The Journal of Experimental Medicine
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Published 22 January 2002. doi:10.1084/jem.200116116
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© Rockefeller University Press, 0022-1007/2002/1/211/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 2, January 21, 2002 211-220

Original Article

 Complement C3 Activation Is Required for Antiphospholipid Antibody-induced Fetal Loss

V. Michael Holers1, Guillermina Girardi2, Lian Mo2, Joel M. Guthridge1, Hector Molina3, Silvia S. Pierangeli4, Ricardo Espinola4, Liu E. Xiaowei4, Dailing Mao3, Christopher G. Vialpando1 and Jane E. Salmon2

1 Departments of Medicine and Immunology, University of Colorado Health Sciences Center, Denver, CO 80262
2 Department of Medicine, Hospital for Special Surgery-Weill Medical College, Cornell University, New York, NY 10021
3 Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
4 Department of Microbiology-Immunology, Morehouse School of Medicine, Atlanta, GA 30310

Address correspondence to Jane E. Salmon, Hospital for Special Surgery, 535 E. 70th St., New York, NY 10021. Phone: 212-606-1422; Fax: 212-717-1192; E-mail: salmonj{at}hss.edu

The antiphospholipid syndrome (APS) is characterized by recurrent fetal loss, vascular thrombosis, and thrombocytopenia occurring in the presence of antiphospholipid (aPL) antibodies. The pathogenesis of fetal loss and tissue injury in APS is incompletely understood, but is thought to involve platelet and endothelial cell activation as well as procoagulant effects of aPL antibodies acting directly on clotting pathway components. Recent studies have shown that uncontrolled complement activation in the placenta leads to fetal death in utero. We hypothesized that aPL antibodies activate complement in the placenta, generating split products that mediate placental injury and lead to fetal loss and growth retardation. To test this hypothesis, we used a murine model of APS in which pregnant mice are injected with human IgG containing aPL antibodies. We found that inhibition of the complement cascade in vivo, using the C3 convertase inhibitor complement receptor 1–related gene/protein y (Crry)-Ig, blocks fetal loss and growth retardation. Furthermore, mice deficient in complement C3 were resistant to fetal injury induced by aPL antibodies. While antigenic epitopes recognized by aPL antibodies are important in the pathogenesis of APS, our data show that in vivo complement activation is required for aPL antibody-induced fetal loss and growth retardation.

Key Words: complement • anticardiolipin antibodies • pregnancy • thrombosis • lupus


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