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1.
Arthritis Rheumatol ; 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31493335

RESUMO

OBJECTIVE: To determine whether SLE can develop in the absence of BAFF in a SLE-prone host. METHODS: Starting with C57BL/6 mice that express a human Bcl2 transgene (Tg) in their B cells (thereby rendering B cell survival largely independent of BAFF-triggered signals), we introgressed this Tg into NZM 2328 mice genetically deficient in BAFF (NZM.Baff-/- ) to generate NZM.Baff-/- .Bcl2Tg mice. Expression of human BCL2 and lymphocyte profiles were assessed by FACS; serologic profiles were assessed by ELISA; renal immunopathology was assessed by immunofluorescence and histology; and clinical disease was assessed by development of severe proteinuria and death. RESULTS: In comparison to their non-Tg NZM.Baff-/- littermates, NZM.Baff-/- .Bcl2Tg mice over-expressed BCL2 in their B cells and developed increased percentages and numbers of B cells and plasma cells, increased serum levels of IgG autoantibodies, increased glomerular deposition of IgG and C3, and increased glomerular and tubulointerstitial pathology, culminating in severe proteinuria and death. The time course for development of SLE features in NZM.Baff-/- .Bcl2Tg mice was more rapid than that previously observed in NZM 2328 wild-type mice (median mortality 4.5 months vs 7.5 months). NZM.Baff-/- .Bcl2Tg mice remained responsive to BAFF, since re-introduction of the Baff gene into these mice further accelerated the course of disease (median mortality 3 months). CONCLUSIONS: BAFF may be dispensable to development of disease as long as B cell survival is preserved via a BAFF-independent pathway. This may help explain the limited and variable clinical success with BAFF antagonists in human SLE. In addition, NZM.Baff-/- .Bcl2Tg mice may serve as a powerful murine model for the study of BAFF-independent SLE. This article is protected by copyright. All rights reserved.

2.
J Autoimmun ; 103: 102291, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31248690

RESUMO

Ultraviolet (UV) light is a known trigger of skin and possibly systemic inflammation in systemic lupus erythematosus (SLE) patients. Although type I interferons (IFN) are upregulated in SLE skin after UV exposure, the mechanisms to explain increased UVB-induced inflammation remain unclear. This paper compares the role of type I IFNs in regulating immune cell activation between wild-type and lupus-prone mice following UVB exposure. 10-week old female lupus-prone (NZM2328), wild-type (BALB/c) and iNZM mice (lack a functional type I IFN receptor on NZM2328 background) were treated on their dorsal skin with 100 mJ/cm2 of UVB for 5 consecutive days. Following UVB treatment, draining lymph node cell populations were characterized via flow cytometry and suppression assays; treated skin was examined for changes in expression of type I IFN genes. Only NZM2328 mice showed an increase in T cell numbers and activation 2 weeks post UVB exposure. This was preceded by a significant increase in UVB-induced type I IFN expression in NZM2328 mice compared to BALB/c mice. Following UVB exposure, both BALB/c and iNZM mice demonstrated an increase in functional T regulatory (TReg) cells; however, this was not seen in NZM2328 mice. These data suggest a skewed UVB-mediated T cell response in lupus-prone mice where activation of T cells is enhanced secondary to a type I IFN-dependent suppression of TReg cells. Thus, we propose type I IFNs are important for UVB-induced inflammation in lupus-prone mice and may be an effective target for prevention of UVB-mediated flares.

