FCGR2B – Systemic Lupus Erythematosus

FCGR2B encodes the inhibitory Fc gamma receptor IIb, a key negative regulator of B cell receptor–mediated activation. Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production and immune complex deposition affecting multiple organs. Impaired FCGR2B function or expression may disrupt peripheral B cell tolerance and promote autoimmunity.

Three independent family-based association studies in Chinese cohorts comprising 119 probands from 95 nuclear families and 316 relatives demonstrated significant transmission disequilibrium for two non-synonymous SNPs in FCGR2B: rs10917661 in exon 2 (Gln50Ter) and rs1050501 in exon 5 (Ile232Thr) (Z=3.444–3.707, P≤0.00057) (PMID:16531013; PMID:17393178). The 50Ter–225C haplotype showed a transmission frequency of 34.1% (Z=3.539, P=0.00042) in affected offspring, consistent across studies (PMID:18625651).

A multi-marker haplotype analysis confirmed that the 50Ter–225C combination is more frequently transmitted in SLE than other haplotypes, establishing a reproducible genetic association in this population. Functional promoter variants, including the –343 G→C polymorphism, reduce FCGR2B transcription by altering AP-1 and Yin-Yang 1 binding, leading to decreased receptor expression (PMID:17130130).

Luciferase reporter assays of human and murine promoter constructs show that deletion polymorphisms abrogate AP-4–mediated activation and downregulate FCGR2B1 expression in germinal center B cells, resulting in augmented IgG responses (PMID:12370366). A knockin mouse model carrying the NZB-type promoter haplotype lacking the AP-1 site fails to up-regulate Fcgr2b on activated B cells, producing enhanced germinal center formation, increased affinity maturation, and autoantibody deposition, culminating in spontaneous glomerular immune complex disease (PMID:23109709).

Together, these data support a pathogenic mechanism whereby FCGR2B promoter and coding variants diminish inhibitory signaling, facilitate aberrant B cell activation, and predispose to SLE. The integration of genetic association, functional promoter assays, and animal modeling provides strong evidence for FCGR2B as a susceptibility locus in SLE, with potential implications for targeted therapies and risk stratification.

Key take-home: FCGR2B coding and promoter variants confer increased SLE risk by reducing inhibitory FcγRIIb expression and function, making this receptor a candidate biomarker and therapeutic target.

References

• Journal of dermatological science • 2006 • Association of Fcgamma receptor IIB gene polymorphism with genetic susceptibility to systemic lupus erythematosus in Chinese populations--a family-based association study. PMID:16531013
• Archives of dermatological research • 2007 • Gln50Ter polymorphism of Fcgamma receptor IIB gene associated with genetic susceptibility to human systemic lupus erythematosus in Chinese populations. PMID:17393178
• Lupus • 2008 • Genetic susceptibility and haplotype analysis between Fcgamma receptor IIB and IIIA gene with systemic lupus erythematosus in Chinese population. PMID:18625651
• The Journal of biological chemistry • 2007 • The role of activating protein 1 in the transcriptional regulation of the human FCGR2B promoter mediated by the -343 G -> C polymorphism associated with systemic lupus erythematosus. PMID:17130130
• Journal of immunology (Baltimore, Md. : 1950) • 2002 • Transcriptional regulation of Fcgr2b gene by polymorphic promoter region and its contribution to humoral immune responses. PMID:12370366
• The Journal of experimental medicine • 2012 • Analysis of a wild mouse promoter variant reveals a novel role for FcγRIIb in the control of the germinal center and autoimmunity. PMID:23109709

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