FcγRIIB regulates (auto)antibody responses by limiting marginal zone B cell activation

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 differentiation. Here, we analysed the effect of B cell-intrinsic Fc{gamma}RIIB expression on B cell activation and plasma cell differentiation. Loss of Fc{gamma}RIIB on B cells (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) and IgG3+ B cells had the highest expression of Fc{gamma}RIIB and the increase in serum IgG3 was linked to increased MZ B cell signaling and activation in the absence of Fc{gamma}RIIB. Likewise, human circulating MZ-like B cells had the highest expression of Fc{gamma}RIIB, and their activation was most strongly inhibited by engaging Fc{gamma}RIIB. Finally, marked increases in IgG3+ plasma cells and B cells were observed during extrafollicular plasma cell responses with both T-dependent and T-independent antigens in Fcgr2b cKO mice. The increased IgG3 response following immunization of Fcgr2b cKO mice was lost in MZ-deficient Notch2/Fcgr2b cKO mice. Thus, we present a model where high Fc{gamma}RIIB expression in MZ B cells prevents their hyperactivation and ensuing autoimmunity. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/471075v1_ufig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@10bf17corg.highwire.dtl.DTLVardef@11b067aorg.highwire.dtl.DTLVardef@1465e36org.highwire.dtl.DTLVardef@d3351c_HPS_FORMAT_FIGEXP M_FIG C_FIG