Résumé
Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease characterized by deposits of immune complexes (ICs) in organs and tissues. The expression of Fc gamma RIIA 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 Fc gamma RIIA in the course of SLE and platelet activation. In patients with SLE, levels of ICs are associated with platelet activation. Because Fc gamma RIIA is absent in mice, and murine platelets do not respond to ICs in any existing mouse model of SLE, we introduced the Fc gamma RIIA (FCGR2A) transgene into the NZB/NZWF1 mouse model of SLE. In mice, Fc gamma RIIA expression by bone marrow cells severely aggravated lupus nephritis and accelerated death. Lupus onset initiated major changes to the platelet transcriptome, both in Fc gamma RIIA-expressing and nonexpressing mice, but enrichment for type I interferon response gene changes was specifically observed in the Fc gamma RIIA mice. Moreover, circulating platelets were degranulated and were found to interact with neutrophils in Fc gamma RIIA-expressing lupus mice. Fc gamma RIIA 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 Fc gamma RIIA in nephritis and in platelet activation in SLE.