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1.  A functional variant in FCRL3 is associated with higher FcRL3 expression on T cell subsets and rheumatoid arthritis disease activity 
Arthritis and rheumatism  2012;64(8):2451-2459.
CD4+FoxP3+ regulatory T cells (Treg) suppress effector T cells and prevent autoimmune disease. Treg function is deficient in active rheumatoid arthritis (RA), a loss which may play a role in the pathogenesis of this disease. We previously showed that a single nucleotide polymorphism in the Fc Receptor Like-3 (FCRL3) gene led to higher expression of FcRL3 on Treg+ and that FcRL3 Treg are functionally deficient in comparison to FcRL3− Treg. The objective of this work was to investigate the potential role of FcRL3 in rheumatoid arthritis.
A cross-sectional study was performed to evaluate the FCRL3 -169 genotype and FcRL3 expression on T cell subsets, including Treg, from peripheral blood samples of 51 patients with RA enrolled in the UCSF RA Cohort. Clinical data were obtained from the UCSF RA Cohort database.
We found that patients with the FCRL3 -169C allele (genotype C/C or C/T) expressed significantly higher levels of FcRL3 on Treg, and on CD8+ and TCRγδ+ T cells, in comparison to RA patients with the T/T genotype. Higher FcRL3 expression on these T cell subpopulations correlated with RA disease activity in those patients harboring the FCRL3 -169C allele. Furthermore, FcRL3 expression on Treg was higher in patients with erosive RA disease and the FCRL3 -169C allele was overrepresented in patients with erosive RA disease.
FcRL3 expression, which is strongly associated with the presence of the FCRL3 -169C allele, may serve as a biomarker of RA disease activity.
PMCID: PMC3374037  PMID: 22392608
2.  Association of Fc receptor like 5 (FCRL5) with Graves’ disease is secondary to the effect of FCRL3 
Clinical endocrinology  2010;73(5):654-660.
The Fc receptor like 3 (FCRL3) molecule, involved in controlling B cell signalling, may contribute to the autoimmune disease process. Recently a genome wide screen detected association of neighbouring gene FCRL5 with Graves’ disease (GD). To determine whether FCRL5 represents a further independent B cell signaling GD susceptibility loci we screened 12 tag SNPs, capturing all known common variation within FCRL5, in 5192 UK Caucasian GD index cases and controls.
A case control association study investigating twelve tag SNPs within FCRL5 which captured the majority of known common variation within this gene region.
A dataset comprising 2504 UK Caucasian GD patients and 2688 geographically matched controls taken from the 1958 British Birth cohort.
We used the chi-squared test and haplotype analysis to investigate association between the tag SNPs and GD before performing regression analysis to determine if association at FCRL5 was independent of the known FCRL3 association.
Three of the FCRL5 tag SNPs, rs6667109, rs3811035 and rs6692977 showed association with GD (P=0.015-0.001, OR=1.15-1.16). Logistic regression performed on all FCRL5 and, previously screened, FCRL3 tag SNPs revealed that association with FCRL5 was secondary to linkage disequilibrium with the FCRL3, rs11264798 and rs10489678 SNPs.
FCRL5 does not appear to be exerting an independent effect on the development of GD in the UK. Fine mapping of the entire FCRL region is required to determine the exact location of the etiological variant/s present.
PMCID: PMC3299549  PMID: 20626413
Linkage disequilibrium; FCRL3; FCRL5; Graves’ disease; genome wide screening
3.  Association of the FCRL3 gene with rheumatoid arthritis: a further example of population specificity? 
Association of a functional promoter polymorphism mapping to the Fc receptor-like 3 (FCRL3) gene has recently been reported and replicated with rheumatoid arthritis (RA) in Japanese populations. The aim of this study was to investigate association of the FCRL3 gene with RA in UK subjects. DNA was available from 1065 patients with RA and 2073 population controls from the UK. Four single nucleotide polymorphism (SNP) markers (FCRL3-169*C/T (fclr3_3, rs7528684), fclr3_4 (rs11264799), fclr3_5 (rs945635), fclr3_6 (rs3761959)) all previously associated with RA in a Japanese population were genotyped in 761 RA samples and 484 controls. In the remaining samples, only the putative disease causal polymorphism, FCRL3-169*C/T, was tested. Genotyping was performed using either the Sequenom MassArray iPlex platform or a 5' Allelic discrimination assay (Taqman, ABI). Extensive linkage disequilibrium was present across the promoter SNPs genotyped (r2 values = 0.60-0.98). Allele frequencies did not differ between RA cases and controls either for the putative disease causal polymorphism (odds ratio FCRL3-169*C allele = 0.97 (0.87-1.07), p = 0.51) or for the other SNPs tested. Similarly, no association was detected with RA using haplotype analysis or when stratification by shared epitope carriage or by presence of rheumatoid factor was undertaken. This study was powered to detect an effect size of 1.24 or greater for the FCRL3-169*C/T functional promoter polymorphism but no evidence for association was detected, suggesting that this gene will not have a substantial effect in determining susceptibility to RA in populations of Northern European descent.
PMCID: PMC1779391  PMID: 16859508
4.  Supportive evidence for a genetic association of the FCRL3 promoter polymorphism with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2005;65(5):671-673.
