Fc gamma RIIB regulates autoantibody responses by limiting marginal zone B cell activation

Abstract

Fc gamma RIIB is an inhibitory receptor expressed throughout B cell development. Diminished expression or function is associated with lupus in mice and humans, in particular through an effect on autoantibody production and plasma cell (PC) differentiation. Here, we analyzed the effect of B cell-intrinsic Fc gamma RIIB expression on B cell activation and PC differentiation. Loss of Fc gamma RIIB on B cells in Fcgr2b-conditional KO (Fcgr2b-cKO) mice led to a spontaneous increase in autoantibody titers. This increase was most striking for IgG3, suggestive of increased extrafollicular responses. Marginal zone (MZ) B cells had the highest expression of Fc gamma RIIB in both mice and humans. This high expression of Fc gamma RIIB was linked to increased MZ B cell activation, Erk phosphorylation, and calcium flux in the absence of Fc gamma RIIB triggering. We observed a marked increase in IgG3+ PCs and B cells during extrafollicular PC responses in Fcgr2b-cKO mice. The increased IgG3 response following immunization of Fcgr2b-cKO mice was lost in MZ-deficient Notch2 Fcgr2b-double KO mice. Importantly, patients with systemic lupus erythematosus (SLE) had a decrease in Fc gamma RIIB expression that was strongest in MZ B cells. Thus, we present a model in which high Fc gamma RIIB expression in MZ B cells prevented their hyperactivation and ensuing autoimmunity.