Role of tissue factor in the maternal immunological attack of the embryo in the antiphospholipid syndrome.
Recurrent fetal loss affects 1-5% of women of childbearing age. Immunological mechanisms may account for 40% of recurrent miscarriages, and in particular, the antiphospholipid syndrome (APS) appears to be implicated in 7-25% of the cases. Because antiphospholipid (aPL) antibodies have thrombogenic properties, fetal loss in patients with APS has been ascribed to thrombosis of placental vessels. However, we have shown that inflammation, specifically activation of complement with generation of the anaphylotoxin C5a, is an essential trigger of fetal injury. Thrombosis and inflammation are linked in many clinical conditions. Tissue factor (TF), the major cellular initiator of the coagulation protease cascade, plays important roles in both thrombosis and inflammation, and its expression is increased in patients with APS. Here we describe how TF, acting as a proinflammatory molecule, induces trophoblast injury and fetal death in a mouse model of APS. Importantly, we will discuss how TF contributes to C5a-induced oxidative burst in neutrophils leading to trophoblasts and fetal injury in APS. The finding that TF is an important effector in aPL-induced inflammation may allow the development of new therapies to abrogate the inflammatory loop caused by tissue factor and improve pregnancy outcomes in patients with aPL antibodies. Statins downregulate TF-induced inflammation and rescued the pregnancies in aPL-treated mice, suggesting they may be a good treatment for women with aPL-induced pregnancy complications.
Girardi
Guillermina
G
Department of Medicine, Weill Medical College of Cornell University, New York, NY, USA. guillerminagirardi@gmail.com
D000026:Abortion, Habitual / Q000276:immunology* / Q000517:prevention & control; D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000276:immunology; D016736:Antiphospholipid Syndrome / Q000150:complications / Q000276:immunology*; D003167:Complement Activation / Q000276:immunology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000276:immunology*; D015942:Factor VIIa / Q000276:immunology; D005260:Female; D005313:Fetal Death / Q000276:immunology* / Q000517:prevention & control; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D051379:Mice; D018375:Neutrophil Activation / Q000276:immunology; D011247:Pregnancy; D044464:Receptor, PAR-2 / Q000032:analysis / Q000276:immunology; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000276:immunology*; D013927:Thrombosis / Q000276:immunology
D017152:Antibodies, Antiphospholipid; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D044464:Receptor, PAR-2; D013925:Thromboplastin; D015942:Factor VIIa