3.
Hum Mol Genet ; 27(21): 3813-3824, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30085094

RESUMO

Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population. In EUR we observed 50 different A-C-B-DRB1-DQA-DQB multilocus haplotype sequences per hundred individuals; in the AA sample, these multilocus haplotypes were twice as common compared to Europeans. We also observed a strong narrow class II signal in AA as opposed to the long-range LD observed in EUR that includes class I alleles. We performed a Bayesian model choice of the classical HLA alleles and a frequentist analysis that combined both single nucleotide polymorphisms (SNPs) and classical HLA alleles. Both analyses converged on a similar subset of risk HLA alleles: in EUR HLA- B*08:01 + B*18:01 + (DRB1*15:01 frequentist only) + DQA*01:02 + DQB*02:01 + DRB3*02 and in AA HLA-C*17:01 + B*08:01 + DRB1*15:03 + (DQA*01:02 frequentist only) + DQA*02:01 + DQA*05:01+ DQA*05:05 + DQB*03:19 + DQB*02:02. We observed two additional independent SNP associations in both populations: EUR rs146903072 and rs501480; AA rs389883 and rs114118665. The DR2 serotype was best explained by DRB1*15:03 + DQA*01:02 in AA and by DRB1*15:01 + DQA*01:02 in EUR. The DR3 serotype was best explained by DQA*05:01 in AA and by DQB*02:01 in EUR. Despite some differences in underlying HLA allele risk models in EUR and AA, SNP signals across the extended MHC showed remarkable similarity and significant concordance in direction of effect for risk-associated variants.

4.
Hum Mol Genet ; 2018 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-29912393

RESUMO

Systemic Lupus Erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly-replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared to the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.

5.
J Immunol ; 201(2): 393-405, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29884703

RESUMO

Systemic lupus erythematosus is an autoimmune disease characterized by increased type I IFNs, autoantibodies, and inflammatory-mediated multiorgan damage. TLR7 activation is an important contributor to systemic lupus erythematosus pathogenesis, but the mechanisms by which type I IFNs participate in TLR7-driven pathologic conditions remain uncertain. In this study, we examined the requirement for type I IFNs in TLR7-stimulated lupus nephritis. Lupus-prone NZM2328, INZM (which lack a functional type I IFN receptor), and NZM2328 IL-1ß-/- mice were treated at 10 wk of age on the right ear with R848 (TLR7 agonist) or control (DMSO). Autoantibody production and proteinuria were assessed throughout treatment. Multiorgan inflammation was assessed at the time of decline in health. Renal infiltrates and mRNA expression were also examined after 14 d of treatment. Both NZM2328 and INZM mice exhibited a decline in survival after 3-4 wk of R848 but not vehicle treatment. Development of splenomegaly and liver inflammation were dependent on type I IFN. Interestingly, autoantibody production, early renal infiltration of dendritic cells, upregulation of IL-1ß, and lupus nephritis occurred independent of type I IFN signaling. Development of TLR7-driven lupus nephritis was not abolished by the deletion of IL-1ß. Thus, although IFN-α is sufficient to induce nephritis acceleration, our data emphasize a critical role for IFN-independent signaling in TLR7-mediated lupus nephritis. Further, despite upregulation of IL-1ß after TLR7 stimulation, deletion of IL-1ß is not sufficient to reduce lupus nephritis development in this model.

6.
Arthritis Rheumatol ; 69(8): 1647-1660, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28471497

RESUMO

OBJECTIVE: We have previously established that the gene for neutrophil cytosolic factor 2 (NCF-2) predisposes to lupus, and we have identified lupus patients with point mutations that are predicted to cause reduced NADPH oxidase activity. We undertook this study to investigate the relationship between reduced leukocyte NADPH oxidase activity and immune dysregulation associated with systemic lupus erythematosus (SLE). METHODS: We generated NCF-2-null mice, in which NADPH oxidase activity is absent, on the nonautoimmune C57BL/6 (B6) mouse background and on the NZM 2328 mouse background, a polygenic model in which mice spontaneously develop lupus. Clinical disease, serology, and immunopathology were evaluated. RESULTS: NCF-2-null mice on the B6 background were susceptible to Aspergillus fumigatus pneumonia characteristic of chronic granulomatous disease, but did not develop systemic lupus disease. In contrast, NCF-2-null and even NCF-2-haploinsufficient mice on the NZM 2328 background developed accelerated full-blown lupus with significantly accelerated lupus kidney disease. This was characterized by more rapid development of hyperactive B cell and T cell immune compartments, increased expression of type I interferon-responsive genes, and generation of neutrophil extracellular traps, which were observed even in the absence of NADPH oxidase activity. CONCLUSION: Just as patients with chronic granulomatous disease who lack NADPH oxidase rarely develop SLE, NCF-2-null mice on a nonautoimmune background were susceptible to a chronic granulomatous disease-like opportunistic infection but did not develop lupus. In contrast, on a lupus-prone background, even haploinsufficiency of NCF-2 accelerated the development of full-blown lupus disease. This establishes an interaction between reduced oxidase activity and other lupus-predisposing genes, paralleling human SLE-associated variants predicted to have only reduced NADPH oxidase activity.


