RESUMO
Interferon regulatory factor 5 (IRF5) regulates type I interferon (IFN)-responsive genes, and has been one of the most consistently associated genes with systemic lupus erythematosus (SLE). We sought to investigate whether IRF5 haplotypes are associated with risk for SLE in the genetically homogeneous Greek population of the island of Crete, as well as whether these haplotypes are associated with increased type I IFN. 322 SLE patients and 247 healthy controls from Crete were genotyped for rs2004640, rs3807306, rs10488631 and rs2280714 SNPs of IRF5 gene by using Taqman primer-probe sets. Type I IFN levels were measured using a functional reporter cell assay. All IRF5 SNPs examined were found to be associated with SLE in univariate case-control analysis. The 4 SNPs formed 5 major haplotypes and the Neanderthal-derived TACA risk haplotype was present in Crete and enriched in the SLE cases (OR=2.01, P=0.0003). Serum IFN levels were measured in a subset of the SLE patients, and carriage of the TACA haplotype was associated with higher circulating type I IFN levels (P=0.037). This study demonstrates the association of IRF5 with an increased susceptibility for SLE in the population of Crete and emphasizes the association of the Neanderthal-derived IRF5 haplotype with SLE susceptibility. Patients carrying allele the Neanderthal allele C had greater type I IFN, supporting a functional consequence of this polymorphism.
Assuntos
Predisposição Genética para Doença , Fatores Reguladores de Interferon/genética , Lúpus Eritematoso Sistêmico/genética , Adulto , Animais , Estudos de Casos e Controles , Feminino , Grécia , Haplótipos , Humanos , Interferon Tipo I/sangue , Interferon Tipo I/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Homem de Neandertal/genéticaRESUMO
In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) group published a new set of classification criteria for systemic lupus erythematosus (SLE). Studies applying these criteria to real-life scenarios have found either equal or greater sensitivity and equal or lower specificity to the 1997 ACR classification criteria (ACR 97). Nonetheless, there are no studies that have used the SLICC 12 criteria to investigate the incidence of lupus. We used the resource of the Rochester Epidemiology Project to identify incident SLE patients in Olmsted County, Minnesota, from 1993 to 2005, who fulfilled the ACR 97 or SLICC 12 criteria. A total of 58 patients met criteria by SLICC 12 and 44 patients met criteria by ACR 97. The adjusted incidence of 4.9 per 100,000 person-years by SLICC 12 was higher than that by ACR 97 (3.7 per 100,000 person-years, p = 0.04). The median duration from the appearance of first criterion to fulfillment of the criteria was shorter for the SLICC 12 than for ACR 97 (3.9 months vs 8.1 months). The higher incidence by SLICC 12 criteria came primarily from the ability to classify patients with renal-limited disease, the expansion of the immunologic criteria and the expansion of neurologic criteria.
Assuntos
Lúpus Eritematoso Sistêmico/classificação , Lúpus Eritematoso Sistêmico/epidemiologia , Reumatologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Minnesota/epidemiologia , Análise de Regressão , Índice de Gravidade de Doença , Sociedades Médicas , Adulto JovemAssuntos
Calcitonina/sangue , Lúpus Eritematoso Sistêmico/sangue , Artrite/tratamento farmacológico , Proteína C-Reativa/análise , Feminino , Febre/etiologia , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prednisona/administração & dosagem , Adulto JovemRESUMO
A classic T-cell phenotype in systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters T-cell receptor signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multiethnic population. We typed 44 contiguous CD247 single-nucleotide polymorphisms (SNPs) in 8922 SLE patients and 8077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99 × 10(-4) < P < 4.15 × 10(-2)), where we further identified a five-marker haplotype (rs12141731-rs2949655-rs16859085-rs12144621-rs858554; G-G-A-G-A; P(hap) = 2.12 × 10(-5)) that exceeded the most associated single SNP rs858554 (minor allele frequency in controls = 13%; P = 4.99 × 10(-4), odds ratio = 1.32) in significance. Imputation and subsequent association analysis showed evidence of association (P < 0.05) at 27 additional SNPs within intron 1. Cross-ethnic meta-analysis, assuming an additive genetic model adjusted for population proportions, showed five SNPs with significant P-values (1.40 × 10(-3) < P< 3.97 × 10(-2)), with one (rs704848) remaining significant after Bonferroni correction (P(meta) = 2.66 × 10(-2)). Our study independently confirms and extends the association of SLE with CD247, which is shared by various autoimmune disorders and supports a common T-cell-mediated mechanism.
