Identification of a family of Fc receptor homologs with preferential B cell expression

Davis, Randall S.; Wang, Yui‐Hsi; Kubagawa, Hiromi; Cooper, Max D.

doi:10.1073/pnas.171308498

Cited by 192 publications

(167 citation statements)

References 50 publications

(36 reference statements)

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“…These two FcR family members are differentially expressed on B cells, including GC B cells, but their function is yet unknown. 18,19 Interestingly, FCRL3, a member of this family in humans, is associated with RA and other autoimmune conditions, including lupus. 20 We are currently investigating whether one or both of these genes present allelic differences between NZW and B6.…”

Section: Resultsmentioning

confidence: 99%

Expression of the autoimmune Fcgr2b NZW allele fails to be upregulated in germinal center B cells and is associated with increased IgG production

et al. 2007

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The inhibitory receptor FcgRIIb regulates B-cell functions. Genetic studies have associated Fcgr2b polymorphisms and lupus susceptibility in both humans and murine models, in which B cells express reduced FcgRIIb levels. Furthermore, FcgRIIb absence results in lupus on the appropriate genetic background, and lentiviral-mediated FcgRIIb overexpression prevents disease in the NZM2410 lupus mouse. The NZM2410/NZW allele Fcgr2b is, however, located in-between Sle1a and Sle1b, two potent susceptibility loci, making it difficult to evaluate Fcr2b NZW independent contribution. By using two congenic strains that each carries only Sle1a (B6.Sle1a(15-353)), or Fcr2b NZW in the absence of Sle1a or Sle1b (B6.Sle1(111-148)), we show that the Fcr2b NZW allele does not upregulate its expression on germinal center B cells and plasma cells, as does the C57BL/6 allele on B6.Sle1a(15-353) B cells. Furthermore, in the absence of the flanking Sle1a and Sle1b, Fcr2b NZW does not produce an autoimmune phenotype, but is associated with an increased number of class-switched plasma cells. These results show that while a lower level of FcgRIIb does not by itself induce the development of autoreactive B cells, it has the potential to amplify the contribution of autoreactive B cells induced by other lupus-susceptibility loci by enhancing the production of class-switched plasma cells.

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Section: Resultsmentioning

confidence: 99%

Expression of the autoimmune Fcgr2b NZW allele fails to be upregulated in germinal center B cells and is associated with increased IgG production

et al. 2007

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“…All are type I transmembrane proteins of the immunoglobulin superfamily, and display potential immunoreceptor tyrosine-based activation and/or inhibitory motifs (ITAMs or ITIMs) in their cytoplasmic domains. [3][4][5][6][7][8][9][10][11] IRTA1/FcRH4/IFGP2 was originally identified as part of an Ig-Ca1 fusion protein resulting from the translocation of chromosome 1q21 with 14q32 in a human multiple myeloma cell line. Expression of this gene was found to be localized within naïve and memory B cells of the marginal zone and epithelium.…”

Section: Introductionmentioning

confidence: 99%

“…More recent analysis of the cytoplasmic domain of this protein has indicated that it is likely to function as a potent inhibitory receptor for regulating memory B-cell activation. 4,[6][7][8]12,13 A second homologous cDNA encoding IRTA2/FcRH5/ BXMAS1 was cloned and found to be dysregulated in Burkitt's lymphoma cell lines with 1q21 abnormalities. Transcript for this gene can be detected within naïve B cells, memory, and plasma cells of the mantle zone, interfollicular, intraepithelial, and germinal center light zones.…”

Section: Introductionmentioning

confidence: 99%

“…Transcript for this gene can be detected within naïve B cells, memory, and plasma cells of the mantle zone, interfollicular, intraepithelial, and germinal center light zones. 3,4,[7][8][9] Three additional members of this family, FcRH1-3 (also designated IRTA5/IFGP1, IRTA4/SPAP1/ IFGP4, and IRTA3/SPAP2/IFGP3, respectively), were identified in both humans and mice, and found to be expressed in naïve B cells of the mantle zone, interfollicular memory B cells, and B cells of the germinal center light zone. While most Fc receptor homologs contain potential ITAM or ITIM motifs, one of these, FcRH1, contains only ITAM-like motifs in its cytoplasmic tail, and has been implicated as a possible coreceptor for B-cell activation.…”

Section: Introductionmentioning

confidence: 99%

“…While most Fc receptor homologs contain potential ITAM or ITIM motifs, one of these, FcRH1, contains only ITAM-like motifs in its cytoplasmic tail, and has been implicated as a possible coreceptor for B-cell activation. [3][4][5][6]8,10,11,14 The sixth FcR homolog, FREB1/FcRx/FCRL, was found to be unique among these FcR homologs in a number of ways. In the place of a transmembrane domain and signaling motifs, FREB1 was found to contain a unique proline-rich sequence and leucine-rich helical motif in its C-terminus.…”

Section: Introductionmentioning

confidence: 99%

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A new Fc receptor homolog, FREB2, found in germinal center B cells

Wilson

Colonna

2005

Genes Immun

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Fc receptor homologs are a recently identified family of proteins homologous to FcgRI, found on human and mouse B cells. One of these, FREB/FcRX/FCRL, was found to be unique since it lacks a transmembrane domain and is expressed intracellularly within germinal center B cells. We have identified in humans and mice a new Fc receptor homolog, FREB2, that blends conserved elements of the classical Fc gamma receptors with structural motifs previously thought to be unique to FREB1. This protein is comprised of three immunoglobulin-like domains with high homology to those in FcgRI, and a C-terminus containing a proline-rich stalk region followed by a leucine-rich amphipathic alpha helix. Like FREB1, FREB2 is expressed as an intracellular protein. In murine splenocytes, RNA transcripts for each of the two proteins can be amplified from germinal center B cells. However, immunohistochemical analysis of human tonsils indicates that expression of FREB1 and FREB2 is mutually exclusive in non-neoplastic cells. Importantly, FREB2 expression within human tonsils appears to be limited to a small subset of nonproliferating germinal center B cells, suggesting that it may play a role in regulating clonal expansion or differentiation of B cells during the germinal center reaction.

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Rheumatoid arthritis association with the FCRL3 –169C polymorphism is restricted to PTPN22 1858T–homozygous individuals in a Canadian population

Newman¹,

Zhang²,

Liu³

et al. 2006

Arthritis & Rheumatism

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Objective. Variants in genes encoding the Fc receptor-like 3 (FcRL-3) and the class II major histocompatibility complex (MHC) transactivator proteins have been associated with an increased risk of rheumatoid arthritis (RA) in Japanese and Nordic populations, respectively. The aim of this study was to investigate these associations in a Canadian Caucasian cohort of RA cases and healthy controls.Methods. A total of 1,187 RA patients and 462 healthy controls were genotyped for FCRL3 and MHC2TA gene variants associated with RA. Epistasis between the FCRL3 -169C and the PTPN22 1858T variants was also examined.Results. An association was detected between RA and both the FCRL3 -169C allele (OR 1.19, P ‫؍‬ 0.023) and the homozygous genotype (OR 1.41, P ‫؍‬ 0.027), but association of the MHC2TA promoter region variant (-168G) with RA was not replicated. Stratification of the RA cohort by PTPN22 genotypes revealed the FCRL3 risk variant and RA association was stronger in the patient subgroup lacking PTPN22 1858T variants (P ‫؍‬ 0.004) and was not detectable in the subgroup with PTPN22 1858T variants (P ‫؍‬ 0.52). The PTPN22 association with RA was greater in the absence than in the presence of the FCRL3 -169C allele (P ‫؍‬ 0.0008 versus P ‫؍‬ 0.001). The PTPN22 1858T variant also increased the risk of autoimmune thyroid disease (AITD) in the RA patients, whereas the FCRL3 risk variant was protective against AITD.Conclusion. Our findings support an association of RA with an FCRL3 functional polymorphism and reveal that this association is stronger in the absence of PTPN22 risk genotypes. These findings support a genetic heterogeneity across RA populations, suggesting that both the FCRL3 and PTPN22 genes play roles in RA susceptibility, but in different individuals.

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Identification of a family of Fc receptor homologs with preferential B cell expression

Cited by 192 publications

References 50 publications

Expression of the autoimmune Fcgr2b NZW allele fails to be upregulated in germinal center B cells and is associated with increased IgG production

Expression of the autoimmune Fcgr2b NZW allele fails to be upregulated in germinal center B cells and is associated with increased IgG production

A new Fc receptor homolog, FREB2, found in germinal center B cells

Rheumatoid arthritis association with the FCRL3 –169C polymorphism is restricted to PTPN22 1858T–homozygous individuals in a Canadian population

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