An association between susceptibility to rheumatoid arthritis and the Fc receptor‐like 3 gene (FCRL3) has been reported in a Japanese population. A case–control study showed that the strongest evidence of the association was derived from a polymorphism in the promoter region of FCRL3, which has a regulatory effect on the expression of the gene.
To validate the findings of this previous report by examining the −169C→T single nucleotide polymorphism (SNP) in a large cohort.
752 unrelated cases and 940 controls were genotyped. All the samples were from the same ethnic background as the original study. Genotyping was done using 5′ allelic discrimination assays. Association between susceptibility to rheumatoid arthritis and −169C→T SNP was examined by χ2 testing.
As in the previous study, the SNP showed significant differences between cases and controls (p = 0.022, odds ratio = 1.18, 95% confidence interval 1.02 to 1.35).
This result supports a genetic association of the FCRL3 promoter polymorphism with rheumatoid arthritis.
PMCID: PMC1798145  PMID: 16176992
rheumatoid arthritis;  FCRL3 ; rheumatoid factor; replication
5.  The FCRL3 −169T>C polymorphism and the risk of endometriosis-related infertility in a Polish population 
Recently, the FCRL3 −169T>C (rs7528684) single-nucleotide polymorphism (SNP) has been demonstrated to be a risk factor of endometriosis related infertility. We studied whether the FCRL −169T>C SNP can be associated with endometriosis-related infertility in a sample of the Polish population
Using PCR–RFLP analysis we genotyped 141 infertile women with endometriosis and 519 fertile women. FCRL3 transcript levels were determined by reverse transcription and real-time quantitative PCR analysis in CD19+ B cells from women with endometriosis-associated infertility and fertile women
We found a significantly increased frequency of the FCRL3 C/C genotype in women with endometriosis-associated infertility than controls [OR = 1.681 (95 % CI = 1.120–2.522, p = 0.0116, pcorr = 0.0348)]. There was also a statistically increased frequency of the C/C and C/T genotypes in patients compared with controls [OR = 2.009 (95 % CI = 1.214–3.324, p = 0.0059, pcorr = 0.0177)]. The p value of the χ2 test for the trend observed for the FCRL3 −169T>C polymorphism was also statistically significant (ptrend = 0.0012, pcorr = 0.0036). We also found significantly increased FCRL3 transcript levels in carriers of the FCRL3 −169 CC vs TT and CT vs TT genotype both in women with endometriosis-related infertility (p = 0.012; p = 0.015) and fertile women (p = 0.017; p = 0.032)
FCRL3 −169T>C polymorphism alters the expression of FCRL3 and can be a risk factor of endometriosis-related infertility.
PMCID: PMC3778220  PMID: 23553198
Polymorphisms; Endometriosis; Infertility
6.  Discriminating gene expression profiles of memory B cell subpopulations 
The Journal of Experimental Medicine  2008;205(8):1807-1817.
Morphologically and functionally distinct subpopulations of human memory B (BMem) cells are identifiable by either their expression of CD27 or Fc receptor–like 4 (FCRL4), an immunoglobulin domain containing a receptor with strong inhibitory potential. We have conducted comparative transcriptome and proteome analyses of FCRL4+ and FCRL4− BMem cells and found that these two subsets have very distinctive expression profiles for genes encoding transcription factors, cell-surface proteins, intracellular signaling molecules, and modifiers of the cell-cycle status. Among the differentially expressed transcription factors, runt-related transcription factor 1 (RUNX1) transcript levels were up-regulated in FCRL4− cells, whereas RUNX2 transcripts were preferentially detected in FCRL4+ cells. In vitro evidence for FCRL4 promoter responsiveness and in vivo promoter occupancy suggested that RUNX transcription factors are involved in the generation of these BMem cell subpopulations. A distinctive signature profile was defined for the FCRL4+ BMem cells by their expression of CD11c, receptor activator for nuclear factor κB ligand, and FAS cell-surface proteins, in combination with increased levels of SOX5, RUNX2, DLL1, and AICDA expression. We conclude that this recently identified subpopulation of BMem cells, which normally resides in epithelial tissue-based niches, may serve a unique role in mucosal defense and, conversely, as a target for neoplastic transformation events.
PMCID: PMC2525601  PMID: 18625746
7.  Expression of the autoimmune susceptibility gene FcRL3 on human regulatory T cells is associated with dysfunction and high levels of PD-1 
CD4+FoxP3+ regulatory T cells (Treg) play a critical role in maintaining self tolerance and inhibiting autoimmune disease. Despite being a major focus of modern immunological investigation, many aspects of Treg biology remain unknown. In a screen for novel candidate genes involved in human Treg function, we detected the expression of an autoimmune susceptibility gene, FcRL3, in Treg but not in conventional CD4+ T cells. FcRL3 is an orphan receptor of unknown function with structural homology to classical Fc receptors. Numerous genetic studies have demonstrated a link between a single nucleotide polymorphism in the FCRL3 promoter and both overexpression of FcRL3 and autoimmune diseases such as rheumatoid arthritis. Given the critical role of Treg in suppressing autoimmunity, we sought to ascertain how expression of FcRL3 relates to the phenotype, differentiation, and function of Treg. We show here that FcRL3 is expressed on a population of thymically derived Treg that exhibits a memory phenotype and high levels of programmed cell death-1 (PD-1). Purified FcRL3+ Treg are less responsive to antigenic stimulation in the presence of IL-2 than their FcRL3− counterparts, despite intact proximal and distal IL-2 signaling as determined by phosphorylation of Stat-5 and upregulation of Bcl2. In vitro suppression assays demonstrated that FcRL3+ Treg have reduced capacity to suppress the proliferation of effector T cells. These data suggest that FcRL3 expression is associated with Treg dysfunction that may, in turn, contribute to the loss of self tolerance and the development of autoimmunity.