Assuntos
Complexo CD3/genética , Lúpus Eritematoso Sistêmico/etnologia , Lúpus Eritematoso Sistêmico/genética , Adulto , Povo Asiático/genética , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Linfócitos T/imunologia , População Branca/genéticaRESUMO
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by inflammation of multiple organ systems and dysregulated interferon responses. SLE is both genetically and phenotypically heterogeneous, greatly reducing the power of case-control studies in SLE. Elevated circulating interferon-alpha (IFN-α) is a stable, heritable trait in SLE, which has been implicated in primary disease pathogenesis. About 40-50% of patients have high IFN-α, and high levels correspond with clinical differences. To study genetic heterogeneity in SLE, we performed a case-case study comparing patients with high vs low IFN-α in over 1550 SLE cases, including genome-wide association study and replication cohorts. In meta-analysis, the top associations in European ancestry were protein kinase, cyclic GMP-dependent, type I (PRKG1) rs7897633 (P(Meta) = 2.75 × 10(-8)) and purine nucleoside phosphorylase (PNP) rs1049564 (P(Meta) = 1.24 × 10(-7)). We also found evidence for cross-ancestral background associations with the ankyrin repeat domain 44 (ANKRD44) and pleckstrin homology domain containing, family F member 2 gene (PLEKHF2) loci. These loci have not been previously identified in case-control SLE genetic studies. Bioinformatic analyses implicated these loci functionally in dendritic cells and natural killer cells, both of which are involved in IFN-α production in SLE. As case-control studies of heterogeneous diseases reach a limit of feasibility with respect to subject number and detectable effect size, the study of informative pathogenic sub-phenotypes becomes an attractive strategy for genetic discovery in complex disease.
Assuntos
Proteína Quinase Dependente de GMP Cíclico Tipo I/genética , Interferon-alfa/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Polimorfismo de Nucleotídeo Único , Purina-Núcleosídeo Fosforilase/genética , Estudos de Casos e Controles , Feminino , Redes Reguladoras de Genes , Humanos , População Branca/genéticaRESUMO
OBJECTIVE: Interleukin-6 (IL-6), interleukin-10 (IL-10), interferon-alpha (IFN-α), and free light chains (FLCs: lambda, kappa) have all been noted to be of importance in systemic lupus erythematosus (SLE). Herein, we quantified and explored the relationship between these inflammatory mediators and disease activity in SLE; and stratified by their current anti-dsDNA antibody status. METHODS: Seventy-seven SLE patients underwent assessment of disease activity using the SLE disease activity index (SLEDAI). Serum FLC (lambda, kappa, and total), IL-6, IL-10, and IFN-α were quantified. Demographics of disease characteristics were determined by chart reviews. Statistical analyses included Mann-Whitney test, chi square, and linear regression analyses. RESULTS: Mean (SD) age of the patients was 44.9 ± 12.7 years; SLEDAI (mean ± SD) was 3.4 ± 4.0. Serum lambda FLC levels had a moderate correlation (r = 0.46 with physician global assessment, 0.44 with SLEDAI) and the strongest correlation with disease activity as compared with other inflammatory mediators including current dsDNA antibody status. After adjusting for prednisone use, the correlation of lambda FLC with PGA (r = 0.48) and SLEDAI (r = 0.52) was better than of current dsDNA antibody status with PGA (r = 0.33) and adjusted SLEDAI (r = 0.24), respectively. IL-10 and IFN-α activity did not correlate with disease activity. Serum FLC and IL-6 levels could differentiate between active and inactive SLE patients. Serum lambda FLC and IL-6 levels differed significantly among patients with and without current dsDNA antibodies. Serum lambda FLC levels accounted for 31% of variance in SLEDAI scores. CONCLUSION: Serum FLC and IL-6 are potentially useful biomarkers of disease activity in SLE. Further studies, with larger study sample and longitudinal design, are indicated.
