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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1552-1557. Prepublished online as a Blood First Edition Paper on October 14, 2004; DOI 10.1182/blood-2004-08-3145. This Article Full Text (PDF) All Versions of this Article: 2004-08-3145v1 105/4/1552    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kuwana, M. Articles by Kawakami, Y. Search for Related Content PubMed PubMed Citation Articles by Kuwana, M. Articles by Kawakami, Y. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 13, 2004 Accepted October 6, 2004 Binding of 2-Glycoprotein I to anionic phospholipids facilitates processing and presentation of a cryptic epitope that activates pathogenic autoreactive T cells Masataka Kuwana*, Eiji Matsuura, Kazuko Kobayashi, Yuka Okazaki, Junichi Kaburaki, Yasuo Ikeda, and Yutaka Kawakami Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan Department of Cell Chemistry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan Department of Internal Medicine, Tokyo Electric Power Company Hospital, Tokyo, Japan Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan * Corresponding author; email: kuwanam{at}sc.itc.keio.ac.jp. Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder in association with autoantibodies to phospholipid (PL)-binding plasma proteins, such as 2-glycoprotein I (2GPI). We have recently found that autoreactive CD4+ T cells to 2GPI in APS patients 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 become visible to the immune system and elicit a pathogenic autoimmune response to 2GPI. Here we show that presentation of a disease-relevant cryptic T-cell determinant in 2GPI is induced as a direct consequence of antigen-processing from 2GPI bound to anionic PL. Dendritic cells or macrophages pulsed with PL-bound 2GPI induced a response of p276-290-specific CD4+ T cell-lines generated from the patients in HLA-DR-restricted and antigen-processing-dependent manners, but those with 2GPI 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 2GPI in vitro. Our finding is the first demonstration of an in vitro mechanism eliciting pathogenic autoreactive T-cell responses to 2GPI, and should be useful in clarifying the pathogenesis of APS. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: The cryptic path from epitope to clot: a story of 2 domains? Mark A. Vickers and Mike Greaves Blood 2005 105: 1371-1372. [Full Text] [PDF] This article has been cited by other articles: T. Atsumi New therapeutic targets for antiphospholipid syndrome Blood, December 15, 2007; 110(13): 4141 - 4141. [Full Text] [PDF] Y. Yamaguchi, N. Seta, J. Kaburaki, K. Kobayashi, E. Matsuura, and M. Kuwana Excessive exposure to anionic surfaces maintains autoantibody response to 2-glycoprotein I in patients with antiphospholipid syndrome Blood, December 15, 2007; 110(13): 4312 - 4318. [Abstract] [Full Text] [PDF] K. Kobayashi, K. Tada, H. Itabe, T. Ueno, P.-H. Liu, A. Tsutsumi, M. Kuwana, T. Yasuda, Y. Shoenfeld, P.G. de Groot, et al. Distinguished effects of antiphospholipid antibodies and anti-oxidized LDL antibodies on oxidized LDL uptake by macrophages Lupus, December 1, 2007; 16(12): 929 - 938. [Abstract] [PDF] K. KOBAYASHI, L. R LOPEZ, and E. MATSUURA Atherogenic Antiphospholipid Antibodies in Antiphospholipid Syndrome Ann. N.Y. Acad. Sci., June 1, 2007; 1108(1): 489 - 496. [Abstract] [Full Text] [PDF] B. Giannakopoulos, F. Passam, S. Rahgozar, and S. A. Krilis Current concepts on the pathogenesis of the antiphospholipid syndrome Blood, January 15, 2007; 109(2): 422 - 430. [Abstract] [Full Text] [PDF] J Swadzba, M Sanak, T Iwaniec, S Dziedzina, and J Musial Valine/Leucine247 polymorphism of {beta}2-glycoprotein I in patients with antiphospholipid syndrome: lack of association with anti-{beta}2-glycoprotein I antibodies Lupus, April 1, 2006; 15(4): 218 - 222. [Abstract] [PDF] B. de Laat, R. H. W. M. Derksen, M. van Lummel, M. T. T. Pennings, and P. G. de Groot Pathogenic anti-beta2-glycoprotein I antibodies recognize domain I of beta2-glycoprotein I only after a conformational change Blood, March 1, 2006; 107(5): 1916 - 1924. [Abstract] [Full Text] [PDF] B. Buttari, E. Profumo, V. Mattei, A. Siracusano, E. Ortona, P. Margutti, B. Salvati, M. Sorice, and R. Rigano Oxidized {beta}2-glycoprotein I induces human dendritic cell maturation and promotes a T helper type 1 response Blood, December 1, 2005; 106(12): 3880 - 3887. [Abstract] [Full Text] [PDF] M. van Lummel, M. T. T. Pennings, R. H. W. M. Derksen, R. T. Urbanus, B. C. H. Lutters, N. Kaldenhoven, and P. G. de Groot The Binding Site in {beta}2-Glycoprotein I for ApoER2' on Platelets Is Located in Domain V J. Biol. Chem., November 4, 2005; 280(44): 36729 - 36736. [Abstract] [Full Text] [PDF]

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