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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.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus 
PLoS Genetics  2013;9(2):e1003336.
We previously reported that the G allele of rs3853839 at 3′untranslated region (UTR) of Toll-like receptor 7 (TLR7) was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [P = 6.5×10−10, odds ratio (OR) (95%CI) = 1.27 (1.17–1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the TLR7-TLR8 region exhibiting consistent and independent association with SLE (Pmeta = 7.5×10−11, OR = 1.24 [1.18–1.34]). The risk G allele was associated with significantly increased levels of TLR7 mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. TLR7 3′UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate TLR7 expression. Indeed, miR-3148 levels were inversely correlated with TLR7 transcript levels in PBMCs from SLE patients and controls (R2 = 0.255, P = 0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by TLR7 3′UTR segment bearing the C allele (P = 0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing TLR7 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of TLR7 as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries (Pmeta = 2.0×10−19, OR = 1.25 [1.20–1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.
Author Summary
Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease contributed to by excessive innate immune activation involving toll-like receptors (TLRs, particularly TLR7/8/9) and type I interferon (IFN) signaling pathways. TLR7 responds against RNA–containing nuclear antigens and activates IFN-α pathway, playing a pivotal role in the development of SLE. While a genomic duplication of Tlr7 promotes lupus-like disease in the Y-linked autoimmune accelerator (Yaa) murine model, the lack of common copy number variations at TLR7 in humans led us to identify a functional single nucleotide polymorphism (SNP), rs3853839 at 3′ UTR of the TLR7 gene, associated with SLE susceptibility in Eastern Asians. In this study, we fine-mapped the TLR7-TLR8 region and confirmed rs3853839 exhibiting the strongest association with SLE in European Americans, African Americans, and Amerindian/Hispanics. Individuals carrying the risk G allele of rs3853839 exhibited increased TLR7 expression at the both mRNA and protein level and decreased transcript degradation. MicroRNA-3148 (miR-3148) downregulated the expression of non-risk allele (C) containing transcripts preferentially, suggesting a likely mechanism for increased TLR7 levels in risk-allele carriers. This trans-ancestral mapping provides evidence for the global association with SLE risk at rs3853839, which resides in a microRNA–gene regulatory site affecting TLR7 expression.
PMCID: PMC3585142  PMID: 23468661
20.  Functional genetic polymorphisms in ILT3 are associated with decreased surface expression on dendritic cells and increased serum cytokines in lupus patients 
Annals of the rheumatic diseases  2012;72(4):596-601.
Hyperactivity of the type I interferon (IFN) pathway is involved in the pathogenesis of systemic lupus erythematosus (SLE). Immunoglobulin like transcript (ILT3) is an immunohibitory transmembrane molecule which is induced by type I IFNs. ILT3 is expressed by plasmacytoid dendritic cells (PDCs), monocytoid dendritic cells (MDCs), and monocytes/macrophages. Given the pathogenic role of IFN in SLE, we hypothesised that the IFN-induced immunosuppressive ILT3 receptor may be dysfunctional in human SLE.
132 European-derived and 79 Hispanic-American SLE patients were genotyped for two coding-change single nucleotide polymorphisms (SNPs) predicted to interfere with protein folding in ILT3 (rs11540761 and rs1048801). 116 control DNA samples and sera from healthy controls were also studied. We detected associations between ILT3 genotype and serum cytokine profiles. ILT3 expression levels on PDCs and MDCs from 18 patients and 10 controls were studied by flow cytometry.
The rs11540761 SNP in the extracellular region was associated with decreased cell surface expression of ILT3 on circulating MDCs and to a lesser extent PDCs in SLE patients. The cytoplasmically located rs1048801 SNP was not associated with a change in dendritic cells expression of ILT3. Both SNPs were significantly and independently associated with increased levels of serum type I IFN activity in SLE patients. The rs1048801 SNP was also associated with increased serum levels of TNF-α.
Loss-of-function polymorphisms in ILT3 are associated with increased inflammatory cytokine levels in SLE, supporting a biological role for ILT3 in SLE.
PMCID: PMC3910490  PMID: 22904259
21.  Differential Genetic Associations for Systemic Lupus Erythematosus Based on Anti–dsDNA Autoantibody Production 
PLoS Genetics  2011;7(3):e1001323.
Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti–dsDNA autoantibody production, a SLE–related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti–dsDNA autoantibody positive (anti–dsDNA +, n = 811) and anti–dsDNA autoantibody negative (anti–dsDNA –, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti–dsDNA + SLE. Far fewer and weaker associations were observed for anti–dsDNA – SLE. For example, rs7574865 in STAT4 had an OR for anti–dsDNA + SLE of 1.77 (95% CI 1.57–1.99, p = 2.0E-20) compared to an OR for anti–dsDNA – SLE of 1.26 (95% CI 1.12–1.41, p = 2.4E-04), with pheterogeneity<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti–dsDNA + SLE and were not associated with anti–dsDNA – SLE. In conclusion, we identified differential genetic associations with SLE based on anti–dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti–dsDNA – SLE.
Author Summary
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can involve virtually any organ system. SLE patients produce antibodies that bind to their own cells and proteins (autoantibodies) which can cause irreversible organ damage. One particular SLE–related autoantibody directed at double-stranded DNA (anti–dsDNA) is associated with kidney involvement and more severe disease. Previous genome-wide association studies (GWAS) in SLE have studied SLE itself, not particular SLE manifestations. Therefore, we conducted this GWAS of anti–dsDNA autoantibody production to identify genetic associations with this clinically important autoantibody. We found that many previously identified SLE–associated genes are more strongly associated with anti–dsDNA autoantibody production than SLE itself, and they may be more accurately described as autoantibody propensity genes. No strong genetic associations were observed for SLE patients who do not produce anti–dsDNA autoantibodies, suggesting that other factors may have more influence in developing this type of SLE. Further investigation of these autoantibody propensity genes may lead to greater insight into the causes of autoantibody production and organ damage in SLE.
PMCID: PMC3048371  PMID: 21408207
22.  A genetic study on C5-TRAF1 and progression of joint damage in rheumatoid arthritis 
The severity of joint damage progression in rheumatoid arthritis (RA) is heritable. Several genetic variants have been identified, but together explain only part of the total genetic effect. Variants in Interleukin-6 (IL-6), Interleukin-10 (IL-10), C5-TRAF1, and Fc-receptor-like-3 (FCRL3) have been described to associate with radiographic progression, but results of different studies were incongruent. We aimed to clarify associations of these variants with radiographic progression by evaluating six independent cohorts.
In total 5,895 sets of radiographs of 2,493 RA-patients included in six different independent datasets from the Netherlands, Sweden, Spain and North-America were studied in relation to rs1800795 (IL-6), rs1800896 (IL-10), rs2900180 (C5-TRAF1) and rs7528684 (FCRL3). Associations were tested in the total RA-populations and in anti-citrullinated peptide antibodies (ACPA)-positive and ACPA-negative subgroups per cohort, followed by meta-analyses. Furthermore, the associated region C5-TRAF1 was fine-mapped in the ACPA-negative Dutch RA-patients.
No associations were found for rs1800795 (IL-6), rs1800896 (IL-10) and rs7528684 (FCRL3) in the total RA-population and after stratification for ACPA. Rs2900180 in C5-TRAF1 was associated with radiographic progression in the ACPA-negative population (P-value meta-analysis = 5.85 × 10−7); the minor allele was associated with more radiographic progression. Fine-mapping revealed a region of 66Kb that was associated; the lowest P-value was for rs7021880 in TRAF1. The P-value for rs7021880 in meta-analysis was 6.35 × 10−8. Previous studies indicate that the region of rs7021880 was associated with RNA expression of TRAF1 and C5.
Variants in IL-6, IL-10 and FCRL3 were not associated with radiographic progression. Rs2900180 in C5-TRAF1 and linked variants in a 66Kb region were associated with radiographic progression in ACPA-negative RA.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-014-0514-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4318544  PMID: 25566937
23.  TLR7 single-nucleotide polymorphisms in the 3' untranslated region and intron 2 independently contribute to systemic lupus erythematosus in Japanese women: a case-control association study 
The Toll-like receptor 7 (TLR7) gene, encoded on human chromosome Xp22.3, is crucial for type I interferon production. A recent multicenter study in East Asian populations, comprising Chinese, Korean and Japanese participants, identified an association of a TLR7 single-nucleotide polymorphism (SNP) located in the 3' untranslated region (3' UTR), rs3853839, with systemic lupus erythematosus (SLE), especially in males, although some difference was observed among the tested populations. To test whether additional polymorphisms contribute to SLE in Japanese, we systematically analyzed the association of TLR7 with SLE in a Japanese female population.
A case-control association study was conducted on eight tag SNPs in the TLR7 region, including rs3853839, in 344 Japanese females with SLE and 274 healthy female controls.