Assuntos
Anticorpos Antinucleares/sangue , Cadeias kappa de Imunoglobulina/sangue , Cadeias lambda de Imunoglobulina/sangue , Interferon-alfa/sangue , Interleucina-10/sangue , Interleucina-6/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
We report the case of a 19-year-old woman with progressive proliferative lupus nephritis (LN) class III after induction and maintenance therapy with mycophenolate mofetil (MMF). Despite a satisfying clinical improvement proteinuria progressed under this medication. We treated the patient with additional belimumab after discussing other options. Following treatment with belimumab, proteinuria rapidly improved to almost normal levels and clinical remission lasted. Belimumab might hold promise for this indication.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Imunossupressores/uso terapêutico , Nefrite Lúpica/tratamento farmacológico , Progressão da Doença , Feminino , Humanos , Nefrite Lúpica/fisiopatologia , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapêutico , Proteinúria/tratamento farmacológico , Proteinúria/etiologia , Indução de Remissão , Resultado do Tratamento , Adulto JovemRESUMO
Alleles of interferon (IFN) regulatory factor 8 (IRF8) are associated with susceptibility to both systemic lupus erythematosus (SLE) and multiple sclerosis (MS). Although high-type I IFN is thought to be causal in SLE, type I IFN is used as a therapy in MS. We investigated whether IRF8 alleles were associated with type I IFN levels or serologic profiles in SLE and MS. Alleles that have been previously associated with SLE or MS were genotyped in SLE and MS patients. The MS-associated rs17445836G allele was associated with anti-double-stranded DNA (dsDNA) autoantibodies in SLE patients (meta-analysis odds ratio=1.92). The same allele was associated with decreased serum IFN activity in SLE patients with anti-dsDNA antibodies, and with decreased type I IFN-induced gene expression in peripheral blood mononuclear cell from anti-dsDNA-negative SLE patients. In secondary progressive MS patients, rs17445836G was associated with decreased serum type I IFN. Rs17445836G was associated with increased IRF8 expression in SLE patient B cells. In summary, IRF8 rs17445836G is associated with human autoimmune disease characterized by low-type I IFN levels, and this may have pharmacogenetic relevance as type I IFN is modulated in SLE and MS. The association with autoantibodies and increased IRF8 expression in B cells supports a role for rs17445836G in humoral tolerance.
Assuntos
Fatores Reguladores de Interferon/genética , Interferon Tipo I/sangue , Lúpus Eritematoso Sistêmico/genética , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único , Autoanticorpos/imunologia , Estudos de Casos e Controles , DNA/imunologia , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologiaRESUMO
Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies manifesting in inflammation of target organs such as the kidneys, skin and joints. Genome-wide association studies have identified genetic variants in the UBE2L3 region that are associated with SLE in subjects of European and Asian ancestry. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, involved in cell proliferation and immune function. In this study, we sought to further characterize the genetic association in the region of UBE2L3 and use molecular methods to determine the functional effect of the risk haplotype. We identified significant associations between variants in the region of UBE2L3 and SLE in individuals of European and Asian ancestry that exceeded a Bonferroni-corrected threshold (P<1 × 10(-4)). A single risk haplotype was observed in all associated populations. Individuals harboring the risk haplotype display a significant increase in both UBE2L3 mRNA expression (P=0.0004) and UBCH7 protein expression (P=0.0068). The results suggest that variants carried on the SLE-associated UBE2L3 risk haplotype influence autoimmunity by modulating UBCH7 expression.
Assuntos
Predisposição Genética para Doença , Haplótipos , Lúpus Eritematoso Sistêmico/genética , Enzimas de Conjugação de Ubiquitina/genética , Negro ou Afro-Americano/genética , Alelos , Povo Asiático/genética , Feminino , Hispânico ou Latino/genética , Humanos , Desequilíbrio de Ligação , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Polimorfismo de Nucleotídeo Único , Enzimas de Conjugação de Ubiquitina/metabolismo , População Branca/genéticaRESUMO
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production and organ damage. Lupus nephritis (LN) is one of the most severe manifestations of SLE. Multiple studies reported associations between renal diseases and variants in the non-muscle myosin heavy chain 9 (MYH9) and the neighboring apolipoprotein L 1 (APOL1) genes. We evaluated 167 variants spanning MYH9 for association with LN in a multiethnic sample. The two previously identified risk variants in APOL1 were also tested for association with LN in European-Americans (EAs) (N = 579) and African-Americans (AAs) (N = 407). Multiple peaks of association exceeding a Bonferroni corrected P-value of P < 2.03 × 10(-3) were observed between LN and MYH9 in EAs (N = 4620), with the most pronounced association at rs2157257 (P = 4.7 × 10(-4), odds ratio (OR) = 1.205). A modest effect with MYH9 was also detected in Gullah (rs8136069, P = 0.0019, OR = 2.304). No association between LN and MYH9 was found in AAs, Asians, Amerindians or Hispanics. This study provides the first investigation of MYH9 in LN in non-Africans and of APOL1 in LN in any population, and presents novel insight into the potential role of MYH9 in LN in EAs.
