No abstract

Background: Systemic lupus erythematosus (SLE)-related autoantibodies are of unknown origin but target multiple apoptotic cell-derived antigens. Results: T cell responses to multiple epitopes on ␤ 2 -glycoprotein I (␤ 2 GPI), an apoptotic cell-binding protein, were associated with SLE-related autoantibody production. Conclusion: Distinct ␤ 2 GPI-reactive T cell responses are associated with SLE-related autoantibodies. Significance: Factors enabling ␤ 2 GPI-reactive T cell responses may predispose individuals to SLE.

Patients with antiphospholipid syndrome (APS) produce antiphospholipid antibodies (aPL) and develop vascular thrombosis that may occur in large or small vessels in the arterial or venous beds. On the other hand, many individuals produce aPL and yet never develop thrombotic events. Toll-like receptor 4 (TLR4) appears to be necessary for aPL-mediated prothrombotic effects in venous and microvascular models of thrombosis, but its role in arterial thrombosis has not been studied. Here, we propose that aPL alone are insufficient to cause thrombotic events in an arterial model of APS, and that a concomitant trigger of innate immunity (e.g. TLR4 activation) is required. We show specifically that anti-β2-glycoprotein I (anti-β2GPI) antibodies, a subset of aPL, accelerated thrombus formation in C57BL/6 wild-type, but not TLR4-deficient, mice in a ferric chloride-induced carotid artery injury model. These aPL bound to arterial and venous endothelial cells, particularly in the presence of β2GPI, and to human TLR4 by enzyme-linked immunoassay. Arterial endothelium from aPL-treated mice had enhanced leukocyte adhesion, compared to control IgG-treated mice. In addition, aPL treatment of mice enhanced expression of tissue factor (TF) in leukocytes induced by the TLR4 ligand lipopolysaccharide (LPS). aPL also enhanced LPS-induced TF expression in human leukocytes in vitro. Our findings support a mechanism in which aPL enhance TF expression by leukocytes, as well as augment adhesion of leukocytes to the arterial endothelium. The activation of TLR4 in aPL-positive individuals may be required to trigger thrombotic events.

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease characterized by deposits of immune complexes (IC) in organs and tissues. The expression of FcγRIIA by human platelets, which is their unique receptor for IgG antibodies, positions them to ideally respond to circulating IC. Whereas chronic platelet activation and thrombosis are well-recognized features of human SLE, the exact mechanisms underlying platelet activation in SLE are still unknown. Here, we evaluated the involvement of FcγRIIA in the course of SLE and platelet activation. In SLE patients, levels of IC are associated with platelet activation. As FcγRIIA is absent in mice and murine platelets do not respond to IC in any existing mouse model of SLE, we introduced the FcγRIIA (FCGR2A) transgene into the NZB/NZWF1 mouse model of SLE. In mice, FcγRIIA expression by bone-marrow cells severely aggravated lupus nephritis and accelerated death. Lupus onset initiated major changes to the platelet transcriptome, both in FcγRIIA-expressing and non-expressing mice, but an enrichment for type-I interferon response gene changes was specifically observed in the FcγRIIA mice. Moreover, circulating platelet were degranulated and were found interacting with neutrophils in FcγRIIA expressing lupus mice. FcγRIIA expression in lupus mice also led to thrombosis in lungs and kidneys. The model recapitulates hallmarks of human SLE and can be utilized to identify contributions of different cellular lineages in the manifestations of SLE. The study further reveals a role for FcγRIIA in nephritis and in platelet activation in SLE.