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Prepublished online as a Blood First Edition Paper on January 16, 2003; DOI 10.1182/blood-2002-08-2349. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-08-2349v1 101/9/3495    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Raschi, E. Articles by Meroni, P. L. Search for Related Content PubMed PubMed Citation Articles by Raschi, E. Articles by Meroni, P. L. Related Collections Hemostasis, Thrombosis, and Vascular Biology Signal Transduction Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 May 2003, Vol. 101, No. 9, pp. 3495-3500 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Brief report Role of the MyD88 transduction signaling pathway in endothelial activation by antiphospholipid antibodies Elena Raschi, Cinzia Testoni, Daniela Bosisio, Maria O. Borghi, Takao Koike, Alberto Mantovani, and Pier Luigi Meroni From the Istituto di Ricovero e Aura a Carattere Scientifico (IRCCS) Istituto Auxologico Italiano, Allergy and Clinical Immunology Unit, Milan, Italy; Mario Negri Institute, Department of Immunology and Cell Biology, Milan, Italy; University of Milan, Department of Internal Medicine, Italy; Okkaido University School of Medicine, Department of Medicine II, Sapporo, Japan; and University of Milan, Department of Pathology, Italy. Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the persistent presence of antiphospholipid antibodies (aPLs) and recurrent thrombosis or fetal loss. The thrombophilic state has been partially related to the induction of a proinflammatory and procoagulant endothelial cell (EC) phenotype induced by anti-2-glycoprotein I (2-GPI) antibodies that bind 2-GPI expressed on the EC surface. Anti-2-GPI antibody binding has been shown to induce nuclear factor-B (NF-B) translocation leading to a proinflammatory EC phenotype similar to that elicited by interaction with microbial products (lipopolysaccharide [LPS]) and proinflammatory cytokines (interleukin 1 [IL-1], tumor necrosis factor  [TNF-]). However, the upstream signaling events are not characterized yet. To investigate the endothelial signaling cascade activated by anti-2-GPI antibodies, we transiently cotransfected immortalized human microvascular endothelial cells (HMEC-1) with dominant-negative constructs of different components of the pathway (TRAF2, TRAF6, MyD88) together with reporter genes (NF-B luciferase and pCMV--galactosidase). Results showed that both human anti-2-GPI IgM monoclonal antibodies as well as polyclonal affinity-purified anti-2-GPI IgG display a signaling cascade comparable to that activated by LPS or IL-1. TRAF6 and MyD88 significantly abrogate antibody-induced as well as IL-1- or LPS-induced NF-B activation, whereas TRAF2 (involved in NF-B activation by TNF) does not affect it. Moreover, anti- 2-GPI antibodies and LPS followed the same time kinetic of IL-1 receptor-activated kinase (IRAK) phosphorylation, suggesting an involvement of the toll-like receptor (TLR) family. Our findings demonstrate that anti-2-GPI antibodies react with their antigen likely associated to a member of the TLR/IL-1 receptor family on the EC surface and directly induce activation. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Z. Romay-Penabad, M. G. Montiel-Manzano, T. Shilagard, E. Papalardo, G. Vargas, A. B. Deora, M. Wang, A. T. Jacovina, E. Garcia-Latorre, E. Reyes-Maldonado, et al. Annexin A2 is involved in antiphospholipid antibody-mediated pathogenic effects in vitro and in vivo Blood, October 1, 2009; 114(14): 3074 - 3083. [Abstract] [Full Text] [PDF] K Oku, T Atsumi, M Bohgaki, O Amengual, H Kataoka, T Horita, S Yasuda, and T Koike Complement activation in patients with primary antiphospholipid syndrome Ann Rheum Dis, June 1, 2009; 68(6): 1030 - 1035. [Abstract] [Full Text] [PDF] R. Urbanus, R. 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