Assuntos
Haploinsuficiência/genética , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/genética , NADPH Oxidases/genética , Animais , Peptídeos Catiônicos Antimicrobianos , Aspergillus fumigatus , Linfócitos B/imunologia , Catelicidinas/imunologia , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Armadilhas Extracelulares/imunologia , Regulação da Expressão Gênica/imunologia , Predisposição Genética para Doença , Doença Granulomatosa Crônica/genética , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Rim/imunologia , Rim/patologia , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Aspergilose Pulmonar/genética , Reação em Cadeia da Polimerase em Tempo Real , Linfócitos T/imunologia
7.
Elife ; 52016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26880555

RESUMO

Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes.


Assuntos
Autoimunidade , Regulação da Expressão Gênica , Antígenos HLA-D/biossíntese , Antígenos HLA-D/genética , Polimorfismo Genético , Células Dendríticas/química , Europa (Continente) , Grupo com Ancestrais do Continente Europeu , Humanos , Lúpus Eritematoso Sistêmico/patologia , Proteínas de Membrana/análise , Estados Unidos
8.
Ann Rheum Dis ; 75(11): 2007-2013, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26783109

RESUMO

OBJECTIVES: Following up the systemic lupus erythematosus (SLE) genome-wide association studies (GWAS) identification of NMNAT2 at rs2022013, we fine-mapped its 150 kb flanking regions containing NMNAT2 and SMG7 in a 15 292 case-control multi-ancestry population and tested functions of identified variants. METHODS: We performed genotyping using custom array, imputation by IMPUTE 2.1.2 and allele specific functions using quantitative real-time PCR and luciferase reporter transfections. SLE peripheral blood mononuclear cells (PBMCs) were cultured with small interfering RNAs to measure antinuclear antibody (ANA) and cyto/chemokine levels in supernatants using ELISA. RESULTS: We confirmed association at NMNAT2 in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at SMG7 tagged by rs2702178 in EA only (p=2.4×10-8, OR=1.23 (95% CI 1.14 to 1.32)). In complete linkage disequilibrium with rs2702178, rs2275675 in the promoter region robustly associated with SMG7 mRNA levels in multiple expression quantitative trait locus (eQTL) datasets. Its risk allele was dose-dependently associated with decreased SMG7 mRNA levels in PBMCs of 86 patients with SLE and 119 controls (p=1.1×10-3 and 6.8×10-8, respectively) and conferred reduced transcription activity in transfected HEK-293 (human embryonic kidney cell line) and Raji cells (p=0.0035 and 0.0037, respectively). As a critical component in the nonsense-mediated mRNA decay pathway, SMG7 could regulate autoantigens including ribonucleoprotein (RNP) and Smith (Sm). We showed SMG7 mRNA levels in PBMCs correlated inversely with ANA titres of patients with SLE (r=-0.31, p=0.01), and SMG7 knockdown increased levels of ANA IgG and chemokine (C-C motif) ligand 19 in SLE PBMCs (p=2.0×10-5 and 2.0×10-4, respectively). CONCLUSION: We confirmed NMNAT2 and identified independent SMG7 association with SLE. The inverse relationship between levels of the risk allele-associated SMG7 mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis.


