Sexual dimorphism of early GPR183-dependent B cell responses in systemic lupus erythematosus

Sensing oxidized cholesterol (oxysterol) ligands by GPR183-expressing B cells spatially regulates B cell activation within secondary lymphoid tissues, which, when dysregulated, could contribute to B cell-driven autoimmunity. Here, we show that in systemic lupus erythematosus, GPR183-expressing B cells are reduced in both humans and mice with established disease, irrespective of sex. However, we further show that GPR183-expressing splenic B cells are increased during the initiation phase of lupus-like disease in female but not male mice, leading to sex differences in the ability of B cells to migrate toward GPR183's principal ligand 7α,25dihydroxycholesterol in vitro and B cell activation in vivo. Accordingly, disrupting early, but not late, GPR183-dependent responses reduces B cell activation and suppresses the severity of lupus-like disease in female mice but not male mice. These data demonstrate that the impact of GPR183-expressing B cells on disease pathology may change over the course of SLE and is sexually dimorphic.