In addition to rs3853839, two SNPs in intron 2, rs179019 and rs179010, which were in moderate linkage disequilibrium with each other (r2 = 0.53), showed an association with SLE (rs179019: P = 0.016, odds ratio (OR) 2.02, 95% confidence interval (95% CI) 1.15 to 3.54; rs179010: P = 0.018, OR 1.75, 95% CI 1.10 to 2.80 (both under the recessive model)). Conditional logistic regression analysis revealed that the association of the intronic SNPs and the 3' UTR SNP remained significant after we adjusted them for each other. When only the patients and controls carrying the risk genotypes at the 3' UTR SNPpositionwere analyzed, the risk of SLE was significantly increased when the individuals also carried the risk genotypes at both of the intronic SNPs (P = 0.0043, OR 2.45, 95% CI 1.31 to 4.60). Furthermore, the haplotype containing the intronic risk alleles in addition to the 3' UTR risk allele was associated with SLE under the recessive model (P = 0.016, OR 2.37, 95% CI 1.17 to 4.80), but other haplotypes were not associated with SLE.
The TLR7 intronic SNPs rs179019 and rs179010 are associated with SLE independently of the 3' UTR SNP rs3853839 in Japanese women. Our findings support a role of TLR7 in predisposition for SLE in Asian populations.
PMCID: PMC3132023  PMID: 21396113
24.  FCRL3 Gene Polymorphisms Confer Autoimmunity Risk for Allergic Rhinitis in a Chinese Han Population 
PLoS ONE  2015;10(1):e0116419.
Heredity and environmental exposures may contribute to a predisposition to allergic rhinitis (AR). Autoimmunity may also involve into this pathologic process. FCRL3 (Fc receptor-like 3 gene), a novel immunoregulatory gene, has recently been reported to play a role in autoimmune diseases.
This study was performed to evaluate the potential association of FCRL3 polymorphisms with AR in a Chinese Han population.
Five single-nucleotide polymorphisms of FCRL3, rs945635, rs3761959, rs7522061, rs10489678 and rs7528684 were genotyped in 540 AR patients and 600 healthy controls using a PCR-restriction fragment length polymorphism assay. Allele, genotype and haplotype frequencies were compared between patients and controls using the χ2 test. The online software platform SHEsis was used to analyze their haplotypes.
This study identified three strong risk SNPs rs7528684, rs10489678, rs7522061 and one weak risk SNP rs945635 of FCRL3 in Chinese Han AR patients. For rs7528684, a significantly increased prevalence of the AA genotype and A allele in AR patients was recorded. The frequency of the GG genotype and G allele of rs10489678 was markedly higher in AR patients than those in controls. For rs7522061, a higher frequency of the TT genotype, and a lower frequency of the CT genotype were found in AR patients. Concerning rs945635, a lower frequency of the CC genotype, and a higher frequency of G allele were observed in AR patients. According to the analysis of the three strong positive SNPs, the haplotype of AGT increased significantly in AR cases (AR = 38.8%, Controls = 24.3%, P = 8.29×10-14, OR [95% CI] 1.978 [1.652~2.368]).
This study found a significant association between the SNPs in FCRL3 gene and AR in Chinese Han patients. The results suggest these gene polymorphisms might be the autoimmunity risk for AR.
PMCID: PMC4296936  PMID: 25594855
25.  Selective Involvement of the Amygdala in Systemic Lupus Erythematosus 
PLoS Medicine  2006;3(12):e499.
Antibodies specifically affect the amygdala in a mouse model of systemic lupus erythematosus (SLE). The aim of our study was to investigate whether there is also specific involvement of the amygdala in human SLE.
Methods and Findings
We analyzed a group of 37 patients with neuropsychiatric SLE (NP-SLE), 21 patients with SLE, and a group of 12 healthy control participants with diffusion weighted imaging (DWI). In addition, in a subset of eight patients, plasma was available to determine their anti-NMDAR antibody status. From the structural magnetic resonance imaging data, the amygdala and the hippocampus were segmented, as well as the white and gray matter, and the apparent diffusion coefficient (ADC) was retrieved. ADC values between controls, patients with SLE, and patients with NP-SLE were tested using analysis of variance with post-hoc Bonferroni correction. No differences were found in the gray or white matter segments. The average ADC in the amygdala of patients with NP-SLE and SLE (940 × 10−6 mm2/s; p = 0.006 and 949 × 10−6 mm2/s; p = 0.019, respectively) was lower than in healthy control participants (1152 × 10−6 mm2/s). Mann-Whitney analysis revealed that the average ADC in the amygdala of patients with anti-NMDAR antibodies (n = 4; 802 × 10−6 mm2/s) was lower (p = 0.029) than the average ADC of patients without anti-NMDAR antibodies (n = 4; 979 × 10−6 mm2/s) and also lower (p = 0.001) than in healthy control participants.