Assuntos
Anticorpos Antinucleares/metabolismo , Proteínas de Transporte/genética , Leucócitos Mononucleares/imunologia , Lúpus Eritematoso Sistêmico/genética , Nicotinamida-Nucleotídeo Adenililtransferase/genética , Alelos , Grupo com Ancestrais Nativos do Continente Americano/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Células HEK293 , Hispano-Americanos/genética , Humanos , Desequilíbrio de Ligação , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Linhagem , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco
9.
Arthritis Rheumatol ; 68(4): 932-43, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26606652

RESUMO

OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a strong genetic component. We undertook the present work to perform the first genome-wide association study on individuals from the Americas who are enriched for Native American heritage. METHODS: We analyzed 3,710 individuals from the US and 4 countries of Latin America who were diagnosed as having SLE, and healthy controls. Samples were genotyped with HumanOmni1 BeadChip. Data on out-of-study controls genotyped with HumanOmni2.5 were also included. Statistical analyses were performed using SNPtest and SNPGWA. Data were adjusted for genomic control and false discovery rate. Imputation was performed using Impute2 and, for classic HLA alleles, HiBag. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: The IRF5-TNPO3 region showed the strongest association and largest OR for SLE (rs10488631: genomic control-adjusted P [Pgcadj ] = 2.61 × 10(-29), OR 2.12 [95% CI 1.88-2.39]), followed by HLA class II on the DQA2-DQB1 loci (rs9275572: Pgcadj = 1.11 × 10(-16), OR 1.62 [95% CI 1.46-1.80] and rs9271366: Pgcadj = 6.46 × 10(-12), OR 2.06 [95% CI 1.71-2.50]). Other known SLE loci found to be associated in this population were ITGAM, STAT4, TNIP1, NCF2, and IRAK1. We identified a novel locus on 10q24.33 (rs4917385: Pgcadj = 1.39 × 10(-8)) with an expression quantitative trait locus (eQTL) effect (Peqtl = 8.0 × 10(-37) at USMG5/miR1307), and several new suggestive loci. SLE risk loci previously identified in Europeans and Asians were corroborated. Local ancestry estimation showed that the HLA allele risk contribution is of European ancestral origin. Imputation of HLA alleles suggested that autochthonous Native American haplotypes provide protection against development of SLE. CONCLUSION: Our results demonstrate that studying admixed populations provides new insights in the delineation of the genetic architecture that underlies autoimmune and complex diseases.


Assuntos
Grupo com Ancestrais Nativos do Continente Americano/genética , Lúpus Eritematoso Sistêmico/genética , Argentina , Antígeno CD11b/genética , Estudos de Casos e Controles , Chile , Cromossomos Humanos Par 10/genética , Proteínas de Ligação a DNA/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígenos HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Haplótipos , Humanos , Fatores Reguladores de Interferon , Quinases Associadas a Receptores de Interleucina-1/genética , Masculino , México , ATPases Mitocondriais Próton-Translocadoras/genética , NADPH Oxidases/genética , Razão de Chances , Peru , Análise de Componente Principal , Fator de Transcrição STAT4/genética , Estados Unidos , beta Carioferinas
10.
Arthritis Rheumatol ; 68(5): 1197-1209, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26663301

