FcγRIIB mediates antigen-independent inhibition on human B lymphocytes through Btk and p38 MAPK

Background: The inhibitory Fc receptor, Fc gamma RIIB, has emerged as a key negative regulator of B cell activation and as such is predicted to play an essential role in controlling antibody-mediated autoimmune diseases in humans. Recent studies have shown that crosslinking the Fc gamma RIIB independently of the B-cell receptor (BCR) results in apoptosis in both mouse and chicken B cells. However, the human B cell subpopulations that are susceptible to BCR-independent, Fc gamma RIIB-mediated regulation are not known. How Fc gamma RIIB mediates this inhibition to affect B cell homeostasis is also not determined. Results: We isolated naive B cells, memory B cells and plasma cells (PCs) from peripheral blood of healthy donors and used differentiated PCs in culture to examine the effects on them by Fc gamma RIIB crosslinking. We showed that human PCs, memory and naive B cells all expressed Fc gamma RIIB with expression on PCs being the highest in circulation. Moreover, they were sensitive to direct inhibition by Fc gamma RIIB through Btk and p38 MAPK. Similarly, PCs resulting from the antigen-independent differentiation of memory B cells in vitro were inhibited by Fc gamma RIIB cross-linking but memory B cell activation itself, as measured by proliferation, was unaffected. In contrast, both the proliferation and differentiation of naive B cells to PCs were blocked by Fc gamma RIIB crosslinking. Conclusion: These results suggest a mechanism to control antibody levels involving the differential expression of Fc gamma RIIB on B cell subpopulations, in which the Fc gamma RIIB functions independently of the BCR to eliminate antibody-secreting effector cells and inhibit naive B cell proliferation without compromising the long-lived antigen-specific memory B cells. Importantly, Fc gamma RIIB requires Btk and p38 MAPK to mediate antigen-independent inhibition in human B cells. Taken together, our data underscore the importance of antigen-independent inhibition by Fc gamma RIIB in the prevention from antibody-mediated autoimmune diseases and in the regulation of B cell homeostasis.