Regulation of B-Cell Activation by Complement Receptors and Fc Receptors

In addition to producing autoantibodies, B cells act as critical antigen presenting cells in autoimmune disease. Tight regulation of B-cell activity is required to ensure humoral immunity against pathogens, on the one hand, and to avoid detrimental autoreactivity, on the other. Activation of B cells is mediated through cross-binding of the B-cell antigen receptor (BCR) and is greatly enhanced by co-engagement of complement receptor type 2 (CD21, CR2) and its signaling element, CD19. Feedback inhibition of B-cell activity is mediated by the binding of IgG antibodies to Fc gamma RIIB (CD32). The extent to which the individual receptors are engaged depends on the context in which antigen is encountered, be it as antigen alone, as complement-opsonized antigen, or as antigen complexed with IgM or IgG antibodies. Both over-expression of CD19 and deficiency of elements centrally involved in negative signaling, e. g. Fc gamma RIIB and Lyn, lead to autoimmune disease in mice. Upon formation of complement-activating ICs with natural or disease-associated antibodies, self-antigen binds to B cells via CD21 and CD35 (CR1) and induces proliferation of self-reactive B cells and CD4+ T cells. Here, we review the role of BCR, CD21/CD19 and Fc gamma RIIB in regulating B-cell activity in immune and autoimmune responses.