This is the first study to our knowledge to observe damage in the amygdala in patients with SLE. Patients with SLE with anti-NMDAR antibodies had more severe damage in the amygdala compared to SLE patients without anti-NMDAR antibodies.
Patients with SLE who also had antibodies against the NMDA receptor had more severe damage in the amygdala as compared with patients with SLE without these antibodies.
Editors' Summary
The human body is continually attacked by viruses, bacteria, fungi, and parasites, but the immune system usually prevents these pathogens from causing disease. To be effective, the immune system has to respond rapidly to foreign antigens (bits of proteins that are unique to the pathogen) but ignore self-antigens. In autoimmune diseases, this ability to discriminate between self and nonself fails for unknown reasons, and the immune system begins to destroy human tissues. In the chronic autoimmune disease systemic lupus erythematosus (SLE or lupus), the immune system attacks the skin, joints, nervous system, and many other organs. Patients with SLE make numerous “autoantibodies” (antibodies are molecules made by the immune system that recognize and attack antigens; autoantibodies attack self-antigens). These autoantibodies start the attack on the body; then other parts of the immune system join in, causing inflammation and forming deposits of immune cells, both of which damage tissues. Common symptoms of SLE include skin rashes and arthritis, but some patients develop NP-SLE, a form of SLE that includes neuropsychiatric symptoms such as amnesia, dementia, mood disorders, strokes, and seizures. There is no cure for SLE, but mild cases are controlled with ibuprofen and other non-steroidal anti-inflammatory drugs; severe cases are kept in check with corticosteroids and other powerful immunosuppressants.
Why Was This Study Done?
In most of the tissues affected by SLE, the damage done by autoantibodies and immune cells can be seen when the tissues are examined with a microscope. But there is little microscopic damage visible in the brains of patients with NP-SLE. More generally, it is unclear how or even whether the immune system affects mental functions and emotion. In this study, researchers used magnetic resonance imaging (MRI) to investigate whether there are any structural changes in the brains of patients with NP-SLE that could explain their neuropsychiatric symptoms. They have also examined whether any changes in the brain can be linked to the presence of autoantibodies that recognize a protein called the NMDA receptor (anti-NMDAR antibodies) that is present on brain cells.
What Did the Researchers Do and Find?
The researchers used an MRI technique called diffusion weighted imaging to examine the brains of several patients with NP-SLE or SLE and the brains of several healthy individuals. Using this technique, it is possible to quantify the amount of structural damage in different regions of the brain. The researchers found no differences in most areas of the brain between the two groups of patients and the healthy controls. However, there were clear signs of damage in the amygdala (the part of the brain that regulates emotions and triggers responses to danger) in the patients with SLE or NP-SLE when compared to the control individuals. The researchers also found that the damage was more severe in the patients who had anti-NMDAR autoantibodies than in those that did not have these autoantibodies.
What Do These Findings Mean?
These findings suggest that autoantibodies produced by patients with SLE specifically damage the amygdala, a discovery that helps to explain some of the neuropsychiatric symptoms of this condition. Previous work has shown that the treatment of mice with anti-NMDAR antibodies and epinephrine, a stress hormone that causes leaks in the blood-brain barrier (antibodies can't usually get into the brain because of this barrier), results in damage to the amygdala and a deficient response to dangerous stimuli. The researchers suggest that a similar series of events might happen in SLE—patients often mention that a period of major stress precedes the development of symptoms. To provide stronger evidence for such a scenario, a detailed study of how stress relates to neuropsychiatric symptoms is needed. The damage to the amygdala (and the lack of damage elsewhere in the brain) and the possible association between brain damage and anti-NMDAR antibodies seen in this small study also need to be confirmed in more patients. Nevertheless, these findings provide an intriguing glimpse into the interplay between the immune system and the brain and into how stress might lead to physical damage in the brain.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus encyclopedia pages on autoimmunity and on systemic lupus erythematosus
US National Institute of Arthritis and Musculoskeletal and Skin Diseases booklet for patients with SLE
American College of Rheumatology information for patients on SLE
NHS Direct Online Health Encyclopedia pages on SLE
The Lupus Foundation of America information and support for patients with SLE
PMCID: PMC1702559  PMID: 17177602

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