Complement C3 activation is required for antiphospholipid antibody-induced fetal loss

• Published in: The Journal of experimental medicine 2002-01, Vol.195 (2), p.211-220
• Main Authors: Holers, V Michael, Girardi, Guillermina, Mo, Lian, Guthridge, Joel M, Molina, Hector, Pierangeli, Silvia S, Espinola, Ricardo, Xiaowei, Liu E, Mao, Dailing, Vialpando, Christopher G, Salmon, Jane E
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Antiphospholipid - immunology; antiphospholipid antibodies; antiphospholipid syndrome; Antiphospholipid Syndrome - blood; Antiphospholipid Syndrome - immunology; Antiphospholipid Syndrome - physiopathology; Complement Activation - immunology; Complement C3 - genetics; Complement C3 - immunology; complement component C3; Epitopes - immunology; Female; Fetal Death - immunology; Humans; Mice; Mice, Inbred BALB C; Mice, Knockout; Original; Pregnancy
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.200116116

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.