Identification of an Fc gamma receptor-independent mechanism by which intravenous immunoglobulin ameliorates antiphospholipid antibody-induced thrombogenic phenotype

Objective. Patients with the antiphospholipid antibody syndrome (APS) often experience recurrent arterial and venous thrombosis and pregnancy losses. Intravenous immunoglobulin (WIG) therapy has prevented pregnancy loss in so me women with APS and has reversed fetal resorption rates in murine models of pregnancy loss. Although the basis for these effects is unknown, effecto r mechanisms of pathogenic antibodies often involve receptors for IgG (Fc g amma receptors [Fc gammaR]). We examined the potential mechanisms of action of MG in an in vivo murine model of antiphospholipid antibody (aPL)-induce d thrombosis and endothelial cell activation. Methods. Mice infused with IgG containing human anticardiolipin antibodies (aCL) were treated with WIG (36 mug M, saline, or ovalbumin. Surgically ind uced thrombus formation and in vivo leukocyte adhesion to endothelial cells were measured. Circulating levels of aCL were measured by enzyme-linked im munosorbent assay. To determine whether Fc gammaR are required for the effe cts of WIG, we treated mice deficient in stimulatory FcyR. To examine the e ffects of IVIG on endogenously generated antibody, we treated mice immunize d with beta (2)-glycoprotein I (beta (2)GPI). Results. WIG treatment inhibited aPL-induced endothelial cell activation an d enhancement of thrombosis in mice passively infused with human aPL-contai ning IgG, and this was associated with a decrease in aPL levels. Similarly, IVIG lowered aPL levels and inhibited thrombogenesis in mice immunized wit h beta (2)GPI. The thrombophilic effects of aPL were evident in Fc gammaR-d eficient mice. Conclusion. Treatment with IVIG inhibits the thrombogenic effects of aPL in vivo and reduces the levels of aCL in the circulation. Blockade of stimula tory Fc gammaR on inflammatory cells is not necessary for this effect. The mechanism of action of IVIG is more likely saturation of the IgG transport receptor, leading to accelerated catabolism of pathogenic aPL. These result s have implications in the management of thrombosis in APS and may have app lications for pregnant patients with a history of APS.