Decreased transcription of the human FCGR2B gene mediated by the -343 G/C promoter polymorphism and association with systemic lupus erythematosus

Blank, Marissa C.; Stefanescu, Radu; Masuda, Eriko; Martí, Francesc; King, Philip D.; Redecha, Patricia; Wurzburger, Robert J.; Peterson, Margaret G. E.; Tanaka, Shizuko; Pricop, Luminita

doi:10.1007/s00439-005-1302-3

Cited by 143 publications

(129 citation statements)

References 33 publications

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“…Genetic variants of CD32B gene are reported to affect the expression and function of this receptor and be associated with select autoimmune conditions in both mice and humans (40)(41)(42). We cannot completely exclude the possibility that specific CD32B polymorphisms, known to affect CD32B expression, partially account for our observations in RA; however, the extremely low prevalence of these polymorphisms limits their potential influence on our findings (41,42).…”

Section: Discussionmentioning

confidence: 76%

CD40 Mediates Downregulation of CD32B on Specific Memory B Cell Populations in Rheumatoid Arthritis

Zhang

Burch

Cai

et al. 2013

The Journal of Immunology

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Altered B cell function is important in the pathogenesis of rheumatoid arthritis (RA). In this report, we show that patients with active RA have an increased frequency of CD32B low/neg cells in the CD27+IgD− memory B cell subset and that these changes are associated with phenotypic and functional B cell activation. Studies using PBMCs from healthy donors revealed that downregulation of CD32B on B cells is mediated by CD40–CD40L interactions and is potentiated by IL-4 and inhibited by both IL-10 and IL-21. These findings appear physiologically relevant because CD4 T cell expression of CD40L correlated with the frequency of CD32B low/neg cells in the CD27+IgD− memory B subset in patients with RA. Our data support a model in which high levels of CD40L, present on circulating T cells in patients with RA, causes B cell activation and CD32B downregulation, resulting in secondary protection of memory B cells from CD32B-mediated cell death.

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Section: Discussionmentioning

confidence: 76%

CD40 Mediates Downregulation of CD32B on Specific Memory B Cell Populations in Rheumatoid Arthritis

Zhang

Burch

Cai

et al. 2013

The Journal of Immunology

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“…rs 3219018. A nested PCR amplified a 15-kb region specific for FCGR2B, which was followed by amplification of the promoter region, with primers as previously described (22). The PCR products were purified using Exosap and sequenced using an ABI 3730 sequencer.…”

Section: Methodsmentioning

confidence: 99%

“…A polymorphism in the promoter region of FCGR2B, rs3219018, has been associated with changes in FcγRIIb expression and SLE in Caucasians (22), and it might have an additional effect on susceptibility to infection. We genotyped 96 Kenyan controls and found no minor alleles, despite finding a MAF of 0.16 in 90 U.K. Caucasians.…”

mentioning

confidence: 99%

A defunctioning polymorphism in FCGR2B is associated with protection against malaria but susceptibility to systemic lupus erythematosus

Willcocks

Carr

Niederer

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

180

141

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Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease more prevalent in people of African and Asian origin than Caucasian origin. FcγRIIb is an inhibitory Fc receptor with a critical role in immune regulation. Mouse data suggest that FcγRIIb deficiency increases susceptibility to autoimmune disease but protects against infection. We show that a SNP in human FCGR2B that abrogates receptor function is strongly associated with susceptibility to SLE in both Caucasians and Southeast Asians. The minor allele of this SNP is more common in Southeast Asians and Africans, populations from areas where malaria is endemic, than in Caucasians. We show that homozygosity for the minor allele is associated with substantial protection against severe malaria in an East African population (odds ratio = 0.56; P = 7

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“…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).…”

Section: T He Only Inhibitory Igg Fcr In the Classical Fcr Family (1mentioning

confidence: 99%

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

Yang

et al. 2007

The Journal of Immunology

165

150

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FcγRIIb (CD32B, Online Mendelian Inheritance in Man 604590), an IgG FcR with a tyrosine-based inhibitory motif, plays a critical role in the balance of tolerance and autoimmunity in murine models. However, the high degree of homology between FcγRIIb and FcγRIIa in humans and the lack of specific Abs to differentiate them have hampered study of the normal expression profile of FcγRIIb and its potential dysregulation in autoimmune diseases such as systemic lupus erythematosus (SLE). Using our newly developed anti-FcγRIIb mAb 4F5 which does not react with FcγRIIa, we found that FcγRIIb is expressed on the cell surface of circulating B lymphocytes, monocytes, neutrophils, myeloid dendritic cells (DCs), and at very low levels on plasmacytoid DCs from some donors. Normal donors with the less frequent 2B.4 promoter haplotype have higher FcγRIIb expression on monocytes, neutrophils, and myeloid DCs similar to that reported for B lymphocytes, indicating that FcγRIIb expression on both myeloid and lymphoid cells is regulated by the naturally occurring regulatory single nucleotide polymorphisms in the FCGR2B promoter. FcγRIIb expression in normal controls is up-regulated on memory B lymphocytes compared with naive B lymphocytes. In contrast, in active SLE, FcγRIIb is significantly down-regulated on both memory and plasma B lymphocytes compared with naive and memory/plasma B lymphocytes from normals. Similar down-regulation of FcγRIIb on myeloid-lineage cells in SLE was not seen. Our studies demonstrate the constitutive regulation of FcγRIIb by natural gene polymorphisms and the acquired dysregulation in SLE autoimmunity, which may identify opportunities for using this receptor as a therapeutic target.

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Decreased transcription of the human FCGR2B gene mediated by the -343 G/C promoter polymorphism and association with systemic lupus erythematosus

Cited by 143 publications

References 33 publications

CD40 Mediates Downregulation of CD32B on Specific Memory B Cell Populations in Rheumatoid Arthritis

CD40 Mediates Downregulation of CD32B on Specific Memory B Cell Populations in Rheumatoid Arthritis

A defunctioning polymorphism in FCGR2B is associated with protection against malaria but susceptibility to systemic lupus erythematosus

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

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