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Biotech / Medical : Neurogen (NRGN) -- Ignore unavailable to you. Want to Upgrade?

To: Miljenko Zuanic who wrote (382)	12/5/2003 2:38:03 AM
From: Miljenko Zuanic	Read Replies (1) \| Respond to of 523

J. Clin. Invest. 112:1644-1654 (2003). doi:10.1172/JCI200318817. Copyright ©2003 by the American Society for Clinical Investigation Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome Guillermina Girardi1, Jessica Berman1, Patricia Redecha1, Lynn Spruce2, Joshua M. Thurman3, Damian Kraus3, Travis J. Hollmann4, Paolo Casali1, Michael C. Caroll5, Rick A. Wetsel4, John D. Lambris2, V. Michael Holers3 and Jane E. Salmon1 1Department of Medicine, Hospital for Special Surgery–Weill Medical College, Cornell University, New York, New York, USA 2Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA 3Departments of Medicine and Immunology, University of Colorado Health Sciences Center, Denver, Colorado, USA 4Institute of Molecular Medicine, University of Texas–Houston, Houston, Texas, USA 5Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA Address correspondence to: Jane E. Salmon, Hospital for Special Surgery–Weill Medical College, Cornell University, 535 East 70th Street, New York, New York 10021, USA. Phone: (212) 606-1422; Fax: (212) 717-1192; E-mail: salmonj@hss.edu. Received for publication May 2, 2003, and accepted in revised form September 23, 2003. Antiphospholipid syndrome (APS) is defined by recurrent pregnancy loss and thrombosis in the presence of antiphospholipid (aPL) Ab’s. Currently, therapy for pregnant women with APS is focused on preventing thrombosis, but anticoagulation is only partially successful in averting miscarriage. We hypothesized that complement activation is a central mechanism of pregnancy loss in APS and tested this in a model in which pregnant mice receive human IgG containing aPL Ab’s. Here we identify complement component C5 (and particularly its cleavage product C5a) and neutrophils as key mediators of fetal injury, and we show that Ab’s or peptides that block C5a–C5a receptor interactions prevent pregnancy complications. The fact that F(ab)'2 fragments of aPL Ab’s do not mediate fetal injury and that C4-deficient mice are protected from fetal injury suggests that activation of the complement cascade is initiated via the classical pathway. Studies in factor B–deficient mice, however, indicate that alternative pathway activation is required and amplifies complement activation. In contrast, activating FcRs do not play an important role in mediating aPL Ab–induced fetal injury. Our findings identify the key innate immune effectors engaged by pathogenic autoantibodies that mediate poor pregnancy outcomes in APS and provide novel and important targets for prevention of pregnancy loss in APS.