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

TLDR

Antiphospholipid syndrome is characterized by recurrent pregnancy loss and thrombosis driven by antiphospholipid antibodies, yet anticoagulation only partially prevents miscarriage. The study aimed to test whether complement activation is the central mechanism of pregnancy loss in APS using a mouse model infused with human aPL‑containing IgG. Pregnant mice received human IgG with aPL antibodies, and the authors examined complement activation via the classical and alternative pathways, neutrophil recruitment, and C5a–C5a receptor interactions. They found that C5/C5a and neutrophils mediate fetal injury, that blocking C5a–C5aR or using F(ab)′2 fragments or C4 deficiency protects, that the alternative pathway amplifies activation, and that FcγRs are not involved, highlighting innate immune effectors as targets to prevent APS pregnancy loss.

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.