ABSTRACT
The role for inhibitory Fc gamma receptors class IIb (FcgammaRIIb) in the onset, progression and severity of several animal models of autoimmune diseases is well established. By contrast, the pathogenic potential of FcgammaRIIb in human autoimmune diseases remains largely unknown. Here we report the identification of a polymorphism in the human FCGR2B promoter (dbSNP no. rs3219018) that is associated in homozygosity with systemic lupus erythematosus (SLE) phenotype in European-Americans (OR=11.1, P=0.003). Experimental evidence correlates the polymorphism (a G-C substitution at position -343 relative to the start of transcription) with altered FcgammaRIIb expression and function. The G-C substitution correlated with decreased transcription of the FCGR2B promoter, and resulted in decreased binding of the AP1 transcription complex to the mutant promoter sequence. The surface expression of FcgammaRIIb receptors was significantly reduced in activated B cells from (-343 C/C) SLE patients. These findings suggest that genetic defects may lead to deregulated expression of the FCGR2B gene in -343 C/C homozygous subjects, and may play a role in the pathogenesis of human SLE.
Subject(s)
Lupus Erythematosus, Systemic/genetics , Polymorphism, Single Nucleotide/genetics , Promoter Regions, Genetic/genetics , Receptors, IgG/genetics , Transcription, Genetic/genetics , B-Lymphocytes/metabolism , Down-Regulation/genetics , Genetic Linkage/genetics , Homozygote , Humans , Lupus Erythematosus, Systemic/metabolism , Lymphocyte Activation/genetics , Receptors, IgG/biosynthesis , Transcription Factor AP-1/metabolismABSTRACT
Multiple lines of evidence have revealed a key role for inhibitory Fc gamma receptors class IIb (FcgammaRIIb) as negative modulators of innate and adaptive immune responses. Acquired and genetic factors regulate the expression of FcgammaRIIb receptors and modify their inhibitory potential. Recent advances have highlighted the importance of FcgammaRIIb receptors in influencing the development of cancer and autoimmunity. The association of increased FcgammaRIIb expression with tumor development is believed to operate at effector cell level resulting in inhibition of antitumor cytotoxicity. In autoimmune diseases, FcgammaRIIb receptors play a major role in controlling the amplitude of antibody- and immune complex-mediated reactions. Generally, FcgammaRIIb deficiency is associated with increased susceptibility and severity to organ-specific and systemic autoimmunity. This article discusses the proposed mechanisms for FcgammaRIIb deregulation associated with malignant and autoimmune pathology in animal models and human diseases.