First published February 15, 2004 - More info
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 FcγRs 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.
Guillermina Girardi, Jessica Berman, Patricia Redecha, Lynn Spruce, Joshua M. Thurman, Damian Kraus, Travis J. Hollmann, Paolo Casali, Michael C. Caroll, Rick A. Wetsel, John D. Lambris, V. Michael Holers, Jane E. Salmon
Original citation: J. Clin. Invest.112:1644–1654 (2003). doi:10.1172/JCI18817.
Citation for this corrigendum: J. Clin. Invest.113:646 (2004). doi:10.1172/JCI18817C1.
During the preparation of this manuscript for publication, an error was included in the Acknowledgments section. The corrected Acknowledgments appears below.
This research was supported by the Alliance for Lupus Research (J.E. Salmon and V.M. Holers), the Mary Kirkland Center for Lupus Research (J.E. Salmon), the S.L.E. Foundation Inc. (J.E. Salmon),the National Kidney Foundation (J.M. Thurman), and NIH grants AI-31105 (to V.M. Holers), AI-25011 (to R.A. Wetsel), and GM-62134 (to J.D. Lambris).