A novel polymorphism in the Fcγ receptor IIB (CD32B) transmembrane region alters receptor signaling

Abstract

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-

Association of a transmembrane polymorphism of Fcγ receptor IIb (FCGR2B) with systemic lupus erythematosus in Taiwanese patients

“…There were significant differences in the genotype distribution between patients with and without pleural effusion ( 2 ϭ 6.59, P ϭ 0.037 by 3 ϫ 2 contingency Strong association of the FCGR2B Ile187Thr polymorphism and SLE in Asian populations. Several published association studies suggest that the FCGR2B minor allele, Thr187, is a risk factor for disease in Thai, Japanese, and Chinese populations, but not in American or Swedish Caucasian or in African American populations (28,29,(32)(33)(34). This differential result does not seem to reflect different population allele frequencies, since the frequencies of the Thr187 allele in these Asian 142 (51) 105 (38) 29 (11) 142 (51) 134 (49) 389 (70) 147 (56) 87 (33) 29 (11) 147 (56) 116 (44) 381 (72) 145 (28) Oral ulcer Positive (n ϭ 112) 59 (53) 42 (38) 11 (10) 0.752 59 (53) 53 (47) 0.853 160 (71) 64 (29) 1.000 Negative (n ϭ 239)…”

“…This segregation of genetic effect by ethnicity suggests that the genetic backgrounds in the different ethnicities may influence the pathogenesis of SLE through the interaction of different genetic risk factors with Ile/Thr187. Therefore, FCGR2B Thr187 might be a risk factor for certain ethnic populations but not for others (28,33).…”

“…Several single-nucleotide polymorphisms (SNPs) have been identified in the promoter and coding regions of FCGR2B (26)(27)(28)(29). The SNP at position c.775TϾC (GenBank accession no.…”

Association of Fcγ receptor IIA, but not IIB and IIIA, polymorphisms with systemic lupus erythematosus: A family‐based association study in Caucasians

“…Since the submission of this manuscript, a report was published describing the finding that the FCGR2B polymorphism examined in the present study was not associated with SLE in Caucasians or African Americans (29). …”

B lymphocyte signaling pathways in systemic autoimmunity: Implications for pathogenesis and treatment

“…More recently, the frequency of an SNP (695T/C) coding for a nonsynonymous Ile 232 /Thr substitution within the transmembrane domain of Fc␥RIIb was significantly increased in Japanese patients with SLE compared with healthy individuals (46). It is of further interest that another allele, called FCGR2B-187T, that mediates a higher level of CD19 dephosphorylation and a greater degree of inhibition of the Ca 2ϩ response when coengaged with the BCR than does FCGR2B-187I, is not associated with SLE in both African Americans and Caucasians (47). This lack of association raises the interesting possibility that FCGR2B-187T may be interacting epistatically with background genes that differ between Japanese patients and both African American and Caucasian patients.…”