Activation of complement mediates antiphospholipid antibody-induced pregnancy loss

Abstract

Although it is clear that the specific antigenic reactivityof antiphospholipid(aPL) antibodiesis critical to their effect, the pathogenicmechanisms that resultin injury in vivo are incompletelyunderstood.We hyphothesized that aPL antibodies targeted to the placenta activate complement locally, generating split products that mediate placental injury and lead to foetal loss and growth retardation. To test this hypothesis, we used a murine model of APS in which pregnant mice are injected with human IgG containing aPL antibodies. Mice treated with inhibitors of complement activation and mice deficient in complement components were protected from aPL antibody-inducedfoetal damage. Although the cause of tissue injury in this disease is probably multifactoral, we have shown that complement activation is an absolute requirement for foetal loss and growth restriction and, therefore, that this pathway acts upstream of other important effector mechanisms. Identification of complement activation as a mechanism that is necessary for aPL-induced tissue damage and definition of the complement components necessary to trigger such injury is likely to lead to a better understandingof the pathogenesis of vascular and tissue injury in SLE and to new and improved treatments.