FcγRIIA expression aggravates nephritis and increases platelet activation in systemic lupus erythematosus in mice.

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.