FcgRIIA expression accelerates nephritis and increases platelet activation in systemic lupus erythematosus

Abstract

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