Complement inhibition keeps mothers calm and avoids fetal rejection.
The paternal antigens presented by the fetus could be considered foreign by the mother's immune system and elicit an immune response. Here we show that the complement system functions as an effector in fetal rejection in two different mouse models of pregnancy loss. In a mouse model of fetal loss and growth restriction (IUGR) induced by antiphospholipid antibodies (aPL), we found that complement activation is a crucial and early mediator of pregnancy loss. We demonstrated that C5a-C5aR interaction and neutrophils are key mediators of fetal injury. We identified tissue factor (TF) as a critical intermediate that, acting downstream of C5 activation, enhances neutrophil activity and trophoblast injury. In an antibody-independent mouse model of spontaneous miscarriage and IUGR (CBAxDBA) we also identified C5a as an essential mediator. Complement activation caused dysregulation of the angiogenic factors (deficiency of free vascular endothelial growth factor (VEGF) and elevated levels of soluble VEGF receptor 1) required for normal placental development. Inhibition of complement activation prevented angiogenesis failure and rescued pregnancies. Our studies in antibody-dependent and antibody-independent models of pregnancy complications identified complement activation as the crucial mediator of damage and will allow development of new interventions to prevent pregnancy loss and IUGR.
Girardi
Guillermina
G
Hospital for Special Surgery, Department of Medicine, Weill Medical College of Cornell University, NewYork, New York 10065, USA. girardig@hss.edu
D000022:Abortion, Spontaneous / Q000276:immunology* / Q000517:prevention & control; D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000276:immunology; D000925:Anticoagulants / Q000276:immunology* / Q000627:therapeutic use; D003167:Complement Activation / Q000276:immunology*; D015936:Complement C5a / Q000276:immunology / Q000378:metabolism; D051056:Complement Inactivating Agents / Q000276:immunology* / Q000627:therapeutic use; D005260:Female; D005313:Fetal Death; D005317:Fetal Growth Retardation / Q000276:immunology* / Q000517:prevention & control; D006131:Growth Inhibitors / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D018384:Oxidative Stress / Q000276:immunology; D011247:Pregnancy; D044087:Receptor, Anaphylatoxin C5a / Q000276:immunology / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000276:immunology / Q000378:metabolism
D017152:Antibodies, Antiphospholipid; D000925:Anticoagulants; D051056:Complement Inactivating Agents; D006131:Growth Inhibitors; D044087:Receptor, Anaphylatoxin C5a; D042461:Vascular Endothelial Growth Factor A; D015936:Complement C5a; D013925:Thromboplastin; D040281:Vascular Endothelial Growth Factor Receptor-1