A Promoter Haplotype of the Immunoreceptor Tyrosine-Based Inhibitory Motif-Bearing FcγRIIb Alters Receptor Expression and Associates with Autoimmunity. II. Differential Binding of GATA4 and Yin-Yang1 Transcription Factors and Correlated Receptor Expression and Function

Abstract

The immunoreceptor tyrosine-based inhibitory motif-containing FcγRIIb modulates immune function on multiple cell types including B cells, monocytes/macrophages, and dendritic cells. The promoter for the human FCGR2B is polymorphic, and the less frequent 2B.4 promoter haplotype is associated with the autoimmune phenotype of systemic lupus erythematosus. In the present study, we demonstrate that the 2B.4 promoter haplotype of FCGR2B has increased binding capacity for GATA4 and Yin-Yang1 (YY1) transcription factors in both B lymphocytes and monocytes, and that overexpression of GATA4 or YY1 enhances the FCGR2B promoter activity. The 2B.4 haplotype leads to elevated expression of the endogenous receptor in heterozygous donors by ≈1.5-fold as assessed on EBV-transformed cells, primary B lymphocytes, and CD14+ monocytes. This increased expression accentuates the inhibitory effect of FcγRIIb on B cell Ag receptor signaling, measured by Ca2+ influx and cell viability in B cells. Our results indicate that transcription factors GATA4 and YY1 are involved in the regulation of FcγRIIb expression, and that the expression variants of FcγRIIb lead to altered cell signaling, which may contribute to autoimmune pathogenesis in humans.

Expression Profile of FcγRIIb on Leukocytes and Its Dysregulation in Systemic Lupus Erythematosus

“…Donors with the 2B.4 haplotype have increased mAb 4F5 staining on CD14 ϩ monocytes compared with 2B.1 homozygous donors (Fig. 7A, p Ͻ 0.002, twotailed, Mann-Whitney U test), which is in agreement with the previously reported expression of Fc␥RIIb in monocytes by Western blot analysis (21). Similarly, donors with the 2B.4 haplotype have increased 4F5 staining levels on neutrophils and CD19 Ϫ BDCA1 ϩ mDCs (Fig.…”

“…Polymorphisms in the human FCGR2B gene are associated with the SLE phenotype (21)(22)(23)(24)(25)(26). We have recently demonstrated that polymorphisms in the regulatory region of FCGR2B form two major haplotypes and that the less frequent 2B.4 haplotype is significantly overrepresented in SLE patients (22).…”

“…Of the two major promoter haplotypes in the human FCGR2B gene, the less frequent 2B.4 haplotype leads to increased Fc␥RIIb expression on B lymphocytes (21,22). Because myeloid lineage cells express both Fc␥RIIa and Fc␥RIIb, the unique cell surface expression of Fc␥RIIb cannot be determined using pan-Fc␥RII mAbs.…”

“…We have previously identified two major promoter haplotypes in the human FCGR2B gene: 2B.1 and 2B.4 (21,22). The less frequent 2B.4 haplotype has higher binding capacity for GATA4 and YYI transcription factors and leads to higher expression in a luciferase reporter system.…”

An intronic variant associated with systemic lupus erythematosus changes the binding affinity of Yinyang1 to downregulate WDFY4

“…[14][15][16] For example, YY1 can enhance FCGR2B promoter activity by a functional promoter haplotype, which is also associated with SLE. 17 A genome-wide expression analysis revealed that YY1 may have a key role in the pathogenesis of multiple sclerosis or its subtypes. 18 In our study, we also showed that YY1 could have a role in transcription of WDFY4, with different affinity for a functional variant in the gene.…”