Assuntos
Apolipoproteínas/genética , Negro ou Afro-Americano/genética , Lipoproteínas HDL/genética , Nefrite Lúpica/etnologia , Nefrite Lúpica/genética , Proteínas Motores Moleculares/genética , Cadeias Pesadas de Miosina/genética , Apolipoproteína L1 , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , População Branca/genéticaRESUMO
Autoimmune diseases affect approximately 5% of the population, but much work remains to define the genetic risk factors and pathogenic mechanisms underlying these conditions. There is accumulating evidence that common genetic factors might predispose to multiple autoimmune disorders. Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are complex autoimmune disorders with multiple susceptibility genes. The functional R620W (C1858T) polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, a member of the PTPs that negatively regulate T-cell activation, has been recently associated with susceptibility to various autoimmune diseases. The aim of this study was to assess whether the C1858T polymorphism of PTPN22 also confers increased risk for SLE and RA in the genetically homogeneous population of Crete. It was found that the minor T allele of the PTPN22 C1858T SNP was more common in SLE patients than in control individuals (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.11 to 3.9, p = 0.017). No significant difference was observed in the frequency of this allele when RA patients were compared with controls (OR = 1.14, 95% CI = 0.65 to 1.9, p = 0.64). Although the PTPN22 1858 T allele is found at decreased frequency in Southern Europe, including Crete, an association was found between this allele and SLE in the population studied.
Assuntos
Artrite Reumatoide/genética , Lúpus Eritematoso Sistêmico/genética , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Adulto , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Grécia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a complex pathogenesis in which genetic, hormonal and environmental factors have a role. Rare mutations in the TREX1 gene, the major mammalian 3'-5' exonuclease, have been reported in sporadic SLE cases. Some of these mutations have also been identified in a rare pediatric neurological condition featuring an inflammatory encephalopathy known as Aicardi-Goutières syndrome (AGS). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of SLE cases and controls. A total of 40 single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the TREX1 gene, were evaluated in â¼8370 patients with SLE and â¼7490 control subjects. Stringent quality control procedures were applied, and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case-control association analyses were performed. P-values, false-discovery rate q values, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. The estimated frequency of TREX1 mutations in our lupus cohort was 0.5%. Five heterozygous mutations were detected at the Y305C polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the E266G polymorphism and, again, none were observed in the African controls. A rare homozygous R114H mutation was identified in one Asian SLE patient, whereas all genotypes at this mutation in previous reports for SLE were heterozygous. Analysis of common TREX1 SNPs (minor allele frequency (MAF)>10%) revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures, with a frequency of 58% in lupus cases compared with 45% in normal controls (P=0.0008, OR=1.73, 95% CI=1.25-2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant rs56203834 (P=2.99E-13, OR=5.2, 95% CI=3.18-8.56). Our data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis.
Assuntos
Exodesoxirribonucleases/genética , Lúpus Eritematoso Sistêmico/genética , Fosfoproteínas/genética , Estudos de Coortes , Feminino , Haplótipos , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Masculino , Mutação , Fenótipo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Osteopontin (OPN) is a multifunctional cytokine involved in long bone remodeling and immune system signaling. Additionally, OPN is critical for interferon-alpha (IFN-alpha) production in murine plasmacytoid dendritic cells. We have previously shown that IFN-alpha is a heritable risk factor for systemic lupus erythematosus (SLE). Genetic variants of OPN have been associated with SLE susceptibility, and one study suggests that this association is particular to men. In this study, the 3' UTR SLE-risk variant of OPN (rs9138C) was associated with higher serum OPN and IFN-alpha in men (P=0.0062 and P=0.0087, respectively). In women, the association between rs9138 C and higher serum OPN and IFN-alpha was restricted to younger subjects, and risk allele carriers showed a strong age-related genetic effect of rs9138 genotype on both serum OPN and IFN-alpha (P<0.0001). In African-American subjects, the 5' region single nucleotide polymorphisms, rs11730582 and rs28357094, were associated with anti-RNP antibodies (odds ratio (OR)=2.9, P=0.0038 and OR=3.9, P=0.021, respectively). Thus, we demonstrate two distinct genetic influences of OPN on serum protein traits in SLE patients, which correspond to previously reported SLE-risk variants. This study provides a biologic relevance for OPN variants at the protein level, and suggests an influence of this gene on the IFN-alpha pathway in SLE.
