Transcriptional Regulation of Fcgr2b Gene by Polymorphic Promoter Region and Its Contribution to Humoral Immune Responses

Abstract

FcγRIIB1 molecules serve as negative feedback regulator for B cell Ag receptor-elicited activation of B cells; thus, any impaired FcγRIIB1 function may possibly be related to aberrant B cell activation. We earlier found deletion polymorphism in the Fcgr2b promoter region among mouse strains in which systemic autoimmune disease-prone NZB, BXSB, MRL, and autoimmune diabetes-prone nonobese diabetic, but not NZW, BALB/c, and C57BL/6 mice have two identical deletion sites, consisting of 13 and 3 nucleotides. In this study, we established congenic C57BL/6 mice for NZB-type Fcgr2b allele and found that NZB-type allele down-regulates FcγRIIB1 expression levels in germinal center B cells and up-regulates IgG Ab responses. We did luciferase reporter assays to determine whether NZB-type deletion polymorphism affects transcriptional regulation of Fcgr2b gene. Although NZW- and BALB/c-derived segments from position −302 to +585 of Fcgr2b upstream region produced significant levels of luciferase activities, only a limited activity was detected in the NZB-derived sequence. EMSA and Southwestern analysis revealed that defect in transcription activity in the NZB-derived segment is likely due to absence of transactivation by AP-4, which binds to the polymorphic 13 nucleotide deletion site. Our data imply that because of the deficient AP-4 binding, the NZB-type Fcgr2b allele polymorphism results in up-regulation of IgG Ab responses through down-regulation of FcγRIIB1 expression levels in germinal center B cells, and that such polymorphism may possibly form the basis of autoimmune susceptibility in combination with other background contributing genes.

Contribution of NZB Autoimmunity 2 to Y-Linked Autoimmune Acceleration-Induced Monocytosis in Association with Murine Systemic Lupus

“…It has been shown that the expression of Fc␥RIIB is defective in activated germinal center B cells of NZB mice because of a polymorphism in the promoter region of the Fcgr2b gene (18,20,37). Notably, Fc␥RIIB also negatively regulates the IC-mediated activation of stimulatory Fc␥R (Fc␥RI and Fc␥RIII) expressed on macrophages and mast cells (22,32,38).…”

Breast Cancer Cells Proliferation Is Regulated by Tyrosine Phosphatase SHP1 through c-jun N-Terminal Kinase and Cooperative Induction of RFX-1 and AP-4 Transcription Factors

“…AP-4 proteins play a key role in cellular differentiation and proliferation (37)(38)(39)(40). AP-4 binding sites often overlap the recognition sequences of AP-1 (40), suggesting that AP-1 and AP-4 may function in concert to induce various genes. For example, AP-1 can act synergistically with AP-4 to activate SV40 late gene transcription (41,42).…”

The lupus phenotype in B6.NZBc1 congenic mice reflects interactions between multiple susceptibility loci and a suppressor locus

“…This region overlaps with the Nba2 and Sle1b loci that were identified in NZB and NZM2410 mouse strains, 17,18 respectively, and contains the previously proposed candidate genes Slam, Ifi202 and Fcgr2b. [8][9][10][11] The Slam locus encodes a family of adhesion/costimulatory molecules that regulate the activation threshold and type of response for many cells involved in the immune system [19][20][21] (and reviewed in ref. 22).…”

“…The first susceptibility allele is located within the 96-100 cM interval and contains the previously identified Slam, Ifi202 and Fcgr2b candidate gene loci. [8][9][10][11] A second lupus susceptibility locus is located in the 88-96 cM interval that leads to an increased number and size of GC and promotes anti-dsDNA production and renal disease. The third lupus susceptibility allele is located in the 70-88 interval and together with the loci in the 96-100 and 88-96 cM intervals is sufficient to induce severe GN and significant mortality.…”