PMCID: PMC2894810  PMID: 20190142
8.  FCRL3 promotes TLR9-induced B cell activation and suppresses plasma cell differentiation 
European journal of immunology  2013;43(11):10.1002/eji.201243068.
Fc receptor-like (FCRL) molecules are preferentially expressed by B lymphocytes and possess tyrosine-based immunoregulatory function. Although they generally inhibit B cell receptor (BCR) signaling, their influence on other activation pathways remains largely unexplored. In humans, FCRL3 encodes a type I transmembrane protein harboring both cytoplasmic ITAM and ITIM elements that can repress BCR activation. Despite this inhibitory property, mounting associations for FCRL3 with autoimmune and lymphoproliferative disorders imply a role for it in promoting B cell pathogenesis. Here we explore its influence on B cell responses to innate Toll-like receptor 9 (TLR9) stimulation. A detailed survey of blood B cell populations found that FCRL3 expression increased as a function of differentiation and was higher among memory subsets with innate-like features. FCRL3 ligation augmented CpG oligodeoxynucleotide TLR9-mediated B cell proliferation, activation, and survival, but surprisingly, abrogated plasma cell differentiation and antibody production. Although FCRL3 amplified the NF-κB and MAPK signaling cascades, it halted CpG triggered BLIMP1 induction in an ERK-dependent fashion. These findings indicate that FCRL3 differentially modulates innate signaling in B cells and provide new insight into the potential of this disease-associated receptor to counter-regulate adaptive and innate immunity.
PMCID: PMC3838486  PMID: 23857366
B cells; Fc Receptor-like; Toll-like receptor
9.  Expression of FcRL4 defines a pro-inflammatory, RANKL-producing B cell subset in rheumatoid arthritis 
Annals of the Rheumatic Diseases  2014;74(5):928-935.
The success of B cell targeting therapies has highlighted the importance of B cells in rheumatoid arthritis pathogenesis. We have previously shown that B cells in the RA synovium are capable of producing pro-inflammatory and bone-destructive cytokines including RANKL. Here we sought to characterise the nature and functional relevance of the RANKL-producing B cell subset in the RA synovium.
Synovial fluid and peripheral blood B cells from patients with RA were analysed by flow cytometry for markers of B cell differentiation and activation and for chemokine receptors. FcRL4+ and FcRL4− B cells sorted from synovial fluid were analysed for cytokine expression using Taqman low-density arrays. Synovial tissue biopsies obtained from patients with RA were analysed by immunofluorescence for CD20, RANKL and FcRL4. FCRL4 mRNA expression was determined in synovial tissue of RA patients and non-inflammatory control subjects by real-time PCR.
RANKL-producing B cells in RA synovial tissue and fluid were identified as belonging to a distinct subset of B cells defined by expression of the transmembrane protein FcRL4. FcRL4+ B cells express a distinct combination of cytokines and surface proteins indicating a function distinct from that of FcRL4− B cells. Notably, FcRL4+ B cells expressed high levels of TNF-α and RANKL mRNA.
We have identified a novel pro-inflammatory B cell population in the RA synovium which is defined by expression of FcRL4 and responsible for RANKL production. This B cell population expresses high levels of CD20, and its removal by rituximab may contribute to the anti-inflammatory effect of this drug.
PMCID: PMC4392201  PMID: 24431391
Cytokines; Rheumatoid Arthritis; Synovitis; Inflammation; B cells
10.  A Refined Study of FCRL Genes from a Genome-Wide Association Study for Graves’ Disease 
PLoS ONE  2013;8(3):e57758.
To pinpoint the exact location of the etiological variant/s present at 1q21.1 harboring FCRL1-5 and CD5L genes, we carried out a refined association study in the entire FCRL region in 1,536 patients with Graves’ disease (GD) and 1,516 sex-matched controls by imputation analysis, logistic regression, and cis-eQTL analysis. Among 516 SNPs with P<0.05 in the initial GWAS scan, the strongest signals associated with GD and correlated to FCRL3 expression were located at a cluster of SNPs including rs7528684 and rs3761959. And the allele-specific effects for rs3761959 and rs7528684 on FCRL3 expression level revealed that the risk alleles A of rs3761959 and C of rs7528684 were correlated with the elevated expression level of FCRL3 whether in PBMCs or its subsets, especially in CD19+ B cells and CD8+ T subsets. Next, the combined analysis with 5,300 GD cases and 4,916 control individuals confirmed FCRL3 was a susceptibility gene of GD in Chinese Han populations, and rs3761959 and rs7528684 met the genome-wide association significance level (Pcombined = 2.27×10−12 and 7.11×10−13, respectively). Moreover, the haplotypes with the risk allele A of rs3761959 and risk allele C of rs7528684 were associated with GD risk. Finally, our epigenetic analysis suggested the disease-associated C allele of rs7528684 increased affinity for NF-KB transcription factor. Above data indicated that FCRL3 gene and its proxy SNP rs7528684 may be involved in the pathogenesis of GD by excessive inhibiting B cell receptor signaling and the impairment of suppressing function of Tregs.