Assuntos
Interferon-alfa/imunologia , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/genética , Osteopontina/sangue , Osteopontina/genética , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Feminino , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Adulto JovemRESUMO
OBJECTIVE: Type I interferons and apoptotic particles contribute to antinuclear autoimmunity in experimental models. This study assessed whether similar mechanisms contribute to break peripheral B-cell tolerance in humans by studying the induction of antinuclear antibodies by tumour necrosis factor blockade in spondyloarthritis. METHODS: 40 spondyloarthritis patients treated with infliximab or etanercept and 20 renal cell carcinoma patients treated with sorafenib were studied. Serum antinucleosome IgM and nucleosomes were measured by ELISA. Type I interferon serum activity was measured using a functional reporter cell assay. Synovial apoptosis was assessed by terminal transferase nick end-labelling (TUNEL) assay and anti-active caspase-3 immunostaining. Complement was measured by nephelometry. RESULTS: Despite a similar clinical improvement and reduction of synovial inflammation, antinucleosome IgM were induced by infliximab but not etanercept. This induction did not correlate with type I interferon activity, which was transiently downmodulated by infliximab but persistently upregulated by etanercept. In contrast, antinucleosome IgM levels did correlate with serum nucleosome levels, which were significantly upregulated by infliximab but not by etanercept treatment. This increase in serum nucleosome levels was not directly related to massive cell death, but rather to a decrease of complement 3 and 4 serum levels during infliximab treatment. CONCLUSION: Infliximab and etanercept have a differential effect on both type I interferon activity and nucleosome levels. Only elevated serum nucleosomes relate to the induction of antinucleosome antibodies after infliximab treatment.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Imunoglobulina G/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Espondilartrite/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral , Adulto , Idoso , Anticorpos Antinucleares/sangue , Formação de Anticorpos , Apoptose , Autoanticorpos/sangue , Complemento C3/análise , Complemento C4/análise , Etanercepte , Feminino , Humanos , Imunoglobulina M/sangue , Infliximab , Interferon Tipo I/sangue , Masculino , Pessoa de Meia-Idade , Nucleossomos/imunologia , Espondilartrite/imunologia , Espondilartrite/patologia , Estatísticas não Paramétricas , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Adulto JovemRESUMO
Interferon alpha (IFN-alpha) levels are elevated in many patients with systemic lupus erythematosus (SLE); however it is not known whether high serum IFN-alpha activity is a cause or a result of the disease. We studied 266 SLE patients and 405 of their healthy relatives, and frequently found high serum IFN-alpha activity in both patients and healthy relatives as compared to healthy unrelated individuals. High IFN-alpha activity was clustered in specific families in both SLE patients and their healthy first-degree relatives, suggesting a heritable trait. Heritability was also supported by quantitative familial correlation of IFN-alpha activity, concordance in affected sib pairs and frequent transmission of the high IFN-alpha activity trait from parents to offspring. Autoantibodies to RNA-binding proteins and double-stranded DNA were associated with high IFN-alpha activity in SLE patients; however these autoantibodies were very uncommon in healthy family members and did not explain the observed familial correlations. The frequency of high IFN-alpha activity was similar across all studied ethnic backgrounds. These data suggest that high serum IFN-alpha activity is a complex heritable trait, which plays a primary role in SLE pathogenesis.
Assuntos
Autoanticorpos/sangue , Interferon-alfa/sangue , Interferon-alfa/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Autoanticorpos/imunologia , Estudos de Casos e Controles , Linhagem Celular , Feminino , Humanos , Interferon-alfa/imunologia , Lúpus Eritematoso Sistêmico/sangue , Masculino , Proteínas de Ligação a RNA/imunologia , Fatores de RiscoRESUMO
Rheumatoid arthritis is both common and chronic, with significant consequences for multiple organ systems. Better understanding of its pathophysiology has led to the development of targeted therapies that have dramatically improved outcomes. The key to therapeutic success lies in identifying individuals who will have severe destructive disease as early as possible, so that effective treatment can be initiated before irreversible damage occurs. Anti-cyclic citrullinated peptide (anti-CCP) antibody testing is particularly useful in the diagnosis of rheumatoid arthritis, with high specificity, presence early in the disease process, and ability to identify patients who are likely to have severe disease and irreversible damage. However, its sensitivity is low, and a negative result does not exclude disease. Anti-CCP antibodies have not been found at a significant frequency in other diseases to date, and are more specific than rheumatoid factor for detecting rheumatoid arthritis. We discuss anti-CCP antibody testing in rheumatoid arthritis, with an emphasis on diagnostic performance, prognostic capability, and relevance to pathogenesis and new treatment paradigms in rheumatoid arthritis.
Assuntos
Anticorpos/sangue , Artrite Reumatoide/diagnóstico , Peptídeos Cíclicos/imunologia , Biomarcadores/sangue , Diagnóstico Precoce , Seguimentos , Humanos , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
We report the case of an adult who developed severe post-streptococcal reactive arthritis (PSRA) and poststreptococcal glomerulonephritis (PSGN) after a subclinical streptococcal infection. Antistreptococcal antibody titres, renal biopsy and the clinical course confirmed the diagnosis. Coincidence of PSRA and PSGN is rare in the adult population and the potential for misdiagnosis exists, particularly when prior streