Abstract
The role for inhibitory Fc gamma receptors class IIb (FcγRIIb) in the onset, progression and severity of several animal models of autoimmune diseases is well established. By contrast, the pathogenic potential of FcγRIIb 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 FcγRIIb 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 FcγRIIb 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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Amigorena S, Bonnerot C, Drake JR, Choquet D, Hunziker W, Guillet JG, Webster P, Sautes C, Mellman I, Fridman WH (1992) Cytoplasmic domain heterogeneity and functions of IgG Fc receptors in B lymphocytes. Science 256:1808–1812
Bolland S, Ravetch JV (2000) Spontaneous autoimmune disease in Fc(gamma)RIIB-deficient mice results from strain-specific epistasis. Immunity 13:277–285
Cerutti A, Zan H, Schaffer A, Bergsagel L, Harindranath N, Max EE, Casali P (1998) CD40 ligand and appropriate cytokines induce switching to IgG, IgA, and IgE and coordinated germinal center and plasmacytoid phenotypic differentiation in a human monoclonal IgM+ IgD+ B cell line. J Immunol 160:2145–2157
Chu ZT, Tsuchiya N, Kyogoku C, Ohashi J, Qian YP, Xu SB, Mao CZ, Chu JY, Tokunaga K (2004) Association of Fcgamma receptor IIb polymorphism with susceptibility to systemic lupus erythematosus in Chinese: a common susceptibility gene in the Asian populations. Tissue Antigens 63:21–27
Clopper CJPE (1934) The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika 26:404–413
Diegel ML, Rankin BM, Bolen JB, Dubois PM, Kiener PA (1994) Cross-linking of Fc gamma receptor to surface immunoglobulin on B cells provides an inhibitory signal that closes the plasma membrane calcium channel. J Biol Chem 269:11409–11416
Enyedy EJ, Mitchell JP, Nambiar MP, Tsokos GC (2001) Defective FcgammaRIIb1 signaling contributes to enhanced calcium response in B cells from patients with systemic lupus erythematosus. Clin Immunol 101:130–135
Greenwel P, Tanaka S, Penkov D, Zhang W, Olive M, Moll J, Vinson C, Di Liberto M, Ramirez F (2000) Tumor necrosis factor alpha inhibits type I collagen synthesis through repressive CCAAT/enhancer-binding proteins. Mol Cell Biol 20:912–918
Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725
Jiang Y, Hirose S, Abe M, Sanokawa-Akakura R, Ohtsuji M, Mi X, Li N, Xiu Y, Zhang D, Shirai J, Hamano Y, Fujii H, Shirai T (2000) Polymorphisms in IgG Fc receptor IIB regulatory regions associated with autoimmune susceptibility. Immunogenetics 51:429–435
Kyogoku C, Dijstelbloem HM, Tsuchiya N, Hatta Y, Kato H, Yamaguchi A, Fukazawa T, Jansen MD, Hashimoto H, van de Winkel JG, Kallenberg CG, Tokunaga K (2002) Fcgamma receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus: contribution of FCGR2B to genetic susceptibility. Arthritis Rheum 46:1242–1254
Li X, Wu J, Carter RH, Edberg JC, Su K, Cooper GS, Kimberly RP (2003) A novel polymorphism in the Fcgamma receptor IIB (CD32B) transmembrane region alters receptor signaling. Arthritis Rheum 48:3242–3252
Liu Y, Masuda E, Blank MC, Kirou K, Gao X, Park MS, Pricop L (2005) Cytokine-mediated regulation of activating and inhibitory Fc{gamma} receptors in human monocytes. J Leukoc Biol 77:767–776
Luan JJ, Monteiro RC, Sautes C, Fluteau G, Eloy L, Fridman WH, Bach JF, Garchon HJ (1996) Defective Fc gamma RII gene expression in macrophages of NOD mice: genetic linkage with up-regulation of IgG1 and IgG2b in serum. J Immunol 157:4707–4716
Magnusson V, Zunec R, Odeberg J, Sturfelt G, Truedsson L, Gunnarsson I, Alarcon-Riquelme ME (2004) Polymorphisms of the Fc gamma receptor type IIB gene are not associated with systemic lupus erythematosus in the Swedish population. Arthritis Rheum 50:1348–1350
Moser KL, Neas BR, Salmon JE, Yu H, Gray-McGuire C, Asundi N, Bruner GR, Fox J, Kelly J, Henshall S, Bacino D, Dietz M, Hogue R, Koelsch G, Nightingale L, Shaver T, Abdou NI, Albert DA, Carson C, Petri M, Treadwell EL, James JA, Harley JB (1998) Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees. Proc Natl Acad Sci USA 95:14869–14874
Muta T, Kurosaki T, Misulovin Z, Sanchez M, Nussenzweig MC, Ravetch JV (1994) A 13-amino-acid motif in the cytoplasmic domain of Fc gamma RIIB modulates B-cell receptor signalling. Nature 369:340
Nishimura T, Narita T, Miyazaki E, Ito T, Nishimoto N, Yoshizaki K, Martial JA, Bellfroid EJ, Vissing H, Taniyama T (2001) Characterization of the human Fc gamma RIIB gene promoter: human zinc-finger proteins (ZNF140 and ZNF91) that bind to different regions function as transcription repressors. Int Immunol 13:1075–1084
Phillips NE, Parker DC (1984) Cross-linking of B lymphocyte Fc gamma receptors and membrane immunoglobulin inhibits anti-immunoglobulin-induced blastogenesis. J Immunol 132:627–632
Pricop L, Redecha P, Teillaud JL, Frey J, Fridman WH, Sautes-Fridman C, Salmon JE (2001) Differential modulation of stimulatory and inhibitory Fc gamma receptors on human monocytes by Th1 and Th2 cytokines. J Immunol 166:531–537
Pritchard NR, Cutler AJ, Uribe S, Chadban SJ, Morley BJ, Smith KG (2000) Autoimmune-prone mice share a promoter haplotype associated with reduced expression and function of the Fc receptor FcgammaRII. Curr Biol 10:227–230
Prokunina L, Castillejo-Lopez C, Oberg F, Gunnarsson I, Berg L, Magnusson V, Brookes AJ, Tentler D, Kristjansdottir H, Grondal G, Bolstad AI, Svenungsson E, Lundberg I, Sturfelt G, Jonssen A, Truedsson L, Lima G, Alcocer-Varela J, Jonsson R, Gyllensten UB, Harley JB, Alarcon-Segovia D, Steinsson K, Alarcon-Riquelme ME (2002) A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 32:666–669
Qiu WQ, de Bruin D, Brownstein BH, Pearse R, Ravetch JV (1990) Organization of the human and mouse low-affinity Fc gamma R genes: duplication and recombination. Science 248:732–735
Rudge EU, Cutler AJ, Pritchard NR, Smith KG (2002) Interleukin 4 reduces expression of inhibitory receptors on B cells and abolishes CD22 and Fc gamma RII-mediated B cell suppression. J Exp Med 195:1079–1085
Sarkar S, Schlottmann K, Cooney D, Coggeshall KM (1996) Negative signaling via FcgammaRIIB1 in B cells blocks phospholipase Cgamma2 tyrosine phosphorylation but not Syk or Lyn activation. J Biol Chem 271:20182–20186
Schlossman S (1995) White cell differentiation antigens. Oxford University Press, New York
Stefanescu RN, Olferiev M., Liu Y, Pricop L (2004) Inhibitory Fc gamma receptors: from gene to disease. J Clin Immunol 24:315–326
Su K, Wu J, Edberg JC, Li X, Ferguson P, Cooper GS, Langefeld CD, Kimberly RP (2004) A promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing FcgammaRIIb alters receptor expression and associates with autoimmunity I. Regulatory FCGR2B polymorphisms and their association with systemic lupus erythematosus. J Immunol 172:7186–7191
Tsao BP (2000) Lupus susceptibility genes on human chromosome 1. Int Rev Immunol 19:319–334
Vyse TJ, Kotzin BL (1998) Genetic susceptibility to systemic lupus erythematosus. Annu Rev Immunol 16:261–292
Warmerdam PA, Nabben NM, van de Graaf SA, van de Winkel JG, Capel PJ (1993) The human low affinity immunoglobulin G Fc receptor IIC gene is a result of an unequal crossover event. J Biol Chem 268:7346–7349
Xiu Y, Nakamura K, Abe M, Li N, Wen XS, Jiang Y, Zhang D, Tsurui H, Matsuoka S, Hamano Y, Fujii H, Ono M, Takai T, Shimokawa T, Ra C, Shirai T, Hirose S (2002) Transcriptional regulation of Fcgr2b gene by polymorphic promoter region and its contribution to humoral immune responses. J Immunol 169:4340–4346
Acknowledgements
We thank Jane Salmon and Heidi Norbis for providing blood and DNA samples from the HSS Autoimmune Registry and Repository, and Francesco Ramirez for reviewing the manuscript. This work was supported by grants from the National Institutes of Health AR49765, the SLE Foundation, the Mary Kirkland Lupus Center and the Arthritis Foundation (to L. Pricop). This investigation was conducted in a facility constructed with support from Research Facilities Improvement Program Grant Number C06-RR12538-01 from the National Center for Research Resources, National Institutes of Health.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Blank, M.C., Stefanescu, R.N., Masuda, E. et al. Decreased transcription of the human FCGR2B gene mediated by the -343 G/C promoter polymorphism and association with systemic lupus erythematosus. Hum Genet 117, 220–227 (2005). https://doi.org/10.1007/s00439-005-1302-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-005-1302-3