PMCID: PMC3591391  PMID: 23505439
11.  Fc receptor-like 3 protein expressed on IL-2 non-responsive subset of human regulatory T cells1 
Fc receptor-like 3 (FCRL3) is a cell surface protein homologous to Fc receptors. The FCRL3 gene is present in humans but not in mice. We found that FCRL3 protein is expressed on 40% of human naturally occurring CD4+ regulatory T (nTreg) cells (CD4+CD25+CD127low). Sorted nTreg cells with the surface phenotype FCRL3+ and FCRL3− were both hypoproliferative to T cell receptor stimulation and both suppressive on proliferation of conventional T cells (CD4+CD25−) in vitro. They both expressed forkhead box p3 (Foxp3) protein, the intracellular regulatory T cell marker. However, in contrast to FCRL3− nTreg cells, FCRL3+ nTreg cells were not stimulated to proliferate by the addition of exogenous IL-2. In addition, Foxp3+ cells induced from conventional T cells by TGF-β treatment did not exhibit FCRL3 expression. These results suggest that the FCRL3+ subset of human nTreg cells identified in this study arise in vivo, and Foxp3 expression alone is not sufficient to induce FCRL3 expression. FCRL3 may be involved in human specific mechanisms to control the generation of nTreg cells.
PMCID: PMC2745186  PMID: 19494275
Human; T Cells; Autoimmunity; Cell Surface Molecules; Cell Differentiation
12.  FCRL3 promoter 169 CC homozygosity is associated with susceptibility to rheumatoid arthritis in Dutch Caucasians 
Annals of the Rheumatic Diseases  2006;66(6):803-806.
Human leucocyte antigen is the only genetic risk factor for rheumatoid arthritis (RA) that has been consistently observed in different populations. A number of other genes such as PTPN22 and PADI4 showed population‐specific association with RA susceptibility. Recently, Fc receptor‐like 3 (FCRL3) gene was found to be associated with RA susceptibility in Japanese, but with conflicting results in other populations.
To investigate the association of FCRL3 polymorphism with RA susceptibility and severity in Dutch Caucasian patients with RA, as well as to perform a meta‐analysis to reveal the contribution of this gene to RA susceptibility.
A total of 931 Dutch RA cases and 570 unrelated Dutch controls were genotyped for four FCRL3 single‐nucleotide polymorphisms (SNPs). Genotyping was performed using the MassArray matrix‐assisted laser desorption ionisation‐time‐of‐flight mass spectrometry. Association of the FCRL3 SNPs with susceptibility to RA was examined by single‐marker, carrier and haplotype analysis.
Carrier analysis of the SNP (rs7528684) revealed the association of CC genotype with a higher risk of developing RA as compared with TT and TC carriers (p = 0.039 and OR = 1.31). There was no significant difference in the genotype and allele frequencies of all investigated SNPs between cases and controls. Meta‐analysis of all studies comparing 9467 individuals showed that the OR for the CC genotype to develop RA was 1.2 and the p value <0.001.
A promoter polymorphism of FCRL3 (rs7528684) is associated with an increased risk of developing RA in Dutch Caucasians, suggesting that this association is relevant for RA in both Japanese and Caucasian populations.
PMCID: PMC1954681  PMID: 17179172
13.  Association of FCRL3 Genetic Polymorphisms With Endometriosis-Related Infertility Risk 
Medicine  2015;94(35):e1168.
The Fc receptor-like 3 (FCRL3) gene was reported to be linked to a variety of autoimmune diseases, including endometriosis-related infertility. However, this linkage has not been studied in Chinese population and there has been no meta-analysis on the interrelationship of FCRL3 gene and endometriosis-related infertility. The aim of the study was to investigate the association between FCRL3 genetic polymorphisms and the risk of endometriosis-related infertility in Han Chinese, and a further meta-analysis was conducted to confirm our results.
Four single nucleotide polymorphisms (SNPs) (rs7528684 [FCRL3_3], rs11264799 [FCRL3_4], rs945635 [FCRL3_5], and rs3761959 [FCRL3_6]) on FCRL3 gene were genotyped in a case–control cohort composed of 217 patients suffering from endometriosis-related infertility and 220 healthy controls using cleaved amplification polymorphism sequence-tagged sites (polymerase chain reaction–restriction fragment length polymorphism, PCR–RFLP). Odds ratio (OR) and its 95% confidence interval (CI) was used to evaluate the association quantitatively. Furthermore, a meta-analysis of previous studies including the present study was implemented through Stata 11.0 (Stata Corporation, College Station, TX).
We found an approximately 1.4-fold significantly increased frequency of the FCRL3_3 variant in women with endometriosis-related infertility over the controls (OR = 1.41 [95% CI = 1.08–1.84], P = 0.013). However, no significant difference was found between women with endometriosis-related infertility and controls for FCRL3_4, FCRL3_5, and FCRL3_6. Regardless of the symptoms and the revised classification of the American Society of Reproductive Medicine (rASRM) stage of endometriosis, there was a significant association between FCRL3_3 variant and an increased risk of endometriosis-related infertility. Meta-analysis of previous studies combined with the present study further confirmed the association between FCRL3_3 and the risk of endometriosis-related infertility.
In summary, the present study suggested that FCRL3_3 variant was associated with an increased risk of endometriosis-related infertility, regardless of symptoms, and rASRM stage of the patients. Meta-analysis of previous studies combined with the present study further confirmed our results. Further large-scale studies in the future are warranted to explore the association between FCRL3 genetic polymorphisms and endometriosis-related infertility, as well as other human diseases, in Asian and other ethnicities.
PMCID: PMC4616513  PMID: 26334889
14.  Correlation between single nucleotide polymorphism of FCRL-3 gene and Graves’ disease in Han population of northern Anhui province, China 
Objective: The frequency distribution of A/G genotype at position-169 in promoter of FCRL3 gene (Fc receptor-like 3) was identified in Han population of northern Anhui Province. The correlation between single nucleotide polymorphism (SNP) at this site and genetic susceptibility of Graves disease (GD) was discussed. How the genotype at this position correlated to age, gender, severity of goiter, presence or absence of exophthalmos, levels of thyrotrophin receptor antibody (TRab), thyroid peroxidase antibody (TpoAb) and anti-thyroglobulin antibody (TgAb) and thyroid function was analyzed in details. Method: Peripheral venous blood was collected for DNA extraction. SNP at position-169 in the promoter of FCRL3 gene was determined by using PCR-RELP among 180 GD cases and 146 normal subjects. Thyroid function tests and antibody detection were performed. Results: The frequency of GG genotype of position-169 in promoter of FCRL3 gene was higher in GD group than in control group. The frequency was 28.9% and 13.8%, respectively, showing significant differences in intergroup comparison (χ2=6.618, P=0.046). The G allele frequency of GD group and control group was 49.4% and 40.4%, respectively, also showing significant differences between the groups (χ2=5.308, P=0.021). GD cases with AA, AG and GG genotypes at position-169 in FCRL3 promoter had significant differences in serum level of TRAb (χ2=7.319, P=0.026). However, no significant differences in gender, severity of goiter, TpoAb and TgAb level, presence or absence of exophthalmos and thyroid function (FT3, FT4, TSH) were found between the three genotypes (P>0.05). Conclusion: A/G SNP at position-169 in promoter of FCRL3 gene was correlated with susceptibility to GD among Han population in northern Anhui Province. G allele may contribute to the susceptibility to GD and correlate to positive TRAb result in thyroid diseases, but not to age of onset, gender, presence or absence of exophthalmos, thyroid function, TpoAb and TgAb level or severity of goiter.
PMCID: PMC4612859  PMID: 26550174
Graves disease (GD); FCRL3 gene; TRAb; single nucleotide polymorphism (SNP)
15.  Epistatic interaction between FCRL3 and NFκB1 genes in Spanish patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2006;65(9):1188-1191.
A Japanese study has described a strong association between rheumatoid arthritis and several polymorphisms located in the Fc receptor‐like 3 (FCRL3) gene, a member of a family of genes related to Fc receptors located on chromosome 1q21–23.
To evaluate the association between rheumatoid arthritis and FCLR3 polymorphisms in a large cohort of Caucasian patients with rheumatoid arthritis and healthy controls of Spanish origin. Owing to the described functional link between the FCRL3 polymorphisms and the transcription factor nuclear factor κB (NFκB), a functional polymorphism located in the NFκB1 gene was included.
734 patients with rheumatoid arthritis from Madrid and Granada, Spain, were included in the study, along with 736 healthy controls. Polymorphisms in the FCRL3 gene were studied by TaqMan technology. The −94ins/delATTG NFκB1 promoter polymorphism was analysed by fragment analysis after polymerase chain reaction with labelled primers. Genotypes were compared using 3×2 contingency tables and χ2 values.
No overall differences were found in any of the FCRL3 polymorphisms and in the NFκB1 promoter polymorphism when patients were compared with controls. However, when stratified according to NFκB1 genotypes, a susceptibility effect of FCRL3 polymorphisms was observed in patients who were heterozygotes for NFκB1 (pc = 0.003).
The FCRL3 polymorphisms associated with rheumatoid arthritis in a Japanese population are not associated per se with rheumatoid arthritis in a Spanish population. A genetic interaction was found between NFκB1 and FCRL3 in Spanish patients with rheumatoid arthritis. These findings may provide a general rationale for divergent genetic association results in different populations.
PMCID: PMC1798300  PMID: 16476711
16.  FCRL5 Delineates Functionally Impaired Memory B Cells Associated with Plasmodium falciparum Exposure 
PLoS Pathogens  2015;11(5):e1004894.
