title: Complement C3 activation is required for antiphospholipid antibody-induced fetal loss.
abstract: 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.
authors.affiliation: Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
authors.forename: Guillermina
authors.initials: G
authors.lastname: Girardi
authors.forename: Lian
authors.initials: L
authors.lastname: Mo
authors.forename: Joel M
authors.initials: JM
authors.lastname: Guthridge
authors.forename: Hector
authors.initials: H
authors.lastname: Molina
authors.forename: Silvia S
authors.initials: SS
authors.lastname: Pierangeli
authors.forename: Ricardo
authors.initials: R
authors.lastname: Espinola
authors.forename: Liu E
authors.initials: LE
authors.lastname: Xiaowei
authors.forename: Dailing
authors.initials: D
authors.lastname: Mao
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Vialpando
authors.forename: Jane E
authors.initials: JE
authors.lastname: Salmon
mesh_terms: D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000276:immunology*; D016736:Antiphospholipid Syndrome / Q000097:blood / Q000276:immunology* / Q000503:physiopathology; D003167:Complement Activation / Q000276:immunology; D003176:Complement C3 / Q000235:genetics / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D005260:Female; D005313:Fetal Death / Q000276:immunology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011247:Pregnancy
chemical_list: D017152:Antibodies, Antiphospholipid; D003176:Complement C3; D000939:Epitopes