Tracing the molecular pathogenesis of antiphospholipid syndrome

Abstract

Fetal loss induced by antiphospholipid antibodies (aPLs) in mice is a complement-driven inflammatory condition. Engagement of the complement receptor C5aR on neutrophils induces expression of the principal initiator of the blood clotting mechanism, tissue factor (TF), and blocking this downstream event of complement activation prevents antibody-induced fetal loss. In this issue of the JCI, the study by Redecha et al. clarifies that in mice, the contribution of TF to this pathogenic mechanism is independent of its role in coagulation and thrombosis, but involves inflammatory signaling through the receptor PAR2 (see the related article beginning on page 3453). The study not only sheds light on a critical effector mechanism of aPL-induced fetal loss, but also suggests that treatment with statins, which decrease TF and PAR2 expression, may hold promise as a therapeutic approach to antiphospholipid syndrome-associated pregnancy complications.

Figure 1. Role of TF/PAR2 signaling in aPL-induced fetal loss.

Maternal aPLs activate the complement system in the placenta. Engagement of C5aR triggers expression by neutrophils of the blood coagulation initiator TF, resulting in generation of reactive oxygen species, injury to fetal trophoblast cells of the placenta, and ultimately loss of the fetus. TF binds and activates coagulation factors FVII and FX circulating in maternal blood to form the ternary TF/FVIIa/FXa complex. The study by Redecha et al. in this issue of the JCI (10) shows that TF-mediated neutrophil activation proceeds through engagement of PAR2 via this initiation complex of blood coagulation. The statin drugs simvastatin and pravastatin prevent C5a-induced upregulation of TF and PAR2 expression, thereby inhibiting the release of reactive oxygen species and suppressing amplification of complement activation by factors released from neutrophils. Statins may hold promise as a therapeutic approach to APS-associated pregnancy complications.