Exposure to Plasmodium falciparum is associated with circulating “atypical” memory B cells (atMBCs), which appear similar to dysfunctional B cells found in HIV-infected individuals. Functional analysis of atMBCs has been limited, with one report suggesting these cells are not dysfunctional but produce protective antibodies. To better understand the function of malaria-associated atMBCs, we performed global transcriptome analysis of these cells, obtained from individuals living in an area of high malaria endemicity in Uganda. Comparison of gene expression data suggested down-modulation of B cell receptor signaling and apoptosis in atMBCs compared to classical MBCs. Additionally, in contrast to previous reports, we found upregulation of Fc receptor-like 5 (FCRL5), but not FCRL4, on atMBCs. Atypical MBCs were poor spontaneous producers of antibody ex vivo, and higher surface expression of FCRL5 defined a distinct subset of atMBCs compromised in its ability to produce antibody upon stimulation. Moreover, higher levels of P. falciparum exposure were associated with increased frequencies of FCRL5+ atMBCs. Together, our findings suggest that FCLR5+ identifies a functionally distinct, and perhaps dysfunctional, subset of MBCs in individuals exposed to P. falciparum.
Author Summary
A subset of “atypical” memory B cells found in individuals with high exposure to P. falciparum has been hypothesized to be dysfunctional, based on phenotypic similarities to analogous cells found in HIV-infected individuals. However, the functional capabilities of these cells have been poorly characterized in the setting of malaria exposure, and previous reports have been controversial regarding whether these cells produce antibody. In our study, we analyze the molecular programming of atypical memory B cells, find that they are dysfunctional in a manner similar to that observed in B cells from HIV-infected individuals, and present data that may reconcile previously conflicting studies. By delineating the transcriptional landscape of atMBCs and identifying expression of FCRL5 as a key marker of dysfunction, we provide a foundation for improving our understanding of the role of these cells in immunity to malaria.
PMCID: PMC4438005  PMID: 25993340
17.  Human FcRL4 and FcRL5 are receptors for IgA and IgG1,2 
Fc Receptor-Like proteins are a family of cellular receptors homologous to FcγRI, and predominantly expressed by B cells. They function to co-stimulate or inhibit B cell receptor signaling through consensus ITAMs and ITIMs, however the extracellular ligands of these receptors remain unknown or controversial. In this study, we tested the ability of human FcRL proteins to bind immunoglobulins and found FcRL4 and FcRL5 to be bona fide Fc receptors. In cellular binding assays, FcRL4 bound efficiently to IgA and FcRL5 binds all IgG isotypes with varied efficiency. In addition, we generated monoclonal antibodies capable of specifically blocking these interactions. Given their expression on activated B cells and potential for inhibitory signaling, FcRL4 and FcRL5 are likely to be important for immune complex-dependent human B cell regulation, and represent novel therapeutic targets for receptor blockade therapies.
PMCID: PMC3634363  PMID: 22491254
18.  The Fc Receptor-Like 3 Polymorphisms (rs7528684, rs945635, rs3761959 and rs2282284) and The Risk of Neuromyelitis Optica in A Chinese Population 
Medicine  2015;94(38):e1320.
Neuromyelitis optica (NMO) appears to be a severe inflammatory demyelinating disease occurring in the central nervous system. Furthermore, the Fc receptor-like 3 (FCRL3) gene was previously found to be susceptible for a certain inflammatory demyelinating diseases (such as multiple sclerosis). The present study, therefore, was aimed to explore the possible association of FCRL3 gene polymorphisms with susceptibility to NMO in a Chinese Han population.
Seven single nucleotide polymorphisms (SNPs) of FCRL3 were, respectively, genotyped in 132 NMO patients and 264 healthy controls via PCR assay. Moreover, the t-test and the chi-square test were used to estimate the association between genetic mutations of FCRL3 and the risk of NMO with Statistical Analysis System (SAS) software (Version 9.0).
It was demonstrated that FCRL3_3, 5, 6 and 8, SNPs were remarkably associated with susceptibility to NMO in both allelic [OR = 1.50 (95% CI: 1.11–2.03, P = 0.008), OR = 1.44 (1.07–1.94, P = 0.015), OR = 1.45 (1.08–1.95, P = 0.014), and OR = 2.01 (1.13–3.60, P = 0.016)] and homozygous models [OR = 2.19 (95% CI: 1.19–3.99, P = 0.010), OR = 2.09 (1.15–3.80, P = 0.014), OR = 2.04 (1.13–3.67, P = 0.016), and OR = 5.33 (1.02–27.9, P = 0.027)]. However, the other 4 SNPs, FCRL3_4, FCRL3_7, FCRL3_9, did not show the significant associations with NMO.
Conclusions in the present study could be drawn that 4 SNPs in FCRL3 (FCRL3_3∗C, 5∗C, 6∗A, 8∗G) might account for increased risk of NMO in a Chinese-Han population. Nevertheless, further cohort studies are in demand to validate the association in the future.
PMCID: PMC4635738  PMID: 26402798
19.  Association between polymorphisms of FCRL3, a non-HLA gene, and Behçet’s disease in a Chinese population with ophthalmic manifestations 
Molecular Vision  2008;14:2136-2142.
Studies have shown a strong association of human leukocyte antigens-B51 (HLA-B51) with Behçet’s disease (BD). However, little is known about the association of non-HLA genes with BD. The polymorphisms of the Fc receptor-like 3 gene (FCRL3), −169C/T, −110A/G, +358C/G, and +1381A/G, have been reported to be associated with several autoimmune diseases. This study was designed to determine whether the polymorphisms of FCRL3 were associated with susceptibility to BD in a Chinese population mainly with ocular involvement.