RESUMO

OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder whose etiology is incompletely understood, but likely involves environmental triggers in genetically susceptible individuals. Using an unbiased genome-wide association (GWA) scan and replication analysis, we sought to identify the genetic loci associated with SLE in a Korean population. METHODS: A total of 1,174 SLE cases and 4,246 population controls from Korea were genotyped and analyzed with a GWA scan to identify single-nucleotide polymorphisms (SNPs) significantly associated with SLE, after strict quality control measures were applied. For select variants, replication of SLE risk loci was tested in an independent data set of 1,416 SLE cases and 1,145 population controls from Korea and China. RESULTS: Eleven regions outside the HLA exceeded the genome-wide significance level (P = 5 × 10(-8) ). A novel SNP-SLE association was identified between FCHSD2 and P2RY2, peaking at rs11235667 (P = 1.03 × 10(-8) , odds ratio [OR] 0.59) on a 33-kb haplotype upstream of ATG16L2. In the independent replication data set, the SNP rs11235667 continued to show a significant association with SLE (replication meta-analysis P = 0.001, overall meta-analysis P = 6.67 × 10(-11) ; OR 0.63). Within the HLA region, the SNP-SLE association peaked in the class II region at rs116727542, with multiple independent effects observed in this region. Classic HLA allele imputation analysis identified HLA-DRB1*1501 and HLA-DQB1*0602, each highly correlated with one another, as most strongly associated with SLE. Ten previously established SLE risk loci were replicated: STAT1-STAT4, TNFSF4, TNFAIP3, IKZF1, HIP1, IRF5, BLK, WDFY4, ETS1, and IRAK1-MECP2. Of these loci, previously unreported, independent second risk effects of SNPs in TNFAIP3 and TNFSF4, as well as differences in the association with a putative causal variant in the WDFY4 region, were identified. CONCLUSION: Further studies are needed to identify true SLE risk effects in other loci suggestive of a significant association, and to identify the causal variants in the regions of ATG16L2, FCHSD2, and P2RY2.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Proteínas Relacionadas à Autofagia/genética , Proteínas de Transporte/genética , Lúpus Eritematoso Sistêmico/genética , Proteínas de Membrana/genética , Receptores Purinérgicos P2Y2/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Humanos , Ligante OX40/genética , Polimorfismo de Nucleotídeo Único , República da Coreia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética
11.
Ann Rheum Dis ; 75(1): 242-52, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25180293

RESUMO

OBJECTIVES: Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (CR2/CD21) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association. METHODS: Genotyped and imputed genetic variants spanning CR2 were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR. RESULTS: The strongest association signal was detected at rs1876453 in intron 1 of CR2 (pmeta=4.2×10(-4), OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control pmeta=7.6×10(-7), OR 0.71; case-only pmeta=1.9×10(-4), OR 0.75). Although allele-specific effects on B cell CR2 mRNA or protein levels were not identified, levels of complement receptor 1 (CR1/CD35) mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR. CONCLUSIONS: These data suggest that rs1876453 in CR2 has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications.


Assuntos
Anticorpos Antinucleares/sangue , Lúpus Eritematoso Sistêmico/genética , Receptores de Complemento 3d/genética , Adolescente , Adulto , Subpopulações de Linfócitos B/imunologia , Estudos de Casos e Controles , DNA/imunologia , Predisposição Genética para Doença , Variação Genética , Genótipo , Haplótipos , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptores de Complemento 3b/biossíntese , Medição de Risco/métodos , Fatores de Transcrição/metabolismo , Adulto Jovem
13.
Clin Immunol ; 161(2): 157-62, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26385092

RESUMO

Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE.


Assuntos
Predisposição Genética para Doença/genética , Leptina/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Genótipo , Humanos
14.
Arthritis Rheumatol ; 67(9): 2523-35, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25989238

