Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome

Abstract

Antiphospholipid syndrome (APS) is defined by recurrent pregnancy loss and thrombosis in the presence of antiphospholipid (aPL) Ab's. Currently, therapy for pregnant women with APS is focused on preventing thrombosis, but anticoagulation is only partially successful in averting miscarriage. We hypothesized that complement activation is a central mechanism of pregnancy loss in APS and tested this in a model in which pregnant mice receive human IgG containing aPL Ab's. Here we identify complement component C5 (and particularly its cleavage product C5a) and neutrophils as key mediators of fetal injury, and we show that Ab's or peptides that block C5a-C5a receptor interactions prevent pregnancy complications. The fact that F(ab)′2 fragments of aPL Ab's do not mediate fetal injury and that C4-deficient mice are protected from fetal injury suggests that activation of the complement cascade is initiated via the classical pathway. Studies in factor B-deficient mice, however, indicate that alternative pathway activation is required and amplifies complement activation. In contrast, activating FcγRs do not play an important role in mediating aPL Ab-induced fetal injury. Our findings identify the key innate immune effectors engaged by pathogenic autoantibodies that mediate poor pregnancy outcomes in APS and provide novel and important targets for prevention of pregnancy loss in APS.

The Journey of Antiphospholipid Antibodies From Cellular Activation to Antiphospholipid Syndrome

“…Use of complement inhibitors affecting both the classical and alternative pathways of complement activation and knock-out mice deficient in C3, C4, C5, and C5a receptors or factor B reduced the frequency of fetal resorption, prevented growth restriction in surviving fetuses, and limited the development of placental lesions in mice treated with aPL [64,65]. These findings point to the involvement of all complement pathways in the development of pregnancy morbidity as a result of aPL activity.…”

Primary Antiphospholipid Syndrome Presenting as HELLP Syndrome

“…Blockage of C5a-C5aR interaction preserved pregnancies. These studies suggest that the C5-C5a receptor interactions are the critical intermediates linking pathogenic aPL to fetal damage [23,24] and they implicate complement blockade, specifically at the level of C5 or C5aR as a potential therapy for APS. Complement C5 monoclonal antibodies have been already utilized to treat other inflammatory conditions, and they could have a role in the prevention of fetal loss and pregnancy complications in APS.…”

The antiphospholipid syndrome: from pathophysiology to treatment

“…Antibodyb2GPI complexes can generate C5a, which therefore induces inflammation and placental insufficiency [47]. C5a may also bind and activate neutrophils leading to the expression of tissue factor, which interacts with factor VIIa leading to the activation of factor X, thrombin generation, and thrombi formation [48].…”