A case-control study was performed in 245 Chinese BD patients and 289 controls. Four single nucleotide polymorphisms (SNPs; −169C/T, −110A/G, +358C/G, and +1381A/G) in FCRL3 were detected using polymerase chain reaction restriction fragment length polymorphisms (PCR-RFLP). HLA-B51 genotyping was performed by the PCR sequence specific primers method as described previously.
The results showed a significantly higher frequency of the G allele at the −110 site in BD patients compared with that in controls (corrected p=0.044, 75.3% versus 67.5%, χ2=7.72). Haplotype CGCG frequency was significantly higher in patients than in controls (corrected p=0.0096) whereas haplotype TACG frequency was significantly lower in patients compared with controls (corrected p=0.032). There was no relationship between clinical signs and FCRL3 polymorphisms. No significant difference was observed between patients and controls after HLA-B51 stratification concerning the four SNPs.
Our study suggests that the −110 G allele and the haplotype CGCG of FCRL3 are positively associated with BD in a Chinese population and that the haplotype ATCG might be a protective haplotype for BD.
PMCID: PMC2592528  PMID: 19050767
20.  Preferential Binding to Elk-1 by SLE-Associated IL10 Risk Allele Upregulates IL10 Expression 
PLoS Genetics  2013;9(10):e1003870.
Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10−8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.
Author Summary
Systemic lupus erythematosus (SLE), a debilitating autoimmune disease characterized by the production of pathogenic autoantibodies, has a strong genetic basis. Variants of the IL10 gene, which encodes cytokine interleukin-10 (IL-10) with known function of promoting B cell hyperactivity and autoantibody production, are associated with SLE and other autoimmune diseases, and serum IL-10 levels are elevated in SLE patients correlating with increased disease activity. In this study, to discover SLE-predisposing causal variant(s), we assessed variants within the genomic region containing IL10 and its gene family member IL19, IL20 and IL24 for association with SLE in case and control subjects from diverse ancestries. We identified SLE-associated SNP rs3122605 located at 9.2 kb upstream of IL10 as the most likely causal variant in subjects of European ancestry. The SLE-risk allele of rs3122605 was dose-dependently associated with elevated IL10 expression at both mRNA and protein levels in peripheral blood samples from SLE patients and controls, which could be explained, at least in part, by its preferential binding to Elk-1, a transcription factor activated in B cells during active disease of SLE patients. Elk-1-mediated IL-10 overexpression could be downregulated by inhibiting activation of mitogen-activated protein kinases, suggesting a potential therapeutic target for SLE.
PMCID: PMC3794920  PMID: 24130510
21.  Polymorphisms of FCRL3 in a Chinese population with Vogt-Koyanagi-Harada (VKH) syndrome 
Molecular Vision  2009;15:955-961.
The polymorphisms of the Fc receptor-like 3 gene (FCRL3), a novel immunoregulatory gene, have been shown to be associated with certain autoimmune diseases. This study was designed to examine whether the polymorphisms of FCRL3 are associated with susceptibility to Vogt-Koyanagi-Harada (VKH) syndrome in a Chinese population.
A case-control study was performed in 230 Chinese VKH patients and 301 healthy controls. Four single nucleotide polymorphisms (SNPs; −169C/T, −110A/G, +358C/G, and +1381A/G) in FCRL3 were detected using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). human leukocyte antigen -DR4 (HLA-DR4) and HLA-DRw53 genotyping was performed using PCR techniques.
The results showed that the frequency of haplotype CACG was significantly lower in patients when compared with that in controls (p=0.0018, corrected p [pc]=0.0288). A significantly higher frequency was found for haplotype CGGG in HLA-DR4 negative patients than in HLA-DR4 negative controls (p=9.94×10−8, Pc=1.59×10−6). There were no significant differences in the allele and genotype frequencies of the four investigated SNPs between VKH patients and controls. HLA-DR4 and HLA-DRw53 were significantly associated with VKH syndrome (p=3.21×10−16 and p=7.08×10−5, respectively). Stratification analysis according to HLA-DR4 and HLA-DRw53 did not show any association of FCRL3 polymorphisms with VKH syndrome.
Our study confirms the previous association of HLA-DR4 and HLA-DRw53 with VKH syndrome but fails to demonstrate an association between FCRL3 polymorphisms and VKH syndrome. Haplotype CACG might be a protective haplotype for VKH syndrome, and haplotype CGGG may be a risk haplotype in HLA-DR4 negative individuals.
PMCID: PMC2683028  PMID: 19452015
22.  Human Fc receptor-like 5 binds intact IgG via mechanisms distinct from that of Fc-receptors 1 
Fc receptor-like 5 (FCRL5) regulates BCR signaling and has been reported to bind aggregated IgG. Using surface plasmon resonance, we analyzed the interaction of native IgG samples with FCRL5, revealing a complex binding mechanism, where isotype is just one factor. FCRL5 bound IgG1 and IgG4 with approximately 1 μM KD, while the interaction with IgG3 was a magnitude weaker. However, IgG2 samples displayed a wide range of affinities, indicating that additional factors affect binding. We used a panel of 19 anti-FCRL5 mAbs with defined reactivity to identify domains involved in ligand binding. Six mAbs blocked IgG binding, indicating critical roles of FCRL5 domains 1 and 3, as well as epitopes at the domain 1/2 and domain 2/3 boundaries. We found that only glycosylated IgG containing both Fab arms and the Fc region bound with high affinity. Furthermore, the presence of sialic acid in the IgG carbohydrate altered FCRL5 binding. The interaction of IgG and FCRL5 consisted of two kinetic components, suggesting a complex binding mechanism. We established that the IgG-Fc and IgG-F(ab’)2 fragments bind FCRL5 independently but with low affinity, revealing the mechanism behind the two-step binding of whole IgG. This complex binding mechanism is distinct from that of Fc-receptors, which bind through the Fc. We propose that FCRL5 is a new type of receptor that recognizes intact IgG, possibly enabling B cells to sense immunoglobulin quality. Recognition of undamaged IgG molecules by FCRL5 could allow B cells to engage recently produced antibodies.