RESUMO

OBJECTIVE: To determine the development of systemic lupus erythematosus (SLE) in NZM 2328 (NZM) mice deficient in 2 BAFF receptors. METHODS: NZM.BR-3(-/-) .BCMA(-/-) , NZM.BR-3(-/-) .TACI(-/-) , and NZM.BCMA(-/-) .TACI(-/-) mice were evaluated on the clinical, pathologic, serologic, and cellular levels. BAFF receptor expression and lymphocyte phenotype were assessed by flow cytometry, IgG-secreting cells by enzyme-linked immunospot assay, B cell responsiveness to BAFF and generation of Treg cells by in vitro culture, serum BAFF and total IgG and IgG autoantibody levels by enzyme-linked immunosorbent assay, renal immunopathology by immunofluorescence and histologic analyses, and clinical disease by assessment of proteinuria and mortality. RESULTS: Renal immunopathology and clinical disease were attenuated in NZM.BR-3(-/-) .BCMA(-/-) and NZM.BR-3(-/-) .TACI(-/-) mice but were accelerated in NZM.BCMA(-/-) .TACI(-/-) mice. Accelerated disease was associated with increases in B cells, IgG-secreting cells, serum autoantibody levels, and T cells (especially CD4+ activated memory cells), whereas attenuated disease was associated with reductions in many of these parameters. Serum BAFF levels were increased in all double-deficient NZM mice. Exogenous BAFF promoted the in vitro survival of B cells from NZM.BCMA(-/-) .TACI(-/-) or NZM wild-type mice but not those from NZM.BR-3(-/-) .BCMA(-/-) or NZM.BR-3(-/-) .TACI(-/-) mice. In vitro generation of Treg cells was reduced in NZM.BCMA(-/-) .TACI(-/-) mice, but not in NZM.BR-3(-/-) .BCMA(-/-) or NZM.BR-3(-/-) .TACI(-/-) mice. CONCLUSION: Elimination of B lymphocyte stimulator receptor 3 (BR-3) and TACI or BR-3 and BCMA inhibits the development of SLE in NZM mice. Selective targeting of BR-3 plus TACI or BR-3 plus BCMA may be an efficacious therapeutic approach in human SLE.


Assuntos
Receptor do Fator Ativador de Células B/genética , Antígeno de Maturação de Linfócitos B/genética , Linfócitos B/imunologia , Rim/patologia , Lúpus Eritematoso Sistêmico/genética , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Animais , Autoanticorpos/imunologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Rim/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Endogâmicos
15.
Am J Hum Genet ; 96(5): 731-9, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25865496

RESUMO

Genetic variants at chromosomal region 11q23.3, near the gene ETS1, have been associated with systemic lupus erythematosus (SLE), or lupus, in independent cohorts of Asian ancestry. Several recent studies have implicated ETS1 as a critical driver of immune cell function and differentiation, and mice deficient in ETS1 develop an SLE-like autoimmunity. We performed a fine-mapping study of 14,551 subjects from multi-ancestral cohorts by starting with genotyped variants and imputing to all common variants spanning ETS1. By constructing genetic models via frequentist and Bayesian association methods, we identified 16 variants that are statistically likely to be causal. We functionally assessed each of these variants on the basis of their likelihood of affecting transcription factor binding, miRNA binding, or chromatin state. Of the four variants that we experimentally examined, only rs6590330 differentially binds lysate from B cells. Using mass spectrometry, we found more binding of the transcription factor signal transducer and activator of transcription 1 (STAT1) to DNA near the risk allele of rs6590330 than near the non-risk allele. Immunoblot analysis and chromatin immunoprecipitation of pSTAT1 in B cells heterozygous for rs6590330 confirmed that the risk allele increased binding to the active form of STAT1. Analysis with expression quantitative trait loci indicated that the risk allele of rs6590330 is associated with decreased ETS1 expression in Han Chinese, but not other ancestral cohorts. We propose a model in which the risk allele of rs6590330 is associated with decreased ETS1 expression and increases SLE risk by enhancing the binding of pSTAT1.


Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Proteína Proto-Oncogênica c-ets-1/genética , Fator de Transcrição STAT1/genética , Alelos , Animais , Grupo com Ancestrais do Continente Asiático , Teorema de Bayes , Genótipo , Haplótipos , Humanos , Camundongos , Ligação Proteica , Proteína Proto-Oncogênica c-ets-1/metabolismo , Fator de Transcrição STAT1/metabolismo
16.
J Immunol ; 194(9): 4055-7, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25888699

RESUMO

Hiromi Kubagawa and John E. Coligan coordinated an online meeting to define an appropriate nomenclature for the cell surface glycoprotein presently designated by different names: Toso, Fas apoptosis inhibitory molecule 3 (FAIM3), and IgM FcR (FcµR). FAIM3 and Faim3 are the currently approved symbols for the human and mouse genes, respectively, in the National Center for Biotechnology Information, Ensembl, and other databases. However, recent functional results reported by several groups of investigators strongly support a recommendation for renaming FAIM3/Faim3 as FCMR/Fcmr, a name better reflecting its physiological function as the FcR for IgM. Participants included 12 investigators involved in studying Toso/FAIM3(Faim3)/FµR, representatives from the Human Genome Nomenclature Committee (Ruth Seal) and the Mouse Genome Nomenclature Committee (Monica McAndrews), and an observer from the IgM research field (Michael Carroll). In this article, we provide a brief background of the key research on the Toso/FAIM3(Faim3)/FcµR proteins, focusing on the ligand specificity and functional activity, followed by a brief summary of discussion about adopting a single name for this molecule and its gene and a resulting recommendation for genome nomenclature committees.


Assuntos
Proteínas Reguladoras de Apoptose , Proteínas de Transporte , Proteínas de Membrana , Terminologia como Assunto , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas de Transporte/genética , Humanos , Imunoglobulina M , Proteínas de Membrana/genética , Camundongos , Receptores Fc/classificação
17.
J Biol Chem ; 290(20): 12595-602, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25795782

RESUMO

In a case-control association study with 3716 North Americans of Hispanic descent and 4867 North Americans of European descent, we show that the associations of rs17849502 (NCF2 His-389 → Gln) and rs13306575 (NCF2 Arg-395 → Trp) with systemic lupus erythematosus are independent. We have shown that His-389 → Gln disrupts the binding of NCF2 to the ZF domain of VAV1, resulting in decreased NADPH oxidase activity. With respect to Arg-395 → Trp, using protein docking and structure analyses, we provide a model for the involvement of this mutation in the structure and function of the NADPH oxidase complex. This model assigns a central role to Arg-395 in the structure and stability of the quaternary NCF2/NCF4/VAV1/RAC1 NADPH oxidase complex. Arg-395 stabilizes the C-terminal tail of NCF4 and the conformation of NCF2 loop 395-402, which in turn stabilize the evolutionarily conserved interactions of NCF2/NCF4 with the DH domain of VAV1 and RAC1 region 120-137. Our findings are consistent with the high levels of conservation of all of the residues involved in these interactions.


Assuntos
Lúpus Eritematoso Sistêmico , Simulação de Acoplamento Molecular , Mutação de Sentido Incorreto , NADPH Oxidases/química , Substituição de Aminoácidos , Estabilidade Enzimática/genética , Grupo com Ancestrais do Continente Europeu , Feminino , Hispano-Americanos , Humanos , Masculino , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Fosfoproteínas/química , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Estrutura Quaternária de Proteína , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-vav/química , Proteínas Proto-Oncogênicas c-vav/genética , Proteínas Proto-Oncogênicas c-vav/metabolismo , Proteínas rac1 de Ligação ao GTP/química , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo
18.
Nature ; 517(7535): 501-4, 2015 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-25363774

