Volume 5 Supplement 3
Antiphospholipid antibodies harness innate effectors, neutrophils and an alternative pathway of complement, to induce fetal damage
© The Author(s) 2003
Published: 12 September 2003
In a murine model of antiphospholipid antibody (aPL)-induced pregnancy loss, we have demonstrated that activation of complement, specifically C5a–C5a receptor interactions, leads to fetal loss and growth restriction. Yet, the effectors of tissue injury, the role of individual complement activation pathways and the precise targets for treatment remain unknown. Because C5a recruits and activates polymorphonuclear leukocytes (PMN) and because PMN infiltration is evident at sites of fetal resorption, we considered the possibility that PMN are critical cellular effectors of fetal damage. To assess the effects of aPL antibodies in mice depleted of granulocytes, we treated pregnant mice with anti-mouse Ly-6G (α-Gr) or control murine IgG2K prior to administration of human IgG containing aPL (aPL-IgG). In the absence of granulocytes, mice did not develop aPL-induced pregnancy complications. The frequency of fetal resorptions was similar to that of mice treated with IgG from healthy controls (NH-IgG), while treatment with control IgG2bK was not protective (% fetal resorption, aPL-IgG + α-Gr, 8.5 ± 1.5%; NH-IgG, 10 ± 2; aPL + IgG2bK, 39 ± 5%*; fetal weight (mg), aPL + α-Gr, 352 ± 48; NH-IgG, 370 ± 56; aPL + IgG2bK, 187 ± 28*; * aPL vs NH-IgG, P < 0.01).
Immunohistochemical analysis of decidual tissues showed that, in the absence of neutrophil infiltration, either as a consequence of neutrophil depletion or due to blockade of the C5a–C5aR interaction, there was limited C3 deposition coincident with improved pregnancy outcomes. It has been suggested that neutrophils promote complement activation by secreting C3 and/or properdin at sites of inflammation, and thereby amplify complement activation via the alternative pathway. To examine the contribution of the alternative pathway to aPL-induced pregnancy loss, we performed studies in mice deficient in factor B (fB). In the absence of fB, mice were protected from aPL-induced fetal resorption and growth restriction (% fetal resorption fB-/- mice, aPL-IgG vs NH-IgG, 9.5 ± 2.4 vs 10.9 ± 2.1), indicating a role for the alternative pathway in fetal damage.
This report, taken together with our previous work, shows that fB, C5 and C5aR are required for pregnancy complications triggered by aPL antibodies. Specifically, we identified the proinflammatory sequelae of C5a–C5aR interactions and the recruitment of neutrophils as the critical intermediates linking pathogenic aPL antibodies to fetal damage. Our findings identify the key innate immune effectors engaged by aPL antibodies that mediate poor pregnancy outcomes and provide novel and important targets for the prevention of pregnancy loss in antiphospholipid syndrome.
Supported by the Alliance for Lupus Research, Mary Kirkland Center for Lupus Research, and SLE Foundation Inc.