PMCID: PMC3660407  PMID: 23616577
23.  B-1 Cell Development and Function 
Coelomic cavity–derived B-1 and splenic marginal zone (MZ) B lymphocytes play principal roles in frontline host protection at homeostasis and during primary humoral immune responses. Although they share many features that enable rapid and broad-based defense against pathogens, these innate-like subsets have disparate B cell receptor (BCR) signaling features. Members of the Fc receptor–like (FCRL) family are preferentially expressed by B cells and possess tyrosine-based immunoregulatory function. An unusual characteristic of many of these cell surface proteins is the presence of both inhibitory (ITIM) and activating (ITAM-like) motifs in their cytoplasmic tails. In mice, FCRL5 is a discrete marker of splenic MZ and peritoneal B-1 B cells and has both ITIM and ITAM-like sequences. Recent work explored its signaling properties and identified that FCRL5 differentially influences innate-like BCR function. Closer scrutiny of these differences disclosed the ability of FCRL5 to counter-regulate BCR activation by recruiting SHP-1 and Lyn to its cytoplasmic motifs. Furthermore, the disparity in FCRL5 regulation between MZ and B-1 B cells correlated with relative intracellular concentrations of SHP-1. These findings validate and extend our understanding of the unique signaling features in innate-like B cells and provide new insight into the complexity of FCRL modulation.
PMCID: PMC4690519  PMID: 25964091
B cells; BCR signaling; regulation; kinase; phosphatase
24.  Involvement of the HCK and FGR src-Family Kinases in FCRL4-Mediated Immune Regulation 
The Journal of Immunology Author Choice  2015;194(12):5851-5860.
FCRL4 is an immunoregulatory receptor expressed by a subpopulation of memory B cells. These tissue-based cells express increased levels of the src-family kinases HCK and FGR. In this study, we investigate the roles of these src-family kinases in FCRL4-mediated immunoregulation of B cells in the context of previously unrecognized palmitoylation of the receptor. We observed enhanced phosphorylation of FCRL4 on tyrosine residues in the presence of the HCK p59 or FGR. This phosphorylation was markedly reduced in assays using a palmitoylation-defective mutant of FCRL4. In reporter gene studies, we observe that FCRL4 expression enhances CpG-mediated activation of NF-κB signaling. Surprisingly, using a reporter gene linked to activation of the MAPK substrate Elk-1 in response to Ag receptor ligation, we find that FCRL4 has inhibitory activity in cells coexpressing FGR but an activating function in cells coexpressing HCK p59. We provide evidence that in primary memory B cells, expression of FCRL4 leads to increased expression of IL-10 in the presence of FGR or HCK p59 in response to CpG, but increased levels of IFN-γ only in the context of coexpression of FGR. Our study supports the specific requirement of HCK p59 and FGR src-family kinases for FCRL4-mediated immunomodulatory activity and indicates that palmitoylation serves as an additional level of regulatory control of FCRL4.
PMCID: PMC4456631  PMID: 25972488
25.  FCRL6 distinguishes mature cytotoxic lymphocytes and is upregulated in patients with B cell chronic lymphocytic leukemia 
European journal of immunology  2008;38(11):3159-3166.
Fc receptor-like 6 (FCRL6), the most recently characterized member of the FCRL family, is a cell surface glycoprotein with tyrosine-based regulatory potential. An extensive survey of human hematopoietic tissues disclosed that FCRL6 expression by NK and T cell subpopulations increases as a function of differentiation and is remarkably restricted to mature lymphocytes with cytotoxic capability. In particular, FCRL6 distinguishes perforin-expressing CD56dim NK cells, Vδ1+ and Vδ2+ γδ T cells, effector and effector memory CD8+ T cells, and rare cytotoxic CD4+ T cells in adult tissues. Analysis of this receptor in B cell chronic lymphocytic leukemia (CLL) was also performed. FCRL6 was found to mark significantly expanded populations of cytotoxic CD8+ T, CD4+ T, and NK cells in patients with CLL. Despite sequence homology with the known Fc receptors for IgG and IgE, FCRL6 did not bind immunoglobulin. Although FCRL6 can be tyrosine-phosphorylated, its antibody-mediated ligation was unable to influence cellular activation. Collectively these results demonstrate that FCRL6 is a distinct indicator of cytotoxic effector lymphocytes that is upregulated in diseases characterized by chronic immune stimulation.
PMCID: PMC2742621  PMID: 18991291
Human NK cells; Human cytotoxic T cells; Fc Receptor-like; Chronic lymphocytic leukemia

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