RESUMO

Immunoglobulins protect against disease to a considerable extent by activating complement and stimulatory immunoglobulin crystallizable fragment receptors (Ig FcRs), and aggregating microbial pathogens. Yet IgG1, the predominant murine serum Ig isotype, cannot activate complement by the classical pathway, binds more avidly to an inhibitory than to stimulatory FcRs, and has limited ability to aggregate pathogens. In these regards, it resembles human IgG4 (ref. 4). We hypothesized that limited ability to activate effector mechanisms might protect against immune complex immunopathology. Here we show that IgG1-deficient (γ1(-)) mice, immunized with a potent antigen, develop lethal renal disease soon after they begin to produce antigen-specific antibody, whereas similarly immunized wild-type mice remain healthy. Surprisingly, renal disease in this model is complement and FcR independent and results from immune complex precipitation in glomerular capillaries, as in some cryoglobulinaemic humans. IgG3, which self-associates to form large immune complexes, accounts for more than 97% of the mouse Ig in this cryoglobulin; furthermore, glomerular disease develops when mice are injected with IgG3 anti-trinitrophenyl (TNP) monoclonal antibody followed by a TNP-labelled protein. Renal disease is prevented in both active and passive immunization models by antigen-specific IgG1; other isotypes are less potent at preventing disease. These observations demonstrate the adaptive significance of Ig isotypes that poorly activate effector mechanisms, reveal an immune-complex-dependent, complement- and FcR-independent nephrotoxic mechanism, and suggest that isotypes that poorly activate effector mechanisms may be useful for inhibiting immune complex immunopathology.


Assuntos
Crioglobulinemia/complicações , Glomerulonefrite/etiologia , Glomerulonefrite/prevenção & controle , Imunoglobulina G/imunologia , Animais , Anticorpos Monoclonais/imunologia , Complexo Antígeno-Anticorpo/química , Complexo Antígeno-Anticorpo/imunologia , Antígenos/imunologia , Ligação Competitiva , Proteínas do Sistema Complemento , Crioglobulinemia/imunologia , Crioglobulinemia/patologia , Modelos Animais de Doenças , Feminino , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Cabras , Masculino , Camundongos , Receptores de IgG , Solubilidade , Trinitrobenzenos/imunologia
19.
J Am Soc Nephrol ; 25(12): 2859-70, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24925725

RESUMO

Lupus nephritis is a manifestation of SLE resulting from glomerular immune complex deposition and inflammation. Lupus nephritis demonstrates familial aggregation and accounts for significant morbidity and mortality. We completed a meta-analysis of three genome-wide association studies of SLE to identify lupus nephritis-predisposing loci. Through genotyping and imputation, >1.6 million markers were assessed in 2000 unrelated women of European descent with SLE (588 patients with lupus nephritis and 1412 patients with lupus without nephritis). Tests of association were computed using logistic regression adjusting for population substructure. The strongest evidence for association was observed outside the MHC and included markers localized to 4q11-q13 (PDGFRA, GSX2; P=4.5×10(-7)), 16p12 (SLC5A11; P=5.1×10(-7)), 6p22 (ID4; P=7.4×10(-7)), and 8q24.12 (HAS2, SNTB1; P=1.1×10(-6)). Both HLA-DR2 and HLA-DR3, two well established lupus susceptibility loci, showed evidence of association with lupus nephritis (P=0.06 and P=3.7×10(-5), respectively). Within the class I region, rs9263871 (C6orf15-HCG22) had the strongest evidence of association with lupus nephritis independent of HLA-DR2 and HLA-DR3 (P=8.5×10(-6)). Consistent with a functional role in lupus nephritis, intra-renal mRNA levels of PDGFRA and associated pathway members showed significant enrichment in patients with lupus nephritis (n=32) compared with controls (n=15). Results from this large-scale genome-wide investigation of lupus nephritis provide evidence of multiple biologically relevant lupus nephritis susceptibility loci.


Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/genética , Adolescente , Adulto , Idoso , Criança , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Antígeno HLA-DR2/genética , Antígeno HLA-DR3/genética , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/metabolismo , Adulto Jovem
20.
Am J Hum Genet ; 94(4): 586-98, 2014 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-24702955

RESUMO

Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses.


Assuntos
Lúpus Eritematoso Sistêmico/genética , Regiões Promotoras Genéticas , Transcrição Genética , Quinases da Família src/genética , Alelos , Cromossomos Humanos Par 8 , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
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