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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 (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 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. Social Bookmarking                   What's this? Submitted August 1, 2002 Accepted December 24, 2002 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* Allergy and Clinical Immunology Unit, IRCCS Istituto Auxologico Italiano, Milan, Italy Department of Immunoloy and Cell Biology, Mario Negri Institute, Milan, Italy Department of Internal Medicine, University of Milan, Milan, Italy Department of Medicine II, Okkaido University School of Medicine, Sapporo, Japan Department of Pathology, University of Milan, Milan, Italy * Corresponding author; email: pierluigi.meroni{at}unimi.it. Antiphospholipid Syndrome (APS) is an autoimmune disease characterized by the persistent presence of anti-phospholipid antibodies (aPL) and recurrent thrombosis and/or fetal loss. The thrombophilic state has been partially related to the induction of a pro-inflammatory and pro-coagulant endothelial cell (EC) phenotype induced by anti-beta 2 glycoprotein I (2GPI) antibodies that bind 2GPI expressed on the EC surface. Anti-2GPI antibody binding has been shown to induce Nuclear Factor-B (NF-B) translocation leading to a pro-inflammatory EC phenotype similar to that elicited by interaction with microbial products (LPS) and pro-inflammatory cytokines (IL-1, TNF). However, the upstream signaling events are not characterized yet. In order to investigate the endothelial signaling cascade activated by anti-2GPI antibodies, we transiently co-transfected 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-2GPI IgM monoclonal antibodies as well as polyclonal affinity purified anti-2GPI IgG display a signaling cascade comparable to that activated by LPS or IL-1. TRAF6 and MyD88 significantly abrogate antibody- as well as IL-1- or LPS-induced NF-B activation, while TRAF2 (involved in NF-B activation by TNF) does not affect it. Moreover anti-2GPI antibodies and LPS followed the same time kinetic of IL-1 receptor-activated kinase (IRAK) phosphorilation, suggesting an involvement of the Toll Like Receptor (TLR) family. Altogether our findings demonstrate that anti-2GPI antibodies react with their antigen likely associated to a member of the TRL/IL-1 receptor family on EC surface and directly induce activation. 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. 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