Results. The nonsynonymous C-to-T transition in the first cytoplasmic exon, originally reported in the Raji cell line, was not found in either the AfricanAmerican or the Caucasian population, but a nonsynonymous T-to-C transition at nucleotide 775 in exon 4 of FCGR2B, which changes isoleucine to threonine at residue 187 in the transmembrane domain, was significantly more common in African Americans. Using the Fc␥RIIb-negative mouse B cell line IIA1.6, we expressed both allelic forms as both full-length and truncated cytoplasmic domain constructs. The FCGR2B-187T allele mediated a higher level of CD19 dephosphorylation (P ؍ 0.029) and a greater degree of inhibition of the calcium response (P ؍ 0.003) when co-engaged with BCR than did FCGR2B-187I, independent of the presence of the ITIM. In contrast, Fc␥RIIb modulation of BCR-induced and anti-Fas antibody-induced cell death rates were similar in IIA1.6 cells expressing either the 187I or the 187T allelic form.Conclusion. The differential activity of FCGR2B alleles suggests a novel mechanism of Fc␥RIIb regulation that may influence the risk of autoimmune disease.The low-affinity, inhibitory IgG receptor Fc␥ receptor IIb (Fc␥RIIb) is expressed on B cells and most myeloid lineage cells. The observation that FCGR2B-deficient mice display elevated Ig levels in response to both thymus-dependent and thymus-independent antigens (1), and that, in the context of the B6 genetic background, FCGR2B-deficient mice develop a lupuslike autoimmune disease (2-4), has focused attention on FCGR2B as a candidate gene for autoimmunity.The structural basis for Fc␥RIIb function includes multiple elements involved in inhibitory or apoptotic signaling. Co-ligation of Fc␥RIIb with B cell antigen receptor (BCR) leads to inhibition of B cell activation (5,6) and causes apoptosis (7). This co-ligation results in the selective dephosphorylation of CD19 tyrosines, the tyrosine phosphorylation of the immunoreceptor tyrosine-based inhibitory motif (ITIM) in the Fc␥RIIb cytoplasmic domain, and the recruitment of SH2-containing inositol 5-phosphatase (SHIP), causing a block in calcium influx (6,(8)(9)(10)(11). Although the C-terminal 16 cytoplasmic domain residues are required for Fc␥RIIb association with and enhanced tyrosine phosphorylation of SHIP (12), Fc␥RIIb-mediated de-