TY - JOUR
T1 - Complement C3 activation is required for antiphospholipid antibody-induced fetal loss
AU - Michael Holers, V.
AU - Girardi, Guillermina
AU - Mo, Lian
AU - Guthridge, Joel M.
AU - Molina, Hector
AU - Pierangeli, Silvia S.
AU - Espinola, Ricardo
AU - Xiaowei, Liu E.
AU - Mao, Dailing
AU - Vialpando, Christopher G.
AU - Salmon, Jane E.
PY - 2002/1/21
Y1 - 2002/1/21
N2 - 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.
AB - 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.
KW - Anticardiolipin antibodies
KW - Complement
KW - Lupus
KW - Pregnancy
KW - Thrombosis
UR - http://www.scopus.com/inward/record.url?scp=0037148520&partnerID=8YFLogxK
U2 - 10.1084/jem.200116116
DO - 10.1084/jem.200116116
M3 - Article
C2 - 11805148
AN - SCOPUS:0037148520
SN - 0022-1007
VL - 195
SP - 211
EP - 220
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 2
ER -