Background: The inhibitory Fc receptor, Fc�³RIIB, has emerged as a key negative regulator of B cell activation and\nas such is predicted to play an essential role in controlling antibody-mediated autoimmune diseases in humans.\nRecent studies have shown that crosslinking the Fc�³RIIB independently of the B-cell receptor (BCR) results in\napoptosis in both mouse and chicken B cells. However, the human B cell subpopulations that are susceptible\nto BCR-independent, Fc�³RIIB-mediated regulation are not known. How Fc�³RIIB mediates this inhibition to affect\nB cell homeostasis is also not determined.\nResults: We isolated na�¯ve B cells, memory B cells and plasma cells (PCs) from peripheral blood of healthy donors\nand used differentiated PCs in culture to examine the effects on them by Fc�³RIIB crosslinking. We showed that\nhuman PCs, memory and na�¯ve B cells all expressed Fc�³RIIB with expression on PCs being the highest in circulation.\nMoreover, they were sensitive to direct inhibition by Fc�³RIIB through Btk and p38 MAPK. Similarly, PCs resulting\nfrom the antigen-independent differentiation of memory B cells in vitro were inhibited by Fc�³RIIB cross-linking but\nmemory B cell activation itself, as measured by proliferation, was unaffected. In contrast, both the proliferation and\ndifferentiation of na�¯ve B cells to PCs were blocked by Fc�³RIIB crosslinking.\nConclusion: These results suggest a mechanism to control antibody levels involving the differential expression of Fc�³RIIB\non B cell subpopulations, in which the Fc�³RIIB functions independently of the BCR to eliminate antibody-secreting\neffector cells and inhibit na�¯ve B cell proliferation without compromising the long-lived antigen-specific memory B cells.\nImportantly, Fc�³RIIB requires Btk and p38 MAPK to mediate antigen-independent inhibition in human B cells. Taken\ntogether, our data underscore the importance of antigen-independent inhibition by Fc�³RIIB in the prevention from\nantibody-mediated autoimmune diseases and in the regulation of B cell homeostasis.
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