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

Abstract

Objective Patients with the antiphospholipid antibody syndrome (APS) often experience recurrent arterial and venous thrombosis and pregnancy losses. Intravenous immunoglobulin (IVIG) therapy has prevented pregnancy loss in some women with APS and has reversed fetal resorption rates in murine models of pregnancy loss. Although the basis for these effects is unknown, effector mechanisms of pathogenic antibodies often involve receptors for IgG (Fcγ receptors [FcγR]). We examined the potential mechanisms of action of IVIG in an in vivo murine model of antiphospholipid antibody (aPL)–induced thrombosis and endothelial cell activation. Methods Mice infused with IgG containing human anticardiolipin antibodies (aCL) were treated with IVIG (36 μg IV), saline, or ovalbumin. Surgically induced thrombus formation and in vivo leukocyte adhesion to endothelial cells were measured. Circulating levels of aCL were measured by enzyme‐linked immunosorbent assay. To determine whether FcγR are required for the effects of IVIG, we treated mice deficient in stimulatory FcγR. To examine the effects of IVIG on endogenously generated antibody, we treated mice immunized with β2‐glycoprotein I (β2GPI). Results IVIG treatment inhibited aPL‐induced endothelial cell activation and enhancement of thrombosis in mice passively infused with human aPL–containing IgG, and this was associated with a decrease in aPL levels. Similarly, IVIG lowered aPL levels and inhibited thrombogenesis in mice immunized with β2GPI. The thrombophilic effects of aPL were evident in FcγR‐deficient mice. Conclusion Treatment with IVIG inhibits the thrombogenic effects of aPL in vivo and reduces the levels of aCL in the circulation. Blockade of stimulatory FcγR 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 results have implications in the management of thrombosis in APS and may have applications for pregnant patients with a history of APS.

Thrombogenicity of β2-glycoprotein I–dependent antiphospholipid antibodies in a photochemically induced thrombosis model in the hamster

“…22,23 Animal models of venous thrombosis have provided evidence for Fc receptor-independent thrombotic mechanisms. 37 In venous thrombosis, bivalent ␤ 2 GPI-antibody complexes may reduce the anticoagulant effects of protein C and protein S by competition for the PL surface on which they function. 19 Immunohistochemical analysis of the arterial thrombus formed (Figure 3) localized 5H2 and its F(abЈ) 2 fragments mainly to platelets in certain areas of the thrombus.…”

The MHC class I–like Fc receptor promotes humorally mediated autoimmune disease

“…FcRn's ability to protect IgG is saturable, however, in that IgG concentration of approximately 10 mg/ml (rodents) and approximately 35 mg/ml (humans) are sufficient to functionally ablate FcRn's ability to protect IgG (38,39). It therefore remained possible that conventional high-dose IVIg regimes also exert their therapeutic benefits by saturating FcRn, resulting in the enhanced clearance of endogenous pathogenic IgG (40)(41)(42)(43)(44)(45).…”

“…pathogenic IgG is substantially accelerated (40)(41)(42)(43)(44)(45). This acceleration reduces the availability of pathogenic IgG for downstream effector events, including those that are counteracted by Fcgr2 engagement.…”

Antiphospholipid Syndrome - An Evolving Story of a Multisystemic Disease

“…Pierangeli et al In summary, these animal models of thrombosis and endothelial cell activation have not only been useful in demonstrating the pathogenic effects of aPL antibodies and their causative role in inducing APS morbidity, but have also been instrumental in dissecting the intracellular mechanisms involved, in identifying cellular receptors activated by aPL antibodies in vivo and in testing potential new treatments for APS (discussed in detail in other sections of this chapter) [37,39,51,[93][94][95][96][97][98][99][100][101][102][103][104][105].…”