of vascular endothelial cells, This investigation aimed at highlighting some insights into the molecular basis by which aCLs exert their biological effects by using anti-beta 2GPI mAbs with well-characterized epitopes from mice and from patients with antiphospholipid syndrome. Anti-beta 2GPI mAbs directed against the third domain (Cof-20 and Cof-22) and fourth domain (Cof-21, EY1C8, and EY2C9) of beta 2GPI inhibited the thrombin generation induced by Russell's viper venom in diluted plasma and that induced by the prothrombinase complex reconstituted with purified clotting factors, This anticoagulant activity was abrogated in the presence of an excess amount of phospholipids, thus resembling the LA activity, In stark contrast, anti-beta 2GPI mAbs directed against the fifth domain and the carboxyterminal region of the fourth domain showed no LA-like activity. These findings suggest that the LA activity of anti-beta 2GPi antibodies depends on their epitope specificity. Experiments carried out to clarify the mechanism of the LA activity showed that anti-beta 2GPI mAbs with LA-like activity, but not those without this effect, enhance the beta 2GPI binding to phospholipids. In addition, the F(ab')(2) fragment, but not the Fab' fragment, of the anti-beta 2GPI mAbs was found to enhance the LA activity and the beta 2GPI binding to phospholipids, suggesting that anti-beta 2GPI antibodies induce formation of multiple complexes of beta 2GPI on the surface of phospholipids because of their bivalent property. This clustering of P2GPI molecules induced by anti-beta 2GPI antibodies, probably because of their multivalent property and epitope specificity, might hinder the lateral mobility and activation of clotting factors on the surface of phospholipids and thus exert LA activity, Clustering of beta 2GPI molecules may also explain the molecular mechanism by which anti-beta 2GPI antibodies alter the function of leukocytes and endothelial cells. The well-documented heterogeneous LA activity of aCLs (anti-beta 2GPI antibodies) may also be explained by their epitope specificity.

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  • beta(2)-glycoprotein I and antiphospholipid syndrome Invited

    T Koike, E Matsuura

    ISRAEL JOURNAL OF MEDICAL SCIENCES   33 ( 4 )   225 - 238   1997.4

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  • Involvement of beta(2)-glycoprotein I and anticardiolipin antibodies in oxidatively modified low-density lipoprotein uptake by macrophages Reviewed

    Y Hasunuma, E Matsuura, Z Makita, T Katahira, S Nishi, T Koike

    CLINICAL AND EXPERIMENTAL IMMUNOLOGY   107 ( 3 )   569 - 573   1997.3

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    Anticardiolipin antibodies (aCL) in the sera of patients with antiphospholipid syndrome (APS) recognize an altered structure of beta 2-glycoprotein I (beta 2-GPI) interacting with solid-phase negatively charged phospholipids. beta(2)-GPI bound to Cu2+-oxidized plasma lipoproteins, i.e. oxidized very low-density lipoprotein (oxVLDL), oxidized low-density lipoprotein (oxLDL), or oxidized high-density lipoprotein (oxHDL). beta 2-GPI inhibited in vitro uptake, i.e. cell surface binding, cellular association, and proteolytic degradation of oxLDL by murine macrophage J774A.1 cells. The binding of oxLDL to the macrophages was inhibited by the addition of polyinosinic acid (poly (I)), a competitor of the scavenger receptor, but not by another polyanionic acid, polycytidylic acid (poly (C)). Conversely, the binding of oxLDL was significantly increased by the simultaneous addition of human beta(2)-GPI and monoclonal aCL derived from NZW x BXSB F-1 (WE F-1) mice, an animal model of APS, or anti-beta(2)-GPI antibodies from BALB/c mice immunized with human beta(2)-GPI. These findings indicate that beta(2)-GPI may be an antiatherogenic protein and that the autoimmune response against beta(2)-GPI may have a role in the development of atherosclerosis in APS.

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  • DNA-alginate complex recognized by autoantibodies against DNA Reviewed

    H Kitamura, E Matsuura, A Nagata, N Sakairi, S Tokura, N Nishi

    INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES   20 ( 1 )   75 - 77   1997.2

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    Double-stranded DNA was effectively complexed with alginic acid and immobilized on a surface of polystyrene microtiter plate. Dose-dependent binding of anti-DNA autoantibodies was finely observed to the solid phase DNA-alginate complex in enzyme-linked immunosorbent assay (ELISA). In contrast, non-specific binding of antibodies to alginate was scarcely detected ratheer than to poly-L-lysine. These results show an availability of the solid phase DNA-alginate complex as an antigen in ELISA for detection of anti-DNA antibodies. (C) 1997 Elsevier Science B.V.

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  • Structure and function of the recombinant fifth domain of human beta(2)-glycoprotein I: Effects of specific cleavage between Lys77 and Thr78 Reviewed

    Y Hagihara, K Enjyoji, T Omasa, Y Katakura, K Suga, M Igarashi, E Matsuura, H Kato, T Yoshimura, Y Goto

    JOURNAL OF BIOCHEMISTRY   121 ( 1 )   128 - 137   1997.1

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    In order to elucidate the mechanism of binding of beta(2)-glycoprotein I (beta(2)-GPI) to cardiolipin (CL), we constructed a high-level expression system for the C-terminal domain (Domain V) of beta(2)-GPI using Pichia pastoris and studied its conformation and liposome-binding activity. Purified Domain V was found to have the native disulfide bonds. It had a compactly folded conformation, judging from the circular dichroism spectrum, and exhibited a cooperative unfolding transition induced by pH or urea. Also, it bound liposomes containing CL. Commercially available human beta(2)-GPI is known to be selectively cleaved between Lys 317 and Thr 318. We found that bovine factor Xa weakly but specifically cleaves the corresponding site of recombinant Domain V, i.e., the peptide bond between Lys 77 and Thr 78. The conformation of the ''nicked'' Domain V, which was cleaved at this site, was examined by circular dichroism and fluorescence measurements, and concluded to be similar to that of the intact protein. The stability of the nicked Domain V to urea was slightly lower than that of the intact protein. Although both Domains V bound to liposomes containing CL, the affinity of the nicked Domain V was greatly reduced in comparison with the intact protein, indicating that the cleavage of the peptide bond between Lys 77 and Thr 78 controls the binding to CL. In addition, analysis of the fluorescence spectra in the presence and absence of CL liposomes indicated that Trp 76 is involved in the binding site. These results suggest that the region including Trp 76, Lys 77, and Thr 78 has a critical role in binding to CL.

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  • β2-グリコプロテインIと抗リン脂質抗体 Invited

    松浦栄次, 北川浩彦, 小池隆夫

    内科   80   34 - 38   1997

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  • 抗カルジオリピン抗体 Invited

    松浦栄次, 北川浩彦, 小池隆夫

    日本アフェレシス学会学会誌   16   353 - 360   1997

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  • Conformational change of DNA on the formation of DNA-anti-DNA antibody immune complex. Reviewed

    Kitamura H, Shindo K, Sasabe M, Matsuura E, Sakairi N, Nishi N

    Nucleic Acids Symp Ser   37   145 - 146   1997

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  • Anti beta 2glycoprotein I antibodies and lupus anticoagulant in patients with recurrent pregnancy loss: Prevalence and clinical significance Reviewed

    M Ogasawara, K Aoki, E Matsuura, H Sasa, Y Yagami

    LUPUS   5 ( 6 )   587 - 592   1996.12

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    Anticardiolipin antibodies (aCL) were found to recognize beta 2glycoprotein I (beta 2GPI) structure altered by its interaction with an oxygen modified solid phase surface by gamma-ray radiation. Lupus anticoagulant (LA) has been reported to comprise anti prothrombin antibodies, anti factor X antibodies and anti beta 2GPI antibodies. The present study focuses on the possible association between antibodies against the altered beta 2GPI structure (anti beta 2GPI antibodies) and LA in patients with recurrent pregnancy loss. Moreover, the clinical significance of both subgroups of so-called antiphospholipid antibodies were investigated to cast light on the controversy of whether aCL and LA are risk factors for pregnancy losses.
    One hundred and ninety five women with a history of two or more unexplained consecutive miscarriages and 100 control pregnant women were tested. Lupus anticoagulant was detected by the dilute phospholipid activated partial thromboplastin time. Anti beta 2GPI antibodies were measured by the ELISA method using commercially oxygenated microtiter plates.
    Twenty two (11.3%) and 19 (9.7%) of the 195 recurrent aborters were, respectively, positive for LA and anti beta 2GPI antibodies. Seven (3.6%) of the aborters had both of them. None of the control pregnant women had LA. Three of the control pregnant women had anti beta 2GPI antibodies.
    Nine (40.9%) of 22 aborters with positive-LA had a history of miscarriages in the second trimester as compared to 8 (4.6%) of 173 aborters with negative-LA (P = 0.000007, Odds ratio = 14.3). None of the 12 aborters with anti beta 2GPI antibodies but no LA had a history of second trimester-fetal loss.
    These results support the hypothesis that aCL and LA define two distinct but partly related populations and that aCL include two subtypes of antibodies, with and without LA activity. LA and anti beta 2GPI antibodies appear to be associated with pregnancy loss, with LA being linked not only to abortions in the first trimester but also to miscarriages in the second trimester.

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  • Anti-beta(2)-glycoprotein I antibody: Specificity and clinical significance Invited

    T Koike, E Matsuura

    LUPUS   5 ( 5 )   378 - 380   1996.10

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    Cardiolipin binding of IgG-class anticardiolipin antibody (aCL) depends on the existence of beta(2)-glycoprotein I (beta(2)-GPI). We developed an EIA system that enables detection of antibodies against beta(2)-GPI, without the presence of cardiolipin. This system involves use of irradiated polystyrene plates, in which oxygen atoms are introduced onto the surfaces of the plates. beta(2)-GPI bound to the surface of these plates is assumed to undergo a conformational change that exposes normally cryptic epitopes. Anti-beta(2)-GPI antibody measured using this EIA system showed good correlation with aCL measured by conventional EIA methods and may prove useful in evaluating the risk of thrombosis and monitoring the clinical course in patients with SLE. Utilizing this ELA system and beta(2)-GPI-deleted mutants, we found that the fourth domain of beta(2)-GPI is involved in expression of one of the cryptic epitopes recognized by aCL. We also found that oxidized LDL are sequentially targeted by beta(2)-GPI and aCL.

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  • Antibodies to beta 2-glycoprotein I and clinical manifestations in patients with systemic lupus erythematosus Reviewed

    A Tsutsumi, E Matsuura, K Ichikawa, A Fujisaku, M Mukai, S Kobayashi, T Koike

    ARTHRITIS AND RHEUMATISM   39 ( 9 )   1466 - 1474   1996.9

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    Objective. To investigate whether anticardiolipin antibodies (aCL) in patients with systemic lupus erythematosus (SLE) bind to beta(2)-glycoprotein I (beta(2)GPI), and to search for a relationship between the presence of IgG and/or IgM anti-beta(2)GPI antibody and clinical manifestations in SLE patients.
    Methods. IgG and IgM anti-beta(2)GPI in 308 Japanese SLE patients were measured using phospholipid-independent enzyme immunoassays. Relationships to clinical histories and to various laboratory data were examined.
    Results. The values of anti-beta(2)GPI and aCL, as measured by conventional enzyme immunoassay, showed a strong correlation, but the anti-beta(2)GPI assay was more useful in distinguishing beta(2)GPI-dependent aCL from beta(2)GPI-independent a CL. The presence of IgG anti-beta(2)GPI was associated with an increased frequency of a history of thrombosis. Comparisons of various laboratory data suggested that the titer of anti-beta(2)GPI may fluctuate with disease activity.
    Conclusion. The results suggest that pathogenic aCL is directed against structurally altered beta(2)GPI and that enzyme immunoassay for anti-beta(2)GPI may prove useful in evaluating the risk of thrombosis and monitoring the clinical course in patients with SLE.

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  • Anticardiolipin antibodies and beta(2)-glycoprotein I Reviewed

    T Koike, E Matsuura

    LUPUS   5 ( 2 )   156 - 157   1996.4

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  • Human beta(2) glycoprotein I as an anticardiolipin cofactor determined using deleted mutants expressed by a baculovirus system Reviewed

    M Igarashi, E Matsuura, Y Igarashi, H Nagae, K Ichikawa, DA Triplett, T Koike

    BLOOD   87 ( 8 )   3262 - 3270   1996.4

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    beta(2)-Glycoprotein I (beta(2)-GPI) consists of five repeats of a homologous domain, We designed a series of human beta(2)-GPI mutant genes, ie, three mutant genes lacking the domain(s) present in the NH2-terminal region and two of those present in the COOH-terminal region. These mutant genes were expressed in Spodoptera frugiperda insect cells (Sf9) infected with recombinant baculoviruses and the mutant proteins were secreted into the culture medium. The molecular mass of the purified mutant proteins, estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, was fairly consistent with the size calculated from their nucleotide sequences. Binding of beta(2)-GPI to solid-phase cardiolipin (CL) was diminished by the deletion of the fifth domain (domain V) from its complete structure. Thus, the phospholipid binding site of beta(2)-GPI is located on its domain V. Monoclonal anti-CL antibodies (aCL) derived either from NZW x BXSB (WB) F1 mice or from patients with antiphospholipid syndrome bound directly to the domain V-deleted mutant protein (DI-IV) absorbed not only on an oxygenated but also on a plain polystyrene surface. We conclude from this study that the epitope for aCL is exposed on a comformationally changed structure of beta(2)-GPI by interacting with negatively charged phospholipid or on the mutant protein, DI-IV. (C) 1996 by The American Society of Hematology.

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  • beta(2)-Glycoprotein I-dependent anticardiolipin antibodies as a predictor of adverse pregnancy outcomes in healthy pregnant women Reviewed

    K Katano, K Aoki, H Sasa, M Ogasawara, E Matsuura, Y Yagami

    HUMAN REPRODUCTION   11 ( 3 )   509 - 512   1996.3

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:OXFORD UNIV PRESS UNITED KINGDOM  

    Our aim was to elucidate prospectively whether beta(2)-glycoprotein I-dependent anticardiolipin antibodies (beta(2)GPI-dependent aCL; autoimmune type) can predict an adverse pregnancy outcome in healthy pregnant women and whether beta(2)GPI-dependent aCL should be applied for routine screening of the pregnant population. A prospective cohort study was performed on 1600 healthy pregnant women from whom blood samples were obtained at about week 10 of gestation. We used a modified enzyme-linked immunosorbent assay with which to divide the subjects into three study groups: beta(2)GPI-dependent aCL positive, beta(2)GPI-independent aCL positive and aCL negative. Their subsequent pregnancy outcomes were ascertained and the three study groups were compared statistically for the following poor pregnancy outcomes: intrauterine fetal death (IUFD) after 12 gestational weeks, intrauterine growth retardation (IUGR) and pre-eclampsia. The total number of patients eligible for this study was 1125. The prevalence of beta(2)GPI-dependent aCL positive was eight (0.7%), beta(2)GPI-independent aCL positive was 17 (1.5%) and aCL negative was 1100 (97.8%). beta(2)GPI-dependent aCL positivity was significantly associated with poor pregnancy outcome: 25.0% of beta(2)GPI-dependent aCL-positive and 0.5% of aCL-negative patients experienced IUFD [relative risk 52.4; 95% confidence interval (CI), 12.7-216.3; P = 0.0009]; 37.5% of beta(2)GPI-dependent aCL-positive and 2.9% of aCL-negative patients experienced IUGR (relative risk 18.4; 95% CI, 4.6-74.0; P = 0.001); and 50.0% of beta(2)GPI-dependent aCL-positive and 4.0% aCL-negative patients experienced pre-eclampsia (relative risk 22.1; 95% CI, 5.7-85.7; P = 0.0002). In contrast, beta(2)GPI-independent aCL did not show any significant association with such adverse pregnancy outcomes, beta(2)GPI-dependent aCL are significantly highly associated with adverse pregnancy outcomes in healthy pregnant women and can be used for prediction purposes, whereas beta(2)GPI-independent aCL cannot. Our results suggest that routine screening for beta(2)GPI-dependent aCL should be introduced for the general pregnant population.

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  • Phospholipid-dependent anti-beta(2)-glycoprotein I (beta(2)-GPI) antibodies and antiphospholipid syndrome Reviewed

    J Kaburaki, M Kuwana, M Yamamoto, S Kawai, E Matsuura, Y Ikeda

    INTERNAL MEDICINE   35 ( 2 )   105 - 110   1996.2

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    A portion of anticardiolipin antibodies is defined as phospholipid-dependent anti-beta(2)-glycoprotein I(beta(2)-GPI) antibodies and recognizes the conformationally altered beta(2)-GPI which interacts with anionic phospholipids. We studied the clinical significance of IgG phospholipid-dependent anti-beta(2)-GPI antibodies in patients with antiphospholipid syndrome (APS), The subjects consisted of 60 APS patients, IgG phospholipid-dependent anti-beta(2)-GPI antibodies were detected by ELISA in 32 of the 60 patients (53%). Significantly higher incidences of prolonged APTT and lupus anticoagulants were found in patients with these anti-beta(2)-GPI antibodies, Moreover, significantly lower incidences of malar rash, serositis, LE cell preparation and anti-Sm antibodies were found in patients with these anti-beta(2)-GPI antibodies. It was found that 88% of the patients with these anti-beta(2)-GPI antibodies satisfied less than five of the revised criteria items for the classification of SLE, These findings indicate the clinical characteristics of APS patients with IgG phospholipid-dependent anti-beta(2)-GPI antibodies.

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  • Participation of alpha(IIb)beta(3) in platelet microparticle generation by collagen plus thrombin Reviewed

    S Nomura, Y Komiyama, E Matsuura, GL Xie, K Katsura, T Miyake, Y Miyazaki, H Kagawa, T Koike, S Fukuhara

    HAEMOSTASIS   26 ( 1 )   31 - 37   1996.1

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    We investigated the role of alpha(IIb)beta(3) in microparticle generation by normal and thrombasthenic platelets stimulated with collagen plus thrombin. Microparticle generation by normal platelets was scarcely inhibited by monoclonal antibodies for glycoprotein Ib and glycoprotein IX. Although one monoclonal anti-alpha(IIb)beta(3) antibody (NNKY1-32) partly inhibited microparticle generation, 3 other monoclonal anti-alpha(IIb)beta(3) antibodies had little effect. However, the combination of 4 monoclonal anti-alpha(IIb)beta(3) antibodies or treatment with a polyclonal anti-alpha(IIb)beta(3) antibody significantly inhibited microparticle generation (p &lt; 0.05). Microparticle generation by thrombasthenic platelets also occurred after stimulation with collagen plus thrombin, although at a significantly lower level compared with normal platelets. Monoclonal antibodies for resting alpha(IIb)beta(3), P-selectin, activated alpha(IIb)beta(3) and beta(2)-glycoprotein I bound to microparticles from healthy platelets. In contrast, only a monoclonal antibody for beta(2)-glycoprotein I bound to thrombasthenic microparticles. These results suggest that microparticle generation by collagen plus thrombin occurs via two different mechanisms which are dependent and independent of alpha(IIb)beta(3), respectively. The alpha(IIb)beta(3)-dependent mechanism appears to require activation of alpha(IIb)beta(3).

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  • 抗リン脂質抗体の多様性 Invited

    松浦栄次, 西 信三, 小池隆夫

    臨床免疫   28   1566 - 1575   1996

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  • 抗リン脂質抗体のエピトープマッピング Invited

    松浦栄次, 小池隆夫

    医学の歩み   176   325 - 329   1996

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  • 抗カルジオリピン抗体の測定法 Invited

    松浦栄次, 小池隆夫

    臨床検査   40   141 - 145   1996

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  • β2-glycoprotein I-dependent anticardiolipin antibodies as a predictor of adverse pregnancy outcomes in a general pregnant population

    Katano K., Aoki K., Sasa H., Ogasawara M., Matsuura E., Yagami Y.

    Nihon Seishokumeneki Gakkai Zassi   10   97 - 98   1996

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    Language:English   Publisher:Japan Society for Immunology of Reproduction  

    DOI: 10.14847/jsirib1987.10.97

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  • PULMONARY SURFACTANT PROTEIN-D IN SERA AND BRONCHOALVEOLAR LAVAGE FLUIDS Reviewed

    Y HONDA, Y KUROKI, E MATSUURA, H NAGAE, H TAKAHASHI, T AKINO, S ABE

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE   152 ( 6 )   1860 - 1866   1995.12

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    Pulmonary surfactant protein D (SP-D) is a hydrophilic glycoprotein with a reduced molecular mass of 43 kDa and a member of the C-type lectin superfamily, along with mannose-binding proteins and surfactant protein A (SP-A). We have recently prepared monoclonal antibodies against human SP-D and developed an enzyme-linked immunosorbent assay (ELISA). In this study, the levels of SP-D in sera and bronchoalveolar lavage (BAL) fluids of patients with lung diseases were determined by ELISA, using human recombinant SP-D as a standard. We demonstrated that the concentrations of SP-D in sera are prominently increased in patients with idiopathic pulmonary fibrosis (IPF), interstitial pneumonia with collagen disease (IPCD), and pulmonary alveolar proteinosis (PAP). Patients with IPF, IPCD, and PAP exhibited levels of serum SP-D 5.1-fold, 7.2-fold, and 7.0-fold, respectively, of those in healthy volunteers; 91.5% of the patients with IPF, 81.3% with IPCD, and 100% with PAP exhibited serum SP-D levels that exceeded the cut-off value (mean + 2 SD of control value). Serum SP-D levels appeared to reflect the disease activity of IPF and IPCD and the disease severity of PAP. High levels of SP-D in BAL fluids were shown in patients with PAP, but not with IPF and IPCD. We conclude that measurement of SP-D in sera can provide an easily identifiable and useful clinical marker for the diagnosis of IPF, IPCD, and PAP, and can predict the disease activity of IPF and IPCD and the disease severity of PAP.

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  • Clinical significance of phospholipid-dependent anti-beta(2)-glycoprotein I (beta(2)-GPI) antibodies in systemic lupus erythematosus Reviewed

    J Kaburaki, M Kuwana, M Yamamoto, S Kawai, E Matsuura, Y Ikeda

    LUPUS   4 ( 6 )   472 - 476   1995.12

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    We investigated the clinical significance of IgG phospholipid-dependent anti-beta(2)-glycoprotein I (beta(2)-GPI) antibodies in patients with SLE. The study population consisted of 140 patients with SLE. Sera were examined for IgG phospholipid-dependent anti-beta(2)-GPI antibodies by ELISA. IgG phospholipid-dependent anti-beta(2)-GPI antibodies were detected in 21 of 140 patients (15%) and remained positive from 4 to 98 months. Significantly higher incidences of thrombosis, intrauterine fetal loss, thrombocytopenia, patients with antiphospholipid syndrome (APS), prolonged APTT, BFP-STS and hemolytic anemia were found in SLE patients with phospholipid-dependent anti-beta(2)-GPI antibodies. Moreover, significantly lower incidences of malar rash and serositis were found in SLE patients with phospholipid-dependent anti-beta(2)-GPI antibodies, and the majority of these patients satisfied four or five of the revised criteria items of the American Rheumatism Association. These differences were not observed when we compared clinical manifestations in anticardiolipin antibody-positive patients with those in antibody-negative patients by conventional ELISA. These results indicated that SLE patients with IgG phospholipid-dependent anti-beta(2)-GPI antibodies show an unique form of SLE.

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  • AUTOIMMUNE-PRONE (NZWXBXSB)F-1 (W/BF1) MICE ESCAPE SEVERE THROMBOCYTOPENIA AFTER TREATMENT WITH DEOXYSPERGUALIN, AN IMMUNOSUPPRESSANT Reviewed

    K NEMOTO, T MAE, K SAIGA, E MATSUURA, T KOIKE

    BRITISH JOURNAL OF HAEMATOLOGY   91 ( 3 )   691 - 696   1995.11

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    Male (NZW x BXSB)F-1 mice spontaneously develop a disease which closely resembles human systemic autoimmune disease, involving idiopathic thrombocytopenic purpura and glomerulonephritis. We investigated whether autoimmune thrombocytopenia in the mice responded to deoxyspergualin, as immunosuppressant. Deoxyspergualin completely prevented the development of thrombocytopenia and suppressed the increase in circulating autoantibodies against platelets. This agent also ameliorated lupus nephritis. These findings suggest that deoxyspergualin may be effective in the prevention of idiopathic thrombocytopenic purpura.

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  • ANTICARDIOLIPIN ANTIBODIES IN PATIENTS WITH PREGNANCY LOSS INDUCE FACTOR XA PRODUCTION IN THE PRESENCE OF BETA-2-GLYCOPROTEIN-I Reviewed

    M OGASAWARA, K AOKI, E MATSUURA, M KUNIMATSU, OHKUBO, I, M GALLI, M SASAKI, Y YAGAMI

    AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY   34 ( 5 )   269 - 273   1995.11

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:MUNKSGAARD INT PUBL LTD  

    PROBLEM: Anticardiolipin antibodies (aCL) are commonly associated with recurrent pregnancy loss, though the mechanism is uncertain. Some investigators have indicated that aCL may be directed at a complex made up of cardiolipin and a blood anticoagulant, beta 2-glycoprotein I (beta 2GPI). We therefore investigated the effects of beta 2GPI-dependent aCL IgG enriched fractions, isolated from sera of patients with pregnancy losses, on blood coagulation.
    METHOD: beta 2GPI-dependent aCL were prepared from sera of three women with second trimester pregnancy losses, by cardiolipin affinity column chromography, following by anti-beta 2GPI affinity column chromatography. The effects of beta 2GPI and beta 2GPI-dependent aCL on the activation of factor X in vitro were examined.
    RESULTS: beta 2GP1 inhibited the activation of factor X and beta 2GPI-dependent aCL blocked this inhibitory effect in a dose dependent manner.
    CONCLUSION: These results imply the possibility of beta 2GPI-dependent aCL induce hypercoagulation or thrombus by blocking the inhibitory effect of beta 2GPI on activation of factor X, which may result in pregnancy loss.

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  • SYSTEMIC LUPUS-ERYTHEMATOSUS AND ANTICARDIOLIPIN ANTIBODIES IN KLINEFELTERS-SYNDROME Reviewed

    S MIYAGAWA, E MATSUURA, W KITAMURA, H OHNO, K KICHIKAWA, H UCHIDA, T SHIRAI, S OKAMOTO

    LUPUS   4 ( 3 )   236 - 238   1995.6

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    A case report of Klinefelter's syndrome is presented that shows features of systemic lupus erythematosus, arteriographically-proven peripheral artery occlusion with leg ulcers, multiple cerebral infarcts and persistent elevations of anticardiolipin antibodies.

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  • ANTIGENIC SPECIFICITY OF THE ANTICARDIOLIPIN ANTIBODIES Reviewed

    T KOIKE, A TSUTSUMI, K ICHIKAWA, E MATSUURA

    BLOOD   85 ( 8 )   2277 - 2278   1995.4

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  • CLINICAL-SIGNIFICANCE OF BETA(2)-GLYCOPROTEIN I-DEPENDENT ANTICARDIOLIPIN ANTIBODIES IN THE REPRODUCTIVE AUTOIMMUNE FAILURE SYNDROME - CORRELATION WITH CONVENTIONAL ANTIPHOSPHOLIPID ANTIBODY DETECTION SYSTEMS Reviewed

    K AOKI, AB DUDKIEWICZ, E MATSUURA, M NOVOTNY, G KABERLEIN, N GLEICHER

    AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY   172 ( 3 )   926 - 931   1995.3

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:MOSBY-YEAR BOOK INC  

    OBJECTIVE: Our purpose was to determine whether beta(2)-glycoprotein I-dependent anticardiolipin antibodies may represent a superior marker of reproductive risk than do conventional antiphospholipid antibodies.
    STUDY DESIGN: The incidence of beta(2)-glycoprotein I-dependent and beta(2)-glycoprotein I-independent anticardiolipin antibodies and of six conventional antiphospholipid antibodies was statistically compared between study groups with and without autoantibody-associated features of reproductive failure. Sera from 356 women were randomly selected from the frozen sera bank at the Center for Human Reproduction, Chicago. They included sera from 259 patients with autoantibody-associated features of reproductive failure such as unexplained infertility, endometriosis, and repeated pregnancy loss and 97 infertile controls. Autoantibody levels by a modified enzyme-linked immunosorbent assay for beta(2)-glycoprotein I-dependent and beta(2)-glycoprotein I-independent anticardiolipin antibodies and a standard enzyme-linked immunosorbent assay for anticardiolipin antibody and five other antiphospholipid antibodies were then compared,
    RESULTS: Patients demonstrated a significantly higher incidence of beta(2)-glycoprotein I-dependent anticardiolipin antibodies (5.4%) than did controls (0%) in a modified enzyme-linked immunosorbent assay (p = 0.01). No such difference was, however, noted for p,beta(2)-glycoprotein I-independent anticardiolipin antibodies or any one of six antiphospholipid antibodies. Two or more among six antiphospholipid antibodies, especially if involving anticardiolipin antibodies, antiphosphatidylserine and antiphosphatidylinositol, as assayed by standard enzyme-linked immunosorbent assay, were significantly more often (p = 0.02) positive in the patients (5.0%) than in the controls (0%). Moreover, positivity in two of those three antiphospholipid antibodies correlated in 59% of cases to positivity in the beta(2)-glycoprotein I-dependent anticardiolipin antibody.
    CONCLUSIONS: As a single test beta(2)-glycoprotein I-dependent anticardiolipin antibody appears to be superior to cofactor-independent anticardiolipin antibody or any other single conventional antiphospholipid antibody for the detection of autoantibody-associated conditions of reproductive failure. A broadly based panel of conventional antiphospholipid antibodies, especially if inclusive of anticardiolipid antibody, antiphosphatidylserine, and antiphosphatidylinositol, may, however, achieve similar results.

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  • DISEASE DISTRIBUTION OF BETA(2)-GLYCOPROTEIN I-DEPENDENT ANTICARDIOLIPIN ANTIBODIES IN RHEUMATIC DISEASES Invited

    J KABURAKI, M KUWANA, M YAMAMOTO, S KAWAI, E MATSUURA, Y IKEDA

    LUPUS   4   S27 - S31   1995.2

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    We investigated the clinical significance of IgG beta(2)-glycoprotein I (GPI)-dependent anticardiolipin antibodies (aCL) in rheumatic diseases. Three hundred and seventeen patients were entered. They consisted of 133 patients with SLE, 60 with RA, 45 with SSc, 37 with PM, 23 with overlap syndrome (overlap), and 19 with unclassified connective tissue disease (UCTD). IgG beta(2)-GPI-dependent aCL were examined by ELISA. While IgG beta(2)-GPI-dependent aCL were detected in 13% of patients with SLE, these aCL were positive in two patients with SSc, two with overlap and 14 with UCTD. A significant association between IgG beta(2)-GPI-dependent aCL and thrombosis was found. Clinical manifestations were studied in 32 patients with secondary APS based on SLE and 14 with primary APS (PAPS). Incidences of malar rash, arthritis, renal disorder, leucopenia, immunological disorders and hypocomplementemia were significantly less frequent in patients with PAPS. IgG beta(2)-GPI-dependent aCL were detected in all patients with PAPS and in 34% of secondary APS. This difference was significant. These data suggest that IgG beta(2)-dependent aCL are useful for identifying a subset in patients with APS.

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  • MOLECULAR STUDIES ON PHOSPHOLIPID-BINDING SITES AND CRYPTIC EPITOPES APPEARING ON BETA(2)-GLYCOPROTEIN-I STRUCTURE RECOGNIZED BY ANTICARDIOLIPIN ANTIBODIES Invited Reviewed

    E MATSUURA, M IGARASHI, Y IGARASHI, T KATAHIRA, H NAGAE, K ICHIKAWA, DA TRIPLETT, T KOIKE

    LUPUS   4 ( Supp 9-1 )   S13 - S17   1995.2

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  • RELATIONSHIP OF MICROPARTICLES WITH BETA(2)-GLYCOPROTEIN-I AND P-SELECTIN POSITIVITY TO ANTICARDIOLIPIN ANTIBODIES IN IMMUNE THROMBOCYTOPENIC PURPURA Reviewed

    S NOMURA, M YANABU, T MIYAKE, Y MIYAZAKI, H KIDO, H KAGAWA, S FUKUHARA, Y KOMIYAMA, E MATSUURA, T KOIKE

    ANNALS OF HEMATOLOGY   70 ( 1 )   25 - 30   1995.1

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    We investigated the association of beta(2)-glycoprotein I and P-selectin with platelet-derived microparticles in 48 patients with immune thrombocytopenic purpura and 20 normal controls using two-color flow cytometric analysis. In addition, anticardiolipin antibodies were detected by an enzyme-linked immunosorbent assay. Platelet microparticles from the patients showed a higher positivity for beta(2)-glycoprotein I than those from the normal controls (23.1+/-15.4% vs. 5.3+/-3.1%, p&lt;0.01), but this positivity was not related to the presence of platelet-associated IgG or to the severity of thrombocytopenia. In the 18 patients with more than 20% P-selectin-positive microparticles, beta(2)-glycoprotein I positivity was significantly higher than in the 30 patients with less than 20% P-selectin-positive microparticles (37.1+/-20.5% vs. 21.5+/-17.3%, p&lt;0.01). In addition, anticardiolipin antibodies were detected in eight patients, and they had a significantly higher level of beta(2)-glycoprotein I-positive microparticles than the patients without such antibodies (42.0+/-22.9% vs. 22.6+/-18.9%, p&lt;0.05). Our results suggest that anticardiolipin antibodies activate platelets in immune thrombocytopenic purpura and cause the generation of microparticles rich in beta(2)-glycoprotein I and P-selectin. These microparticles may then act to regulate coagulation abnormalities in patients with anticardiolipin antibodies.

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  • 抗リン脂質抗体症候群の病型とβ2-glycoprotein I Reviewed

    鏑木淳一, 桑名正隆, 山本美保子, 河合眞一, 松浦栄次, 池田康夫

    臨床血液   36   1170 - 1174   1995

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  • 抗β2-グリコプロテインI抗体 Invited

    松浦栄次, 小池隆夫

    Modern Physician   15   1599 - 1602   1995

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  • Phospholipid-dependent anti-β2-glycoprotein I autoantibodies

    Matsuura Eiji, Koike Takao

    Nihon Seishokumeneki Gakkai Zassi   9   19 - 20   1995

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    DOI: 10.14847/jsirib1987.9.19

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  • THE EFFECTS OF β2-GLYCOPROTEIN I AND β2-GLYCOPROTEIN I DEPENDENT ANTICARDIOLIPIN ANTIBODIES ON COAGULATION

    Ogasawara M., Sasa H., Aoki K., Matsuura E., Yagami Y.

    Nihon Seishokumeneki Gakkai Zassi   9   73 - 74   1995

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    DOI: 10.14847/jsirib1987.9.73

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  • BETA(2)-GLYCOPROTEIN-I REACTIVITY OF MONOCLONAL ANTICARDIOLIPIN ANTIBODIES FROM PATIENTS WITH THE ANTIPHOSPHOLIPID-SYNDROME Reviewed

    K ICHIKAWA, MA KHAMASHTA, T KOIKE, E MATSUURA, GRV HUGHES

    ARTHRITIS AND RHEUMATISM   37 ( 10 )   1453 - 1461   1994.10

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    Objective. To elucidate the specificity of anticardiolipin antibodies (aCL) from patients with the antiphospholipid syndrome (APS) to various phospholipids (PLs), DNA, and beta(2)-glycoprotein I (beta(2)-GPI).
    Methods. Five monoclonal aCL were established from peripheral blood lymphocytes of 3 patients with the APS. The reactivity of monoclonal aCL with various PLs, with DNA, and with beta(2)-GPI was examined by enzyme-linked immunosorbent assay (ELISA).
    Results. All of the monoclonal aCL bound to anionic PLs, only in the presence of beta(2)-GPI. Neither monoclonal aCL nor beta(2)-GPI bound to DNA. Monoclonal aCL bound to solid-phase beta(2)-GPI on polystyrene ELISA plates that had carboxyl groups on their surface, but did not react with solid-phase beta(2)-GPI on ordinary polystyrene plates. A mixture of beta(2)-GPI and CL inhibited the binding of monoclonal aCL to beta(2)-GPI, but CL or beta(2)-GPI alone did not.
    Conclusion. Monoclonal aCL may recognize a cryptic epitope, which appears as a result of beta(2)-GPI binding to anionic PLs or to polystyrene with carboxyl groups.

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  • BETA(2)-GLYCOPROTEIN-I-DEPENDENT AND BETA(2)-GLYCOPROTEIN-I-INDEPENDENT ANTICARDIOLIPIN ANTIBODIES IN HEALTHY PREGNANT-WOMEN Reviewed

    K AOKI, E MATSUURA, H SASA, Y YAGAMI, AB DUDKIEWICZ, N GLEICHER

    HUMAN REPRODUCTION   9 ( 10 )   1849 - 1851   1994.10

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:OXFORD UNIV PRESS UNITED KINGDOM  

    The purpose of this study was to determine the association between beta(2)-glycoprotein I (beta(2)GPI)-dependent anticardiolipin antibodies (aCL) and beta(2)GPI-independent aCL and their respective relevance to adverse pregnancy outcomes. Therefore, we prospectively studied 210 normal pregnant women, utilizing a modified enzyme-linked immunosorbent assay method for beta(2)GPI-dependent and -independent aCL. Seven of the 210 pregnant women (3.3%) demonstrated evidence for beta(2)GPI-independent immunoglobulin G (IgG)-aCL. Two patients, who also appeared positive for beta(2)GPI-dependent IgG-aCL, were proven to be false positives. Amongst the 210 patients, not one was thus positive for beta(2)GPI-dependent aCL. Women with beta(2)GPI-independent aCL demonstrated no adverse pregnancy outcomes. These results suggest that the presence of beta(2)GPI-independent aCL is not associated with the presence of beta(2)GPI-dependent aCL, though it may give rise to false positive results. Since the presence of beta(2)GPI-independent aCL does not appear to be associated with adverse pregnancy outcomes, beta(2)GPI-dependent assays may represent better markers of miscarriage risk.

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  • ENZYME-LINKED-IMMUNOSORBENT-ASSAY FOR HUMAN PULMONARY SURFACTANT PROTEIN-D Reviewed

    T INOUE, E MATSUURA, A NAGATA, Y OGASAWARA, A HATTORI, Y KUROKI, S FUJIMOTO, T AKINO

    JOURNAL OF IMMUNOLOGICAL METHODS   173 ( 2 )   157 - 164   1994.8

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    We developed a simple and sensitive enzyme-linked immunosorbent assay (ELISA) for human pulmonary surfactant protein D (SP-D). Human SP-D was purified from bronchoalveolar lavage fluids of patients with pulmonary alveolar proteinosis. Nine monoclonal antibodies (MAbs) were established from BALB/c mice immunized with the purified human SP-D. All MAbs were directed to either 43 kDa SP-D contained in lung lavage fluids of patients with pulmonary alveolar proteinosis or in amniotic fluids from healthy normal pregnancies. The ELISA is based on a sandwich method using two MAbs, 6B2 and 7C6. Cross-reactivity to human SP-A or rat SP-D was evaluated as below 0.6%. The recovery of different concentrations of SP-D ranged from 94.4% to 111.2%, and serial dilutions of amniotic fluids showed good linearity. SP-D concentrations in 21 amniotic fluids from normal pregnancies were measured by the ELISA. The mean concentration in amniotic fluids from pregnancies in the third trimester was significantly higher than that from earlier stages of gestation (p &lt; 0.001), indicating that this ELISA may be applicable for prediction of fetal lung maturity.

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  • COFACTOR (BETA(2)-GLYCOPROTEIN-1) DEPENDENT ANTICARDIOLIPIN ANTIBODIES AND THROMBOSIS - REPLY Reviewed

    J ORDIROS, A SELVAOCALLAGHAN, P PEREZPEMAN, C FALGA, E CUCURULL

    JOURNAL OF RHEUMATOLOGY   21 ( 7 )   1371 - 1372   1994.7

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  • COFACTOR (BETA(2)-GLYCOPROTEIN-1) DEPENDENT ANTICARDIOLIPIN ANTIBODIES AND THROMBOSIS

    J KABURAKI, M KUWANA, Y IKEDA, M YAMAMOTO, S KAWAI, E MATSUURA

    JOURNAL OF RHEUMATOLOGY   21 ( 7 )   1371 - 1371   1994.7

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  • BETA(2)-GLYCOPROTEIN-I AND ANTICARDIOLIPIN ANTIBODY INFLUENCE FACTOR XA GENERATION BUT NOT FACTOR XA BINDING TO PLATELET-DERIVED MICROPARTICLES Reviewed

    S NOMURA, S FUKUHARA, Y KOMIYAMA, H TAKAHASHI, E MATSUURA, T NAKAGAKI, A FUNATSU, T SUGO, M MATSUDA, T KOIKE

    THROMBOSIS AND HAEMOSTASIS   71 ( 4 )   526 - 527   1994.4

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  • ANTICARDIOLIPIN ANTIBODIES RECOGNIZE BETA(2)-GLYCOPROTEIN-I STRUCTURE ALTERED BY INTERACTING WITH AN OXYGEN MODIFIED SOLID-PHASE SURFACE Reviewed

    E MATSUURA, Y IGARASHI, T YASUDA, DA TRIPLETT, T KOIKE

    JOURNAL OF EXPERIMENTAL MEDICINE   179 ( 2 )   457 - 462   1994.2

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ROCKEFELLER UNIV PRESS  

    Anticardiolipin antibodies (aCL) derived from the sera of individuals exhibiting the antiphospholipid syndrome (APS) directly bind to beta(2)-glycoprotein I (beta(2)-GPI), which is adsorbed to an oxidized polystyrene surface. Oxygen atoms were introduced on a polystyrene surface by irradiation with electron or gamma-ray radiation. X-ray photoelectron spectroscopy revealed the irradiated surfaces were oxidized to generate C-O and C=O moieties. aCL derived from either APS patients or (NZW x BXSB)F-1 mice bound to beta(2)-GPI coated on the irradiated plates, depending on the radiation dose. Antibody binding to beta(2)-GPI on the irradiated plates was competitively inhibited by simultaneous addition of cardiolipin (CL)-coated latex beads mixed together with beta(2)-GPI but were unaffected by addition of excess beta(2)-GPI, CL micelles, or CL-coated latex beads alone. There was a high correlation between binding values of aCL in sera from 40 APS patients obtained by the anti-beta(2)-GPI enzyme-linked immunosorbent assay (ELISA) using the irradiated plates and those by the beta(2)-GPI-dependent aCL ELISA. Therefore, aCL have specificity for an epitope on beta(2)-GPI. This epitope is expressed by a conformational change occurring when beta(2)-GPI interacts with an oxygen-substituted solid phase surface.

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  • 抗リン脂質抗体症候群 Invited

    松浦栄次, 小池隆夫

    Immuno-Review   11   75 - 80   1994

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  • BETA(2)-GPI-DEPENDENT AND INDEPENDENT BINDING OF ANTICARDIOLIPIN ANTIBODIES IN PATIENTS WITH RECURRENT SPONTANEOUS-ABORTIONS Reviewed

    N OZAWA, T MAKINO, H MATSUBAYASHI, T HOSOKAWA, K SOMEYA, S NOZAWA, E MATSUURA

    JOURNAL OF CLINICAL LABORATORY ANALYSIS   8 ( 5 )   255 - 259   1994

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:WILEY-LISS  

    We measured anticardiolipin antibodies (aCL) in plasma samples from 214 women with a history of recurrent spontaneous abortions by an enzyme-linked immunosorbent assay (ELISA) utilizing solid phase cardiolipin (CL) and beta(2)-glycoprotein I (beta(2)-GPI). Sixteen patients (7.5%) were positive for beta(2)-GPI-dependent aCL. Though beta(2)-GPI appeared to enhance the binding of aCL, beta(2)-GPI-independent aCL were also observed in these patients (4.7%). The patients were classified into three groups on the basis of their medical history, and analysis of data of individual groups revealed that the incidence of beta(2)-GPI-dependent aCL was significantly higher in patients who had experienced at least one fetal loss in the second or third trimester. (C) 1994 Wiley-Liss, Inc.

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  • 抗リン脂質抗体の対応抗原 Invited

    松浦栄次, 小池隆夫

    臨床免疫   26   431 - 437   1994

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  • 抗カルジオリピン抗体 Invited

    松浦栄次

    Mebio   11   45 - 53   1994

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  • 抗リン脂質抗体症候群の名称は果たして妥当か Invited

    松浦栄次, 小池隆夫

    臨床免疫   26   222 - 230   1994

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  • 巨大網状皮斑、腎機能低下を呈し、シェーグレン症候群に合併した抗リン脂質抗体症候群の1例 Reviewed

    中林 厳, 久保田孝雄, 明石好弘, 高田高志, 鈴木康史, 清水 潤, 清水栄一, 石田亜希, 西山淳一, 岡田純一, 田沢慶次, 押川泰浩, 近藤修市, 竹内昭彦, 大嶋 智, 吉澤信行, 松浦栄次

    アレルギーの臨床   14   40 - 43   1994

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  • BINDING OF BETA-2-GLYCOPROTEIN-I TO PLATELET-DERIVED MICROPARTICLES Reviewed

    EM BEVERS

    BRITISH JOURNAL OF HAEMATOLOGY   85 ( 3 )   640 - 640   1993.11

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  • BINDING OF BETA-2-GLYCOPROTEIN-I TO PLATELET-DERIVED MICROPARTICLES

    S NOMURA, Y KOMIYAMA, E MATSUURA, T KOKAWA, H TAKAHASHI, T KOIKE

    BRITISH JOURNAL OF HAEMATOLOGY   85 ( 3 )   639 - 639   1993.11

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  • EXPRESSION OF ANTICARDIOLIPIN COFACTOR, HUMAN BETA-2-GLYCOPROTEIN-I, BY A RECOMBINANT BACULOVIRUS-INSECT CELL SYSTEM Reviewed

    M IGARASHI, E MATSUURA, Y IGARASHI, H NAGAE, Y MATSUURA, K ICHIKAWA, T YASUDA, DR VOELKER, T KOIKE

    CLINICAL AND EXPERIMENTAL IMMUNOLOGY   93 ( 1 )   19 - 25   1993.7

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    A full-length cDNA coding a human beta2-glycoprotein I (beta2-GPI) was introduced into the baculovirus genome to construct a recombinant baculovirus. Spodoptera frugiperda (Sf 9) cells were infected with the recombinant baculovirus. A protein (mol. wt 43 000) reactive with anti-beta2-GPI antisera was produced in the insect cells and secreted into the culture medium. The recombinant beta2-GPI was purified from the culture supernatant by sequential cardiolipin (CL)-affinity column chromatography and gel filtration. The N-terminal amino acid sequence of the protein was identical to that of the native beta2-GPI purified from human sera, and a putative signal peptide was cleaved from the secreted form of the recombinant protein. The purified recombinant protein had a cofactor activity which enhances CL binding of anticardiolipin antibodies (aCL) in systemic lupus erythematosus (SLE) patients, as well as the native beta2-GPI. Thus, the beta2-GPI expressed in insect cells is an immunologically active cofactor.

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  • ANTICARDIOLIPIN ANTIBODIES RECOGNIZE AN ALTERED BETA-2-GLYCOPROTEIN-I STRUCTURE

    E MATSUURA, Y IGARASHI, H NAGAE, M IGARASHI, T KOIKE

    THROMBOSIS AND HAEMOSTASIS   69 ( 6 )   1012 - 1012   1993.6

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  • 抗リン脂質抗体症候群の臨床−内科から:cofactor (β2-glycoprotein I) 依存性抗カルジオリピン抗体の臨床的意義− Invited

    鏑木淳一, 池田康夫, 桑名正隆, 山本美保子, 川合眞一, 松浦栄次

    臨床免疫学会誌   16   555 - 560   1993

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  • 抗リン脂質抗体症候群 Reviewed

    松浦栄次, 小池隆夫

    感染・炎症・免疫   23   9 - 17   1993

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  • 膠原病におけるcofactor(β2-glycoprotein I)依存性抗カルジオリピン抗体の疾患特異性 Reviewed

    山本美保子, 鏑木淳一, 桑名正隆, 河合眞一, 松浦栄次, 池田康夫

    臨床血液   34   879 - 881   1993

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  • 抗リン脂質抗体の対応抗原 Invited

    松浦栄次, 小池隆夫

    臨床免疫学会誌   16   537 - 544   1993

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  • ANTICARDIOLIPIN ANTIBODIES IN NZWXBXSB F1-MICE - A MODEL OF ANTIPHOSPHOLIPID SYNDROME Reviewed

    Y HASHIMOTO, M KAWAMURA, K ICHIKAWA, T SUZUKI, T SUMIDA, S YOSHIDA, E MATSUURA, S IKEHARA, T KOIKE

    JOURNAL OF IMMUNOLOGY   149 ( 3 )   1063 - 1068   1992.8

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    NZW x BXSB F1 (W/B F1) male mice develop systemic lupus-like disease, and several autoantibodies, circulating immune complexes, and lupus nephritis become apparent. The abnormally high incidence of degenerative coronary vascular disease with myocardial infarction and thrombocytopenia due to the presence of both platelet-associated antibodies and circulating antiplatelet antibodies in this animal has been reported. We found that W/B F1 male mice produced autoantibodies against cardiolipin (aCL) and that the titer of aCL increases with age. aCL from W/B F1 male mice were mainly IgG and binding activity to cardiolipin was aCL-cofactor (beta-2-glycoprotein I (beta-2-GPI)) dependent. We developed monoclonal aCL from these animals and examined specificity of the autoantibodies. All the mAb used reacted with the negatively charged phospholipids, cardiolipin, phosphatidylserine, and phosphatidylinositol, and some reacted with platelets and DNA. The addition of human or mouse beta-2-GPI enhanced the titer for monoclonal aCL from the W/B F1 mice. From the results of competitive inhibition enzyme immunoassay with monoclonal aCL and purified beta-2-GPI, aCL from the W/B F1 mice recognized the complex of CL and beta-2-GPI. The W/B F1 male mouse may be an appropriate model for use in studies on the pathologic significance of aCL in patients with antiphospholipid syndrome.

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  • HETEROGENEITY OF ANTICARDIOLIPIN ANTIBODIES DEFINED BY THE ANTICARDIOLIPIN COFACTOR Reviewed

    E MATSUURA, Y IGARASHI, M FUJIMOTO, K ICHIKAWA, T SUZUKI, T SUMIDA, T YASUDA, T KOIKE

    JOURNAL OF IMMUNOLOGY   148 ( 12 )   3885 - 3891   1992.6

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    Anticardiolipin antibodies (aCL) found in sera from patients with SLE react with cardiolipin (CL) in the presence of a 50-kDa serum cofactor. The cofactor, which was identified to be beta-2-glycoprotein I by sequencing the N-terminal amino acids, not only enhances CL binding by antibodies in SLE but also depresses it by antibodies associated with syphilis. Cofactor-dependent binding of aCL in SLE to solid phase CL was competitively inhibited by the simultaneous addition of fluid phase CL but was unaffected by either prior or simultaneous addition of a high excess of the cofactor. Binding of aCL in syphilis to solid phase CL was competitively inhibited by either addition of the cofactor or fluid phase CL. aCL in SLE reacted with CL, PS, and PA in the presence of cofactor. In contrast, biotinyl-cofactor bound directly to these anionic phospholipids (PL) and also to PG. These results show that the cofactor-CL complex bears an epitope that confers recognition specificity for aCL in SLE, in contrast with direct CL recognition by syphilitic aCL. The direct binding of the cofactor to PL suggests that the cofactor dependence of aCL binding to PL is due to recognition by aCL of a unique epitope generated upon the formation of the cofactor-CL complex.

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  • 抗カルジオリピン抗体と測定法 Invited

    松浦栄次, 小池隆夫

    神経内科   37   542 - 550   1992

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  • β2-グリコプロテインIの新しい機能 Invited

    家子正裕, 松浦栄次, 小池隆夫

    臨床検査   37   794 - 796   1992

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  • 抗リン脂質抗体測定法の実際 Invited

    松浦栄次, 小池隆夫

    リウマチ科   5   408 - 414   1992

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  • シェーグレン症候群にMLF症候群を合併した1例:SLCキットにより抗カルジオライピン抗体高値の原因が梅毒との鑑別可能であった一例 Reviewed

    向井正也, 佐川 昭, 渥美達也, 浄土 智, 天崎吉晴, 中林 透, 渡辺一郎, 藤咲 淳, 中川昌一, 小池隆夫, 松浦栄次

    リウマチ科   6   238 - 242   1992

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  • 抗カルジオリピン抗体・コファクターの核酸配列と蛋白発現 Invited

    松浦栄次, 小池隆夫

    臨床免疫   24   1396 - 1403   1992

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  • 抗カルジオリピン抗体 Invited

    松浦栄次, 小池隆夫

    Chronic Disease   3   399 - 403   1992

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  • 抗リン脂質抗体の対応抗原 Invited

    松浦栄次, 小池隆夫

    臨床免疫   24   207 - 214   1992

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  • MOLECULAR DEFINITION OF HUMAN BETA-2-GLYCOPROTEIN-I (BETA-2-GPI) BY CDNA CLONING AND INTERSPECIES DIFFERENCES OF BETA-2-GPI IN ALTERNATION OF ANTICARDIOLIPIN BINDING

    E MATSUURA, M IGARASHI, Y IGARASHI, H NAGAE, K ICHIKAWA, T YASUDA, T KOIKE

    INTERNATIONAL IMMUNOLOGY   3 ( 12 )   1217 - 1221   1991.12

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    Human beta-2-glycoprotein I (beta-2-GPI) is involved in cardiolipin (CL) binding of anticardiolipin antibodies (aCL) in systemic lupus erythematosus (SLE). We examined the inter-species differences of beta-2-GPI in alternation of CL binding of aCL. beta-2-GPI preparations were obtained from human, bovine, and rat sera by sequential CL-polyacrylamide affinity, DEAE-cellulose, and anti-human IgG-conjugated Sepharose CL-4B column chromatography, and they had apparent molecular weights of 50, 53, and 55 kDa respectively. Human beta-2-GPI not only enhanced CL binding by aCL in SLE but also depressed it by those in syphilis. Either bovine and rat beta-2-GPI exerted no or quite small inhibition of the binding of syphilitic aCL compared with human beta-2-GPI whereas all three species of beta-2-GPI generated binding of aCL in SLE to a similar degree. Further, a complete cDNA clone, p-beta-2-GPI, was isolated from a human hepatoma cell line, HepG2, and its nucleotide sequence was analyzed. The sequences of bovine and rat counterpart molecules (beta-2-GPI) are highly homologous to that of the deduced sequence, and their corresponding regions are 84.0 and 82.5% identical to the complete domain and to the amino acid sequence 53-326 of human beta-2-GPI respectively. One of major differences appears at position 154 in human beta-2-GPI, and might be associated with the inhibitory effect on the binding of syphilitic aCL. The sequencing analysis of these beta-2-GPI proteins might provide leads to functional sites of domains which would be associated with such serological phenomena.

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  • SPECIFICITY AND CLINICAL-SIGNIFICANCE OF ANTICARDIOLIPIN AUTOANTIBODIES DETECTED BY AN IMPROVED ELISA SYSTEM USING THE COMPLEX OF CARDIOLIPIN AND A COFACTOR

    T KOIKE, T SUZUKI, K ICHIKAWA, M FUJIMOTO, Y IGARASHI, E MATSUURA

    THROMBOSIS AND HAEMOSTASIS   65 ( 6 )   1256 - 1256   1991.6

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  • CHARACTERIZATION OF THE ANTICARDIOLIPIN COFACTOR AND A PRECISE ASSAY SYSTEM FOR ANTICARDIOLIPIN ANTIBODIES IN PATIENTS WITH AUTOIMMUNE-DISEASES

    E MATSUURA, Y IGARASHI, M FUJIMOTO, K ICHIKAWA, T SUZUKI, T KOIKE

    THROMBOSIS AND HAEMOSTASIS   65 ( 6 )   848 - 848   1991.6

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  • WHAT IS THE TRUE ANTIGEN FOR ANTICARDIOLIPIN ANTIBODIES Reviewed

    T KOIKE, E MATSUURA

    LANCET   337 ( 8742 )   671 - 672   1991.3

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  • A SIMPLE AND SENSITIVE RADIOIMMUNOASSAY FOR ADENOSINE Reviewed

    R YAMANE, T NAKAMURA, E MATSUURA, H ISHIGE, M FUJIMOTO

    JOURNAL OF IMMUNOASSAY   12 ( 4 )   501 - 519   1991

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    We developed a simple and sensitive radioimmunoassay (RIA) for adenosine. The RIA is based on the double antibody method with adenosine 2',3'-O-disuccinyl-3-[I-125]-iodotyrosine methyl ester (diSc-adenosine-[I-125]-TME) as a tracer. Anti-adenosine antiserum for the RIA was raised in rabbits immunized with diSc-adenosine conjugated to human serum albumin (diSc-adenosine-HSA). All samples and standards were succinylated prior to assay. The present immunoassay allows detection of 6.25-400 pmol/ml of adenosine in sample. Values obtained by the RIA and by a HPLC analysis showed a high correlation with correlation coefficient of 0.997.
    In order to determine adenosine in plasmas, blood cells must be separated in the presence of 6 mM EDTA, 0.006% dipyridamole (Dip) and 23-mu-M 2'-deoxycoformycin (dCF) at 2-degrees-C. Adenosine in plasma could be accurately determined by the proposed method even without any pretreatments by deproteinizing. The adenosine levels with or without EDTA-treated normal human plasmas determined were 26.2 +/- 7.26 and 100 +/- 3.62 pmol/ml (Mean +/- SEM), respectively.

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  • 抗カルジオリピン抗体測定法の標準化 Invited

    松浦栄次, 小池隆夫

    臨床免疫   23   749 - 754   1991

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  • ANTICARDIOLIPIN COFACTOR(S) AND DIFFERENTIAL-DIAGNOSIS OF AUTOIMMUNE-DISEASE Reviewed

    E MATSUURA, Y IGARASHI, M FUJIMOTO, K ICHIKAWA, T KOIKE

    LANCET   336 ( 8708 )   177 - 178   1990.7

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  • 抗リン脂質抗体の測定原理と多様性 Invited

    松浦栄次, 小池隆夫

    臨床免疫   22   170 - 179   1990

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  • INHIBITION OF CELL-PROLIFERATION WITH ANTIBODY-TARGETED LIPOSOMES CONTAINING METHOTREXATE-GAMMA-DIMYRISTOYLPHOSPHATIDYLETHANOLAMINE Reviewed

    C NOE, J HERNANDEZBORRELL, SC KINSKY, E MATSUURA, L LESERMAN

    BIOCHIMICA ET BIOPHYSICA ACTA   946 ( 2 )   253 - 260   1988.12

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  • Detection and clinical significance of acetoneinsoluble liver cell membrane antigen in sera of patients with chronic active liver diseases Reviewed

    Takao Tsuji, Kenji Takahashi, Masahiko Sawahara, Eiji Matsuura, Itaru Yamamoto

    Gastroenterologia Japonica   20 ( 1 )   37 - 47   1985.2

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Springer-Verlag  

    An enzyme-linked immunosorbent assay was developed to detect insoluble liver cell membrane antigen (LMAg) which gives rise to serum LMA (anti-LM) in HBsAg-negative patients. The optical density (OD) ratio of the average LMAg level of normal subjects was less than 1.2. In HBsAg-positive cases, high LMAg levels (OD ratio &gt
    2.4) were noted in 8 of 8 patients with acute hepatitis (AH), 3 of 8 with chronic persistent hepatitis (CPH), 5 of 10 with moderate chronic aggressive hepatitis (CAH), 7 of 10 severe CAH and 4 of 8 with liver cirrhosis (LC). In HBsAg-netative cases, however, high LMAg levels were noted in only 6 of 8 patients with AH, 1 of 10 with CPH, 1 of 10 with moderate CAH, 1 of 10 with severe CAH, 0 of 8 with LC, 0 of 8 with fatty liver and 5 of 10 with alcoholic hepatitis. In micro-immunodiffusion experiments, intensively absorbed rabbit anti-rat LM precipitated two organ-specific components of rat liver homogenate, one of which was identical to liver specific protein (LSP). In immunohistochemical demonstrations of LMAg and LSP, anti-LM, prepared from the serum of a HBsAg-negative CAH patient, bound to both human and rat acetone-fixed liver cell membranes, but not to those of human or rat kidneys. Absorbed rabbit anti-rat LM also bound to liver cell membranes, but absorbed anti-rat LSP lacked organ-specificity when assayed with the immunofluorescence technique using acetone-fixed liver sections. In conclusion, the appearance of serum LMAg was associated with high-SGPT patients and HBsAg-positive CAH patients. © 1985 The Japanese Society of Gastroenterology.

    DOI: 10.1007/BF02774672

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  • ENZYME-IMMUNOASSAY FOR MABUTEROL, A SELECTIVE BETA-2-ADRENERGIC STIMULANT IN THE TRACHEA Reviewed

    YAMAMOTO, I, E MATSUURA, M HORIBA, K AKIMA, K NOMURA, T AIZAWA

    JOURNAL OF IMMUNOASSAY   6 ( 3 )   261 - 276   1985

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  • SHR脾細胞のCon A応答 Reviewed

    山本 格, 山口知栄子, 山内 宏, 松浦栄次, 辻 淳一

    消化器と免疫   14   37 - 40   1985

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  • MONOCLONAL-ANTIBODY FOR CALCITRIOL (1-ALPHA,25-DIHYDROXYVITAMIN-D3) Reviewed

    YAMAMOTO, I, E MATSUURA

    JOURNAL OF BIOCHEMISTRY   98 ( 4 )   991 - 998   1985

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  • Immunoregulatory α-globulinのリンパ球幼若化反応および実験的慢性関節炎抑制作用 Reviewed

    松浦栄次, 土本雅弘, 山口知栄子, 末吉俊幸, 杉江邦夫, 辻 淳一, 山本 格

    消化器と免疫   14   46 - 49   1985

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  • DEFICIENCY OF PLASMA IMMUNOSUPPRESSIVE ALPHA-GLOBULINS IN SPONTANEOUSLY HYPERTENSIVE RATS

    E MATSUURA, T SUEYOSHI, YAMAMOTO, I

    CLINICAL AND EXPERIMENTAL HYPERTENSION PART A-THEORY AND PRACTICE   7 ( 12 )   1772 - 1772   1985

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  • EFFECT OF IMMUNOREGULATORY ALPHA-GLOBULIN (IRA) ON EXPERIMENTAL ARTHRITIS IN RATS

    E MATSUURA, M TSUCHIMOTO, C YAMAGUCHI, T SUEYOSHI, YAMAMOTO, I

    FOLIA PHARMACOLOGICA JAPONICA   85 ( 5 )   P57 - P58   1985

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  • AN EXPERIMENTAL-MODEL OF NEPHRITIS INDUCED BY CALF SERUM INJECTION IN MICE Reviewed

    M TSUCHIMOTO, K KOMORIYA, T KOYAMA, K HOSODA, T TAKESHITA, T NARUCHI, E MATSUURA, YAMAMOTO, I

    JAPANESE JOURNAL OF PHARMACOLOGY   36 ( 2 )   223 - 234   1984

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▼display all

Books

  • The Heart in Systemic Autoimmune Diseases (Second edition)

    Matsuura E, Tan XW, Shen LH, Nuriza UA, Lopez LR( Role: Contributor ,  Inflammasomes and inflammatory cytokines in early atherosclerosis)

    Elsevier Science BV, Amsterdam, The Netherlands  2017 

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  • Autoantibodies (Third edition)

    Matsuura E, Lopez LR( Role: Contributor ,  Anti-β2-glycoprotein I antibodies)

    Elsevier Science BV, Amsterdam, The Netherlands  2012 

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  • 平成18年度~19年度科学研究費補助金(基盤研究C)研究成果報告書

    松浦栄次( Role: Sole author ,  感染による動脈硬化の進展とその抑制に関する病態生化学的・免疫学的解析)

    2008 

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  • 日本テンペ研究会誌

    松浦栄次( Role: Contributor ,  テンペと生活習慣病)

    2007 

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  • Autoantibodies (Second Edition)

    Matsuura E, Dier K, Lopez LR( Role: Contributor ,  Anti-β2-glycoprotein I antibodies)

    Elsevier Science BV, Amsterdam, The Netherlands  2007 

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  • 平成16年度〜平成17年度バイオアクティブおかやま委託研究事業成果報告書

    松浦栄次( Role: Contributor ,  「テンペ」の脂質代謝の改善(抗動脈硬化)食品としての実用化研究)

    2006 

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  • 平成16-17年度文部科学省科学研究補助金(萌芽研究)研究成果報告書

    松浦栄次( Role: Sole author ,  “タンパク質”修飾酸化LDLの診断法の確と動脈硬化における意義に関する研究)

    2006 

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  • 厚生労働科学研究費補助金難治性疾患克服研究事業平成15年度-平成17年度総合研究報告書

    松浦栄次( Role: Contributor ,  PBCマウスモデルの作製に関する研究.難治性自己免疫性肝疾患の画期的治療法の開発に関する臨床研究)

    2006 

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  • Hughes Syndrome: Antiphospholipid Syndrome (Second Edition)

    Matsuura E, Kobayashi K, Lopez LR( Role: Contributor ,  Atherogenesis and antiphospholipid antibodies)

    Springer, London, UK  2006 

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  • 自己抗体と自己免疫

    松浦栄次( Role: Contributor ,  酸化LDL・β2-glycoprotein I複合体と動脈硬化性疾患)

    医学生物学研究所、名古屋  2006 

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  • 図説ARTマニュアル、改訂第2版

    小林和子, 井上勝美, 保田晋助, 松浦栄次( Role: Contributor ,  抗リン脂質抗体症候群)

    永井書店、大阪  2005 

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  • 厚生労働科学研究費補助金難治性疾患克服研究事業平成16年度研究報告書

    松浦栄次( Role: Contributor ,  LDLの変性およびタンパク質修飾:免疫が関与する動脈硬化の進展機序と早期診断法.自己免疫疾患に関する調査研究)

    2005 

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  • Systemic Lupus Erythematosus (Fourth Edition),

    Atsumi T, Matsuura E, Koike T( Role: Contributor ,  Immunology of antiphospholipid antibodies and cofactors)

    Elsevier Science BV, Amsterdam, The Netherlands  2004 

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  • Recent Research of Developments in Lipids (Vol 7)

    Lopez LR, Matsuura E( Role: Contributor ,  Autoimmune-mediated atherosclerosis: pathogenic role of oxLDL/β2GPI complexes)

    Transworld Research Network, Kerala, India  2004 

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  • 三共生命科学研究振興財団研究助成報告書

    松浦栄次( Role: Contributor ,  酸化ストレスにより誘導される酸化LDL・β2-グリコプロテインI複合体の病因的意義)

    2004 

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  • 厚生科学研究費補助金特定疾患対策研究事業平成15年度研究報告書

    松浦栄次( Role: Contributor ,  抗リン脂質抗体症候群の診断法に関する検討.自己免疫疾患に関する調査研究)

    2004 

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  • Autoantigens, Autoantibodies, Autoimmunity (Vol 4)

    Inagaki J, Kondo A, Lopez LR, Shoenfeld Y, Matsuura E( Role: Contributor ,  Anti-laminin-1 autoantibodies in reproductive failure: animal and human studies)

    Pabst Science Publisher, Lengerich, Germany  2004 

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  • 平成14-15年度文部科学省科学研究補助金 (基盤研究(C)(2)) 研究成果報告書

    松浦栄次( Role: Sole author ,  抗リン脂質抗体症候群におけるマクロファージの役割:抗原提示および血栓形成の機序)

    2004 

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  • 厚生科学研究費補助金特定疾患対策研究事業平成14年度研究報告書

    松浦栄次, 小池隆夫( Role: Contributor ,  抗リン脂質抗体症候群の診断法:酸化LDL・β2-グリコプロテイン I 複合体(自己抗原)とそれらの免疫複合体の測定意義.自己免疫疾患に関する調査研究)

    2003 

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  • 厚生科学研究費補助金特定疾患対策研究事業平成11-13年度研究報告書

    松浦栄次( Role: Contributor ,  自己免疫疾患の病因・病態解析と新たな治療法の開発に関する研究)

    2003 

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  • アニムス

    松浦栄次, 小林和子( Role: Contributor ,  酸化LDL研究の現状)

    アニムス刊行会  2003 

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  • 平成9年度〜平成12年度文部省科学研究費(特定領域研究 A1) 動脈硬化の分子機構研究成果報告書

    松浦栄次, 小池隆夫( Role: Contributor ,  新規酸化LDLリガンドと自己抗体が関与する動脈硬化の発症機序に関する研究)

    2002 

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  • 厚生科学研究費補助金特定疾患対策研究事業平成13年度研究報告書

    松浦栄次( Role: Contributor ,  酸化LDLの測定法と抗リン脂質抗体症候群における酸化LDLの臨床意義に関する研究.自己免疫疾患の病因・病態解析と新たな治療法の開発に関する研究)

    2002 

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  • 血小板と生理活性脂質

    小林和子, 近藤朱音, 松浦栄次( Role: Contributor ,  脂質の酸化と生理活性)

    金芳堂  2002 

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  • 厚生科学研究費補助金特定疾患対策研究事業平成12年度研究報告書

    松浦栄次( Role: Contributor ,  病因となる自己抗体の検出とその臨床意義:抗β2-GPI抗体、抗 laminin-1抗体、および抗sulfatide抗体.自己免疫疾患の病因・病態解析と新たな治療法の開発に関する研究)

    2001 

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  • Atherosclerosis and Autoimmunity

    Matsuura E, Kobayashi K, Kasahara J, Kaihara K, Shoenfeld Y, Koike T( Role: Contributor ,  Oxidized autoantigens in atherosclerosis)

    Elsevier Science BV, Amsterdam, The Netherlands  2001 

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  • 生体機能分子データブック

    松浦栄次( Role: Contributor ,  自己抗原・自己抗体)

    中外医学社、東京  2001 

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  • 厚生科学研究費補助金特定疾患対策研究事業平成11年度研究報告書

    松浦栄次( Role: Contributor ,  抗リン脂質抗体症候群における自己抗体の関与した動脈硬化の発症機序の解明.自己免疫疾患の病因・病態解析と新たな治療法の開発に関する研究)

    2000 

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  • Systemic Lupus Erythematosus (Third Edition)

    Koike T, Matsuura E( Role: Contributor ,  Immunology of anti-phospholipid antibodies)

    Academic Press, New York, USA  1999 

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  • 平成9年度厚生省厚生科学研究費補助金感覚器障害及び免疫・アレルギー等研究事業研究成果報告書

    松浦栄次( Role: Contributor ,  免疫・アレルギー性疾患の症状発現および増悪に関する研究)

    1999 

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  • The Medical Bulletin(The Ryouichi Naito Foundation for Medical Research)

    松浦栄次( Role: Contributor ,  抗リン脂質抗体症候群における血管病変の発症機序の解明)

    内藤医学研究振興財団  1999 

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  • The Decade of Autoimmunity

    Koike T, Matsuura E( Role: Contributor ,  Anticardiolipin antibody, thrombosis and atherosclerosis)

    Elsevier Science BV, Amsterdam, The Netherlands  1999 

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  • 厚生省特定疾患免疫疾患調査研究班自己免疫疾患分科会.平成10年度報告書

    小池隆夫, 市川健司, 堤 明人, 渥美達也, 松浦栄次, 小林清一( Role: Contributor ,  IgG抗カルジオリピン抗体測定系の標準となりうる、ヒトIgG型キメラ抗体の作成)

    1999 

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  • 厚生省特定疾患調査研究班免疫疾患調査研究班平成9年度報告書

    小池隆夫, 市川健司, 笠原英樹, 堤 明人, 渥美達也, 松浦栄次, 山本大助( Role: Contributor ,  抗カルジオリピン抗体が認識するアミノ酸配列の解析)

    1998 

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  • 臨床免疫学

    松浦栄次, 小池隆夫( Role: Contributor ,  抗カルジオリピン抗体)

    朝倉書店、東京  1997 

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  • 文部省がんに係る重点領域研究平成8年度報告書

    西 信三, 酒井正春, 小山芳一, 松浦栄次( Role: Contributor ,  発生工学を応用した α-フェトプロテインの糖鎖構造及び機能の解析)

    1997 

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  • 厚生省特定疾患調査研究班免疫疾患調査研究班平成8年度報告書

    小池隆夫, 松浦栄次, 北川浩彦, 市川健司, 堤 明人, 西 信三( Role: Contributor ,  β2-グリコプロテインI (β2-GPI) および抗β2-GPI抗体の動脈硬化およびアポトーシスへの関与)

    1997 

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  • 厚生省特定疾患自己免疫疾患調査研究班平成8年度報告書

    小池隆夫, 堤 明人, 市川健司, 松浦栄次, 小林清一( Role: Contributor ,  全身性エリテマトーデス患者血清中の抗β2-GPI抗体の臨床的意義)

    1997 

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  • 別冊・医学のあゆみ「全身性エリテマトーデス」

    松浦栄次, 小池隆夫( Role: Contributor)

    医歯薬出版、東京  1997 

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  • 1995年度国際血栓止血学会SSC報告書

    ( Role: Contributor ,  Subcommittee on Lupus Anticoagulants and Phospholipid-Dependent Antibodies)

    1996 

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  • 厚生省特定難治性血管炎調査研究班1995年度報告書

    小池隆夫, 牧田善二, 蓮沼祐子, 松浦栄次, 片平智禎( Role: Contributor ,  β2-グリコプロテインIおよび自己抗体による酸化LDL取り込みの制御)

    1996 

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  • Autoantibodies

    Matsuura E, Koike T( Role: Contributor ,  β2-Glycoprotein I antibodies)

    Elsevier Science BV, Amsterdam, The Netherlands  1996 

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  • 厚生省特定疾患自己免疫疾患調査研究班平成6年度報告書(2)

    小池隆夫, 堤 明人, 市川健司, 小林清一, 松浦栄次( Role: Contributor ,  抗カルジオリピン抗体の新しい測定法の開発)

    1995 

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  • 厚生省特定難治性血管炎調査研究班1994年度報告書

    小池隆夫, 堤 明人, 市川健司, 松浦栄次( Role: Contributor ,  抗カルジオリピン抗体と酸化LDL)

    1995 

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  • 厚生省特定疾患自己免疫疾患調査研究班平成6年度報告書(1)

    小池隆夫, 市川健司, 堤 明人, 松浦栄次( Role: Contributor ,  β2-グリコプロテインI上のリン脂質結合部位と抗原決定基の分子生物学的解析)

    1995 

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  • 厚生省特定疾患自己免疫疾患調査研究班平成5年度研究報告

    小池隆夫, 市川健司, 松浦栄次( Role: Contributor ,  抗リン脂質抗体症候群患者より樹立したモノクローナル抗カルジオリピン抗体の特異性の検討)

    1994 

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  • 免疫93-94

    小池隆夫, 松浦栄次( Role: Contributor ,  抗カルジオリピン抗体とその対応抗原)

    中山書店、東京  1993 

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  • 自己免疫とトレランス

    小池隆夫, 松浦栄次( Role: Contributor ,  抗カルジオリピン抗体)

    中外医学社、東京  1993 

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  • 厚生省特定疾患自己免疫疾患調査研究班平成4年度研究報告書

    小池隆夫, 松浦栄次, 住田孝之( Role: Contributor ,  抗カルジオリピン抗体の対応抗原)

    1993 

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  • Interactable Vasculitis

    Koike T, Matsuura E( Role: Contributor ,  Anticardiolipin antibody and β2-glycoprotein I)

    University Press, Sapporo, Japan,  1993 

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  • 厚生省特定疾患自己免疫疾患調査研究班平成2年度研究報告書

    小池隆夫, 市川健二, 鈴木隆弘, 住田孝之, 藤本正雄, 五十嵐佳子, 松浦栄次( Role: Contributor ,  抗カルジオリピン抗体測定系の確立)

    1991 

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  • 厚生省特定疾患系統的脈管障害調査研究班・自己免疫疾患調査研究班平成元年度合同シンポジウム報告書

    小池隆夫, 市川健司, 石原貞子, 佐藤俊子, 松浦栄次( Role: Contributor ,  抗カルジオリピン抗体の測定)

    1990 

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MISC

  • ニトベギク由来オリザビンはPMA刺激ヒト単球THP-1細胞のPTEN発現を促進しAktリン酸化とCD36の発現を抑制する

    井出将博, 井出将博, 三嶋隆, 吉田泉, 高橋有志, 熊谷百慶, 五十嵐友二, 松浦栄次

    日本栄養・食糧学会大会講演要旨集   73rd   2019

Presentations

  • ニトベギク由来オリザビンはPMA刺激ヒト単球THP-1細胞のPTEN発現を促進しAktリン酸化とCD36の発現を抑制する

    井出将博, 井出将博, 三嶋隆, 吉田泉, 高橋有志, 熊谷百慶, 五十嵐友二, 松浦栄次

    日本栄養・食糧学会大会講演要旨集  2019 

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  • ニトベギク茎葉由来orizabinのヒト臍帯静脈内皮細胞とヒト単球細胞THP1における細胞接着と泡沫化の抑制作用

    井出将博, 井出将博, 熊谷百慶, 三嶋隆, 吉田泉, 高橋有志, 中村宗知, 松浦栄次

    日本生化学会大会(Web)  2018 

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  • A novel single chain valiant of antibody (scFv) against mesothelin (MSLN) established by phage library for PET imaging International conference

    Matsuura E, Yakushiji H, Kobayash K, Takenaka F, Akehi M, Sasaki T

    World Mol Imaging Conference, Seattle, USA  2018.9 

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  • roteolysis-resistant domains in β2-glycoprotein I (β2GPI): Features and potent applications in lipidomics Invited International conference

    Matsuura E

    nternational Congress on Autoimmunity, Lisbon, Portugal  2018.5 

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  • Autoimmunity and angiogenesis Invited International conference

    Matsuura E

    International Congress on Autoimmunity, Lisbon, Portugal  2018.5 

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  • New era of in vivo molecular imaging and targeted medical care: Antibody-based theranostics Invited

    Matsuura E

    NewYork Pharma Forum (NYPF) , New York、USA  2018.3 

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  • Theranostics: A holistic and revolutionized regime in cardiovascular medicine Invited International conference

    Matsuura E

    Joint Meeting of Coronary Revascularization Convenes in Busan. Busan, South Korea  2017.12 

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  • Theranostics: The modern revolution and future of cancer medicine and oncological management Invited International conference

    Matsuura E

    Scholar Summit 2017. Depok, Indonesia  2017.10 

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  • A holistic and revolutionized regime in cardiovascular medicine Invited International conference

    Matsuura E

    International Conference on Advance Pharmacy and Pharmaceutical Sciences (ICAPPS)  2017.10 

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  • Harnessing disease-specific antibodies and its variant in theranostics Invited International conference

    Matsuura E

    oint meeting of Australia’s MedTech Conference and International Conference on Mechanics in Medicine and Biology (ICMMB), Melbourne, Australia,  2017.5 

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  • Harnessing autoimmunity (disease-specific autoantibodies and its variant) in theranostics of disease Invited International conference

    Matsuura E

    Joint meeting of Lupus and Asian Congress on Autoimmunity, Melbourne, Australia  2017.5 

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  • Natural ameliorative biomaterial for oxidative stress and inflammation International conference

    Tan XW, Wang SS, Matsuura E

    Joint meeting of Australia’s MedTech Conference and International Conference on Mechanics in Medicine and Biology (ICMMB), Melbourne, Australia  2017.5 

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  • Evaluation of whole-body biodistribution of 89Zr-labeled antibodies in cynomolgus macaque with PET International conference

    Sasaki T, Kimura S, Noda A, Murakami Y, Takenaka F, Miyoshi S, Matsuura E

    Annual Meeting of the European Association of Nuclear Medicine, Barcelona, Spain,  2016.10 

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  • Okayama Medical Innovation Center (OMIC) and molecular imaging Invited International conference

    Matsuura E

    The 1st Asian Researcher Symposium 2016. Depok, Indonesia  2016.8 

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  • Intensive Scientific Writing Coaching Clinic. Invited

    Matsuura E

    2016.8 

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  • Immuno-thera-diagnostics (theranostics) in autoimmunity and oncology Invited International conference

    Matsuura, E

    International Congress on Autoimmunity, Leipzig, Germany  2016.4 

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  • Narcolepsy as an autoimmune disease International conference

    Arango M, Kivity S, Sasaki T, Blank M, Matsuura E, Shoenfeld Y

    International Congress on Autoimmunity, Leipzig, Germany  2016.4 

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  • The role of lipoprotein oxidative inflammation and β2-glycoprotein I in innate immunity of early atherosclerosis Invited International conference

    Matsuura E

    International Congress on Autoimmunity, Leipzig, Germany,  2016.4 

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  • Okayama Medical Innovation Center (OMIC) and molecular targeting technology Invited International conference

    Matsuura, E

    International Symposium on Bio-imaging and Gene Targeting Sciences in Okayama. Okayama, Japan  2015.2 

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  • Okayama Medical Innovation Center (OMIC) and a novel molecular targeting technology Invited International conference

    Matsuura E

    National Conference for Clinical Research 2014, Kuching, Malaysia  2014.10 

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  • Elucidation of the pharmacokinetic difference of regioisomeric retinoid X receptor agonists having an alkoxy group by PET imaging International conference

    Kobayashi T, Kawata K, Nakayama M, Furusawa Y, Yamada S, Hirano H, Takenaka F, Akehi M, Sasaki T, Matsuura E, Tai A, Kakuta H

    National Meeting of the American Chemical Society (ACS), San Francisco, USA  2014.8 

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  • Circulating pro-atherogenic oxidized LDL/β2-glycoprotein I complexes are detected in arterial and venous diseases and are independent predictors of carotid arterial disease International conference

    Lopez LR, Matsuura E, Guyer KE, Rockman CB, Berger JS

    Congress of the European Atherosclerosis Society, Madrid, Spain  2014.5 

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  • Significant accumulation of oxLDL/β2-glycoprotein I complexes in arterial lesions of WHHL rabits: PET/CT imaging using an autoantibody’s scFv variant International conference

    Sasaki T, Matsunami Y, Takanaka F, Kita S, Hirano H, Shen L, Kobayashi K, Matsuura E, Guyer KE, Rockman CB, Berger JS

    Congress of the European Atherosclerosis Society, Madrid, Spain  2014.3 

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  • Autoimmune and infection-mediated atherosclerosis: possible mechanisms and innovation from translational biomedical researches Invited International conference

    Matsuura E

    International Congress on Autoimmunity, Nice, France  2014.3 

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  • Immunogenic oxidized low-density lipoprotein/β2-glycoprotein I (oxLDL/β2GPI) complexes in atherothrombotic cardiovascular diseases: clinical determinants and significance International conference

    Berger JS, Guyer K, Rockman CB, Matsuura E, Lopez LR

    International Congress on Autoimmunity, Nice, France  2014.3 

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  • In vivo molecular imaging using humanized anti-β2-glycoprotein I autoantibodies to detect arterial lesions in the atherosclerosis-prone ApoE-/- mice International conference

    Matsunami Y, Sasaki T, Takenaka F, Kobayashi K, Kita S, Kojima K, Matsuura E

    International Congress on Autoimmunity, Nice, France  2014.3 

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  • Oxidized lipids composed of atherogenic complex autoantigen: by liposome analyses with cutting-edge imaging mass microscope (IMscope) International conference

    Shen L, Arum Tri W, Kobayashi K, Yamamoto T, Ogata K, Ando E, Ozeki E, Matsuura E

    International Congress on Autoimmunity, Nice, France  2014.3 

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  • Recombinant domain V of β2-glycoprotein I inhibits the formation of atherogenic oxLDL/β2-glycoprotein I complexes International conference

    Liu Q, Chi Y, Li J, Wang R, Matsuura E

    Autoimmune Congress Asia, Hong Kong  2013.11 

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  • Infection and immunity-mediated atherosclerosis Invited International conference

    Matsuura E

    Autoimmune Congress Asia, Hong Kong  2013.11 

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  • Autoantibodies against β2-glycoprotein I really atherogenic?: Answers from in vivo PET imaging studies in apolipoprotein E-deficient mice International conference

    Matsunami, Y, Sasaki T, Takenaka F, Kobayashi K, Kojima K, Kita S, Hirano H, Matsuura E

    Autoimmune Congress Asia, Hong Kong  2013.11 

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  • A non-invasive PET/CT imaging procedure for diagnosing atherosclerotic lesions: immunologic targeting to oxLDL/β2-glycoprotein I in the WHHL rabbits International conference

    Sasaki T, Matsunami Y, Takenaka F, Hirano F, Kita S, Matsuura E

    Autoimmune Congress Asia, Hong Kong  2013.11 

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  • etection of oxidized lipoproteins accumulated in atherosclerosis lesions byimaging mass microscopy (iMS) International conference

    Shen L, Arum Tri Wahyuningsih, Kobayashi K, Sasaki T, Matsunami Y, Takenaka F, Ando E, Yamamoto T, Ogata K, Matsuura E

    Autoimmune Congress Asia, Hong Kong  2013.11 

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  • Pathological implication of autoantibodies against β2-glycoprotein I and a novel “Immuno-TheranoDiagnostics” in atherosclerosis Invited International conference

    Matsuura E

    Autoimmune Congress Asia, Hong Kong  2013.11 

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  • Lipoprotein/β2-Glycoprotein I (oxLDL/β2GPI) complexes in atherothrombotic cardiovascular diseases International conference

    Lopez LR, Guyer K, Matsuura E, Rockman CB, Berger JS

    Autoimmune Congress Asia, Hong Kong  2013.11 

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  • Autoimmunity accelerates atherogenesis: oxidized-LDL/β2-glycoprotein I complexes and anti-β2-glycoprotein I antibodies enhance the risk of cardiovascular events in acute coronary syndrome International conference

    Lopez LR, Greco TP, Hurley B, Boisen M, Matsuura E

    Autoimmune Congress Asia, Hong Kong  2013.11 

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  • Autoimmunity, oxidative inflammation, and β2-glycoprotein I in early atherogenesis Invited International conference

    Matsuura E

    Controversies and Rheumatology & Autoimmunity 2013. Budapest, Hungary  2013.4 

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  • Pathophysiology of atherosclerosis: acceleration by inflammation and immunity Invited International conference

    Matsuuura E

    International Conference “Bioactive Okayama 2012, Okayama, Japan  2012.9 

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  • β2-Glycoprptein I and oxidative inflammation in atherogenesis of autoimmune atherothrombotic diseases Invited International conference

    Matsuura E

    International Congress on Autoimmunity, Granada, Spain  2012.5 

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  • Aspirin inhibition of thromboxane does not affect oxidative stress, nitric oxide matabolites, paraoxonase activity or P-selectin levels in diabetes International conference

    Lopez LR, Batuca JR, Muncy IJ, De La Torre, IG Matsuura E, Ames PRJ

    European Association for Study of Diabetes (EASD 2011) Annual Meeting, Lisbon, Portugal  2011.9 

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  • Anti-atherogenic plaque reduction, inhibition of oxLDL/β2GPI autoantigen and thromboxane platelet activation by persimmon (Diospyros kaki) peel in LDLR-/--deficient mice International conference

    Matsuura E, Quan N, Kobayashi K, Matsunami Y, Ide M, Makarova M, Shen L, Ohno S, Zheng Y, Kobayashi H, Lopez LR

    Congress of the International Society on Thrombosis and Haemostasis (ISTH 2011), Kyoto, Japan  2011.7 

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  • Rosuvasutatin decreases serum levels of oxidized low-density lipoprotein/β2-glycoprotein I complex through the nitric oxide pathway in diabetes mellitus International conference

    Lopez LR, Muncy I, Matsuura E, Batuca J, Garcia-De La Torre I, Ames PRJ

    Congress of the International Society on Thrombosis and Haemostasis (ISTH 2011), Kyoto, Japan  2011.7 

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  • Distinctive aspirin effect on the arachidonic acid pathway, oxidative stress, Nitric oxide metabolites and P-selectin in diabetes mellitus International conference

    Lopez LR, Muncy I, Matsuura E, Batuca J, Guyer K, Garcia-De La Torre I, Ames PRJ

    Congress of the International Society on Thrombosis and Haemostasis (ISTH 2011), Kyoto, Japan  2011.7 

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  • Simultaneous occurrence of natural immunity, atherogenic in vivo LDL oxidation and thromboxane-mediated platelet activation in atherosclerosis-prone (LDLR+/- apoE+/-) mice International conference

    Matsuura E, Shen L, Matsunami Y, Quan N, Kobayashi K, Shoenfeld Y, Oguma K, Lopez LR

    Congress of the International Society on Thrombosis and Haemostasis (ISTH 2011), Kyoto, Japan  2011.7 

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  • Anti-atherogenic effects of Persimmon (Diospyros Kaki) peel in LDLR-/--deficient mice. Plaque reduction, inhibition of oxLDL/β2GPI autoantigeni and thromboxane platelet activation International conference

    Matsuura E, Quan N, Kobayashi K, Matsunami Y, Ide M, Makarova M, Shen L, Ohno S, Zheng Y, Kobayashi H, Lopez LR

    European Atherosclerosis Society Congress (EAS 2011), Gothenburg, Sweden  2011.6 

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  • Differential effect of aspirin on oxidative stress, thromboxane, nitric oxide metabolites and P-selectin in type 2 diabetes mellitus International conference

    Lopez LR, Muncy I, Matsuura E, Batuca J, Oregon-Miranda A, Garcia De, La Torre I, Ames PR

    European Atherosclerosis Society Congress (EAS 2011), Gothenburg, Sweden  2011.6 

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  • Atherogenic in vivo oxidation, thromboxane-mediated platelet activation and simultaneous occurrence of natural immunity in atherosclerosis-prone (LDLR-/- and ApoE-/-) mice International conference

    Matsuura E, Shen L, Matsunami Y, Quan N, Kobayashi K, Shoenfeld Y, Oguma K, Lopez LR

    European Atherosclerosis Society Congress (EAS 2011), Gothenburg, Sweden  2011.6 

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  • Atherogenic oxLDL/β2GPI and nitric oxide metabolites in type 2 diabetes: baseline relationships and effect of rosuvastatin treatment International conference

    Ames PRJ, Garcia-De La Torre I, Batuca J, Ortiz-Cadenas A, Oregon-Miranda A, Kojima K, Matsuura E, Lopez LR

    International Congress on Autoimmunity, Ljubljana, Slovenia  2011.5 

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  • Accelerated Atherosclerosis in APS Invited International conference

    Matsuura E

    International Congress on APL antibodies, Galveston, Texas, USA  2010.8 

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  • Oxidized-LDL/β2-glycoprotein I complexes and antiphospholipid antibodies are associated with disease severity and risk for adverse outcomes in acute coronary syndrome International conference

    Lopez LR, Greco TP, Conti-Kelly AM, Anthony JR, Doyle R, Geske FJ, Boisen M, Matsuura E

    European Atherosclerosis Society Congress, Hamburg, Germany  2010.6 

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  • Rosuvastatin promotes antioxidant effect through nitric oxide pathway and reduces serum levels of oxidized-LDL/β2GPI complexes in patients with diabetes mellitus International conference

    Lopez LR, Ames PRJ, Batuca J, Garcia-De La Torre I, Kojima K, Matsuura E

    European Atherosclerosis Society Congress, Hamburg, Germany  2010.6 

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  • Co-presence of oxidized-LDL/β2-glycoprotein I complexes and antiphospholipid antibodies enhances the risk of adverse cardiovascular events International conference

    Lopez LR, Greco TP, Conti-Kelly AM, Anthony R, Greco T Jr, Boisen M, Kojima K, Matsuura E

    International Congress on Autoimmunity, Ljubljana, Slovenia  2010.5 

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  • Pathophysiological roles of β2-glycoprotein (β2GPI) and anti-β2GPI antibodies Invited International conference

    Matsuura E

    International Congress on Autoimmunity, Ljubljana, Slovenia  2010.5 

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  • Effect of bacterial heat shock protein 60 on immunological reactions in Behcet’s disease and in mouse model for atherosclerosis International conference

    Oguma K, Yokota K, Lianhua S, Kaneko F, Isogai E, Matsuura E

    International Congress on Autoimmunity, Ljubljana, Slovenia  2010.5 

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  • The role of oxidized LDL/β2GPI complexes and anti-β2GPI antibodies in autoimmune-mediated atherosclerosis International conference

    Lopez LR, Greco T, Conti-Kelly AM, Anthony R, Boisen M, Kojima K, Matsuura E

    International Congress on APL antibodies, Galveston, Texas, USA  2010.4 

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  • The role of oxidized LDL/β2GPI complexes and anti-β2GPI antibodies in autoimmune-mediated atherosclerosis. Atherogenic oxLDL/β2GPI complexes and nitric oxide metabolites in type 2 DM: baseline relationships and effect of Rosuvastatin treatment International conference

    Ames PRJ, Garcia-De La Torre I, Batuca J, Kojima K, Matsuura E, Lopez LR

    International Congress on APL antibodies, Galveston, Texas, USA  2010.4 

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  • 自己免疫・感染免疫が惹起する動脈血栓 Invited

    松浦栄次

    岡山研究皮膚科フォーラム  2010.1 

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  • APL antibodies (anti-β2GPI and anti-oxLDL/β2GPI) predict adverse outcomes in patients with acute coronary syndromes International conference

    Greco T, Conti-Kelly AM, Doyle R, Greco T Jr, Matsuura E, Anthony R, Lopez LR

    International Congress on Coronary Artery Disease, Prague, Czech Republic  2009.10 

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  • Elevated serum levels of oxidized LDL/β2GPI complexes increase the risk for cardiovascular adverse outcomes in patients with acute coronary syndromes International conference

    Lopez LR, Conti-Kelly AM, Doyle R, Kojima K, Matsuura E, Anthony R, Greco T

    International Congress on Coronary Artery Disease, Prague, Czech Republic  2009.10 

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  • Rosuvastatin reduces serum levels of oxidized LDL/β2GPI complexes in patients with type 2 DM International conference

    Lopez LR, Ortiz-Cadenas A, Garcia-De La Torre I, Nava A, Oregon-Miranda A, Kojima K, Matsuura E

    International Congress on Coronary Artery Disease, Prague, Czech Republic  2009.10 

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  • Atherogenesis an angiogenesis in autoimmunity Invited International conference

    Matsuura E

    Asian Congress on Autoimmunity. Singapore  2009.9 

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  • Immunity in infection-triggered atherosclerosis Invited International conference

    Matsuura E

    International Congress on Autoimmunity. Porto, Portugal  2008.9 

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  • Antiphospholipid antibodies predict adverse outcomes in patients with acute coronary syndrome International conference

    Greco T, Conti-Kelly AM, Doyle R, Matsuura E, Lopez LR

    International Congress on Autoimmunity. Porto, Portugal  2008.9 

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  • Oxidized low-density lipoprotein I and β2-glycoprotrein I in patients with systemic lupus erythematosus: implications in autoimmune-mediated atherosclerosis International conference

    Lopez LR, Salazar-Paramo M, Palafox-Sanchez C, Matsuura E, Garcia De La Torre I

    International Congress on Autoimmunity. Porto, Portugal  2008.9 

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  • Atherothrombosis in autoimmunity Invited International conference

    Matsuura E

    International Congress on Autoimmunity. Porto, Portugal  2008.9 

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  • Recent progress in understanding on immune- and infection-mediated atherosclerosis and cardiovascular disease Invited International conference

    Matsuura E

    Moscow International Conference “Immunophysiology: Natural Autoimmunity in Physiology and Pathology. Moscow, Russia  2008.9 

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  • An abnormal lipid profile in primary antiphospholipid syndrome relates to oxidized low-density lipoprotein bound to β2-glycoprotein I International conference

    Ames A, Batuca J, Foglia M, Delgado Alves J, Ciampa A, Antinolfi I, Lopez LR, Matsuura E

    International Congress on Autoimmunity. Porto, Portugal  2008.9 

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  • Antiphospholipid Syndrome and pro-atherogenic oxidized low-density lipoprotein β2-glycoprotein I complexes Invited International conference

    Matsuura E

    International Conference on Cutaneous Lupus Erythematosus, Kyoto, Japan  2008.5 

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  • Low grade inflammation and in vivo immune activation in primary antiphospholipid syndrome International conference

    Ames PR, Ciampa A, Matsuura E, Lopez LR, Scenna G, Antinolfi I, Iannaccone L, Ferrara F

    Annual Meeting of the British Society Rheumatology/Spring Meeting of British Professonal Rheumatology, Liverpool, UK  2008.4 

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  • 自己免疫・感染免疫が惹起する動脈硬化 Invited

    松浦栄次

    第12回九州セロトニン研究会  2008.3 

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  • Preventing autoimmune and infection triggered atherosclerosis for an enduring healthful lifestyle

    The Mosaic of Autoimmunity An International Satellite of the Congress on Autoimmunity  2008 

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  • Are Antiphospholipid Antibodies Risk Factors for Coronary Artery Disease? International conference

    Greco TP, Conti-Kelly AM, Matsuura E, Greco T Jr, Dier KJ, Svanas G, Doyle R, Lopez LR

    International Society on Thrombosis and Haemostasis, Geneva, Switzerland  2007.8 

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  • Reduction of diabetes-related lipid oxidative stress by statin therapy as monitored by serum oxidized LDL/β2GPI complex levels International conference

    Svanas G, Boisen M, Oottamasathein D, Matsuura E, Lopez LR

    International Society on Thrombosis and Haemostasis, Geneva, Switzerland  2007.8 

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  • Association of IgG anti-oxLDL/β2GPI and 2GPI-dependent anti-cardiolipin (aCL) antibodies with vascular thrombosis in patients with antiphospholipid syndrome (APS) International conference

    Svanas G, Boisen M, Oottamasathein D, Matsuura E, Lopez LR

    International Society on Thrombosis and Haemostasis, Geneva, Switzerland  2007.8 

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  • 自己免疫・感染免疫と動脈硬化 Invited

    松浦栄次

    第30回日本基礎老化学会・シンポジウム  2007.6 

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  • Clinical significance of antiphospholipid antibodies and autoimmune-accelerated atherosclerosis Invited International conference

    Matsuura E

    The 2007 Changsha International Symposium on Lupus. Changsha, China  2007.5 

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  • Infection and atherosclerosis Invited International conference

    Matsuura E

    International Congress on SLE. Shanghai, China  2007.5 

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  • Accelerated atherosclerosis in autoimmune rheumatic diseases International conference

    Shoenfeld Y, Gerli R, Doria A, Matsuura E, Cerinic MM, Ronda N, Jara LJ, Abu-Shakra M, Meroni PL, Sherer Y

    International Congress on Autoimmunity, Sorrento, Italy  2006.12 

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  • Antiphospholipid antibodies involved in atherosclerosis in APS International conference

    Kobayashi K, de Groot PG, Matsuura E

    International Congress on Autoimmunity, Sorrento, Italy  2006.12 

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  • ntiphospholipid and anti-oxidized LDL antibodies in patients with undergoing coronary artery angiography International conference

    Greco TP, Conti-Kelly AM, Greco, TP Jr, Dier K, Matsuura E, Lopez LR

    International Congress on Autoimmunity, Sorrento, Italy,  2006.11 

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  • Excessive exposure to anionic surfaces maintains autoimmune response to β2-glycoprotein I in patients with antiphospholipid syndrome International conference

    Yamaguchi Y, Seta N, Okazaki Y, Kaburaki J, Matsuura E, Kuwana M

    American College of Rheumatology (ACR) Meeting Washington DC, USA  2006.11 

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  • ew aspects on autoimmunity, infection, and atherosclerosis Invited International conference

    Matsuura E, Shoenfeld Y

    International Congress on Autoimmunity. Sorrento, Italy  2006.11 

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  • Elicited Th1 immune response to Helicobacter pylori promotes atherosclerosis in mice International conference

    Ayada K, Yokota K, Kobayashi K, Okada T, Yoshino T, Shoenfeld Y, Matsuura E, Oguma K

    International Congress on Autoimmunity, Sorrento, Italy  2006.11 

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  • Atherosclerosis in primary antiphospholipid syndrome International conference

    Ames PRJ, Lopez LR, Margarita A, Scenna G, Matsuura E, Ciampa A, Brancaccio V

    International Congress on Autoimmunity, Sorrento, Italy  2006.11 

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  • Determination of oxidized-LDL versus oxidized-LDL/β2GPI complexes for the assessment of autoimmune-mediated atherosclerosis. Atherosclerosis in primary antiphospholipid syndrome International conference

    Lopez LR, Hurley BL, Kobayashi K, Matsuura E

    International Congress on Autoimmunity, Sorrento, Italy  2006.11 

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  • 自己免疫・感染免疫と動脈硬化 Invited

    松浦栄次

    Helicobacter pyloriフォーラム  2006.9 

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  • Atherosclerosis in primary antiphospholipid syndrome International conference

    Ames PRJ, Margarita A, Scenna G, Lopez LR, Matsuura E, Ciampa A, Brancaccio V

    Congress of the Pan American League of Associations for Rheumatism, Lima, Peru  2006.8 

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  • Measurement of oxidized low-density lipoproteins (oxLDL) and oxLDL/β2GPI complexes by ELISA for the assessment of autoimmune-mediated atherosclerosis International conference

    Lopez LR, Hurley BL, Matsuura E

    Congress of the Pan American League of Associations for Rheumatism, Lima, Peru  2006.8 

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  • Autoimmune-mediated atherosclerosis: Carotid intima-media thickness and oxidized low-density lipoproteins in SLE International conference

    Palofox-Sanchez C, Salazar-Paramo M, Lopez LR, Matsuura E, Garcia de, la Torre I

    Congress of the Pan American League of Associations for Rheumatism, Lima, Peru  2006.8 

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  • Update “Autoimmunity and atherosclerosis" Invited International conference

    Matsuura E

    Methodist Hospital Special Lecture. Indianapolis, USA  2006.6 

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  • 酸化LDL・2-glycoprotein Iと動脈硬化性疾患 Invited

    松浦栄次

    第13回自己抗体と自己免疫シンポジウム「臓器特異的自己抗体 ―新たな展開―」  2006.1 

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  • Clinical significance of natural and autoantibodies against oxidized low-density lipoprotein (oxLDL) and its complexes with β2-glycoprotein I Invited International conference

    Matsuura E

    Moscow International Working Conference "Natural Autoimmunity in Physiology and Pathology. Moscow, Russia  2005.9 

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  • Autoantibodies to oxLDL/β2GPI complexes and autoimmune-mediated athero-thrombotic disease in patients with systemic autoimmune disorders and antiphospholipid syndrome Invited International conference

    Matsuura E, Lopez LR

    Scientific Subcommittees of the Scientific and Standardization Committee. International Society on Thrombosis and Haemostasis, Sydney, Australia  2005.7 

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  • Basic and clinical aspects on oxidized LDL complexes with 2-glycoprotein I and CRP Invited International conference

    Matsuura E

    Conference on Heart, Rheumatism, and Autoimmunity, Pescara, Italy  2005.5 

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  • Clinical significance of protein-oxLDL complexes and related autoantibodies Invited International conference

    Matsuura E

    Tutzing Antiphospholipid Conference. Tutzing, Germany  2005.4 

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  • Pro-atherogenic role for IgG anti-oxidized low-density lipoprotein-β2-glycoprotein I complex in primary antiphospholipid syndrome International conference

    Ames PRJ, Delgado Alves J, Lopez LR, Iannaccone L, Margarita A, Scenna G, Brancaccio V, Matsuura E

    International Congress on Autoimmunity, Budapest, Hungary  2004.11 

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  • IgG and IgM anti-oxLDL/β2GPI antibodies in patients with autoimmune disorders and antiphospholipid syndrome International conference

    Lopez LR, Kuca J, Hurley B, Fink C, Matsuura E

    International Congress on Autoimmunity, Budapest, Hungary  2004.11 

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  • IgG anti-oxLDL/β2GPI antibodies in the antiphospholipid syndrome: association with arterial thrombosis International conference

    Lopez LR, Dier K, Andrews J, Fink C, Merrill, JT, Matsuura E

    International Congress on Antiphospholipid Antibodies, Sydney, Australia  2004.11 

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  • T lymphocyte subsets in primary antiphospholipid syndrome International conference

    Ames PRJ, Tommasino C, Fossati G, Lopez LR, Matsuura E, Margarita A, Scenna G, Brancaccio V

    International Congress on Antiphospholipid Antibodies, Sydney, Australia  2004.11 

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  • Reduced concentration of β2-GPI in RA and aPL positive patients - a probable marker of accelerated atherosclerosis? International conference

    Ambrozic A, Pahor V, Rozman B, Tomsic M, Kveder T, Kobayashi K, Matsuura E

    International Congress on Autoimmunity, Budapest, Hungary  2004.11 

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  • Anti-laminin-1 autoantibodies, pregnancy loss and endometriosis International conference

    Inagaki J, Kondo A, Lopez LR, Shoenfeld Y, Matsuura E

    nternational Congress on Autoimmunity, Budapest, Hungary  2004.11 

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  • OxLDL/β2GPI complexes in patients with systemic lupus erythematosusu and systemic sclerosis: pathogenic implications for vascular involvement International conference

    Lopez LR, Hurley B, Dier K, Fink C, Matsuura E

    International Congress on Autoimmunity, Budapest, Hungary  2004.11 

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  • The relationship of oxLDL, β2GPI andβ2GPI-oxLDL complexes in patients with APS International conference

    Ambrozic A, Kveder T, Rosman B, Matsuura E

    International Congress on Antiphospholipid Antibodies, Sydney, Australia,  2004.11 

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  • Circulation oxLDL/β2GPI complexes in autoimmune disease: pathogenic implications for systemic lupus erythematosus and systemic sclerosis International conference

    Lopez LR, Dier K, Hurley B, Kuca J, Fink C, Matsuura E

    International Congress on Antiphospholipid Antibodies, Sydney, Australia  2004.11 

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  • OxLDL/β2GPI complexes in type II diabetes mellitus International conference

    Lopez LR, Hurley B, Kuca J, Dier K, Fink C, Matsuura E

    International Congress on Antiphospholipid Antibodies, Sydney, Australia  2004.11 

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  • Role of natural antibodies and autoantibodies on development of atherosclerosis International conference

    Matsuura E, Kobayashi K, Shoenfeld Y, Lopez LR

    International Congress on Autoimmunity, Budapest, Hungary  2004.11 

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  • IgG antibodies to oxLDL/β2GPI complexes are associated with arterial thrombosis in patients with antiphospholipid syndrome International conference

    Lopez LR, Kuca J, Hurley B, Andrews J, Fink C, Merrill JT, Matsuura E

    International Congress on Autoimmunity, Budapest, Hungary  2004.11 

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  • Thrombogenic autoantigen in APS Invited International conference

    Matsuura E

    International Congress of Reproductive Immunology. Hakone, Japan  2004.10 

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  • icked β2-glycoprotein I binds plasminogen and play a role in extrinsic fibrinolysis via negative feedback mechanism International conference

    Yasuda S, Atsumi T, Ieko M, Matsuura E, Amasaki Y, Koike T

    American College of Rheumatology (ACR) Meeting, San Antonio, USA  2004.10 

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  • Anti-laminin-1 autoantibodies in endometriosis International conference

    Inagaki J, Nakatsuka M, Nomizu M, Aoki K, Matsuura E

    International Congress of Reproductive Immunology, Hakone, Japan  2004.10 

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  • Anti-laminin-1 autoantibodies in reproductive failure: human and animal studies Invited International conference

    Matsuura E

    Dresden Symposium on Autoantibodies. Dresden, Germany  2004.9 

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  • Atherogenic role of protein modified oxidized low-density lipoproteins and their autoantibodies Invited International conference

    Matsuura E

    Dresden Symposium on Autoantibodies. Dresden, Germany  2004.9 

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  • 抗リン脂質抗体と酸化LDL Invited

    松浦栄次

    臨床化学会夏期セミナー(シンポジウム)  2004.8 

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  • Oxidized low-density lipoprotein complexed with β2-glycoprotein I: a common metabolic form and a possible thrombogenic autoantigen International conference

    Matsuura E, Kobayashi K, Yasuda T, Makino H, Lopez LR

    International Congress of Immunology, Montreal, Canada  2004.7 

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  • Hybridomas expressing γδT cell receptor respond to cardiolipin and β2-glycoprotein I (apolipoprotein H) International conference

    Born W, Vollmer M, Readon C, Matsuura E, Voelker DR

    International Congress of Immunology, Montreal, Canada  2004.7 

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  • Autoantibodies to β2GPI/oxLDL complexes: a novel risk factor for thromboembolic disease in SLE? International conference

    Lopez LR, Garcia De, La Torre I, Matsuura E

    Int Congress on Thrombosis. Ljubljana, Slovenia  2004.6 

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  • Carboxyl variants of cholesteryl-linoleate as a ligand for β2-GPI and a possible mechanism on autoantibody mediated atherosclerosis Invited International conference

    Matsuura E

    Tutzing Antiphospholipid Conference. Tutzing, Germany  2004.4 

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  • Binding of β2-glycoprotein I to anionic phospholipids facilitates processing and presentation of a cryptic epitope that activates pathogenic autoreactive T cells International conference

    Kuwana M, Okazaki Y, Kaburaki J, Kawakami Y, Matsuura E

    American College of Rheumatology (ACR) Meeting, Orlando, USA  2003.10 

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  • Anti-idiotypes against oxidized LDL antibodies intravenous immunoglobulin preparations explanation for its immunomolulatory effects in atherosclerosis International conference

    Sherer Y, Wu R, Matsuura E, Gilburd B, Koike T, Peter JB, Shoenfeld Y

    Annual European Congress of Rheumatology, Lisbon, Portugal  2003.7 

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  • IgG autoantibodies to oxLig-1/β2GPI complex are associated with arterial thrombosis in patients with antiphospholipid syndrome International conference

    Lopez D, Merrill JT, Matsuura E, Lopez LR

    Congress of the International Society on Thrombosis and Haemostasis, Birmingham, UK  2003.7 

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  • Detection and clinical significance of oxidized LDL complexes with β2-glycoprotein I and/or C-reactive protein International conference

    Kobayashi, K, Kishi M, Atsumi T, Bertolaccini ML, Kasahara J, Makino H, Sakairi N, Yamamoto I, Yasuda T, Khamashta MA, Hughes GRV, Koike T, Voelker DR, Matsuura E

    Atherosclerosis, Gordon Research Conference, Meriden, USA  2003.6 

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  • OxLDL/β2GPI complexes are frequent in SLE whereas autoantibodies to oxLig-1/β2GPI are more prevalent in patients with antiphospholipid syndrome International conference

    Lopez D, Garcia-Valladares I, Palafox-Sanchez C, Matsuura E, De La Torre IG, Lopez LR

    Congress of the International Society on Thrombosis and Haemostasis, Birmingham, UK  2003.6 

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  • 酸化LDL研究の現状と将来.概論・臨床面・近年の動向 Invited

    松浦栄次

    第13回日本生物試料分析学会総会・シンポジウム  2003.3 

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  • Increased levels of oxidized-LDL and autoantibodies to oxLig-1/β2GPI Complex in systemic lupus erythematosus International conference

    Matalon ST, Blank M, Matsuura E, Inagaki J, Nomizu M, Koike T, Sherer Y, Ornoy A, Lopez LR, Lopez D, Dier KJ, Fink CA, Kobayashi K, Matsuura E

    American College of Rheumatology Annual Scientific Meeting, New Orleans, USA  2002.10 

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  • Determination and significance of Autoantibodies to oxLig-1/β2GPI complex in patients with APS International conference

    Lopez D, Garcia-Valladares I, Dier K, Fink C, Kobayashi K, Matsuura E, Lopez LR

    International Congress on Antiphospholipid Antibodies, Taormina, Italy  2002.10 

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  • Oxidized LDL, not anti-oxidized LDL, predicts coronary calcification International conference

    Petri M, Shoenfeld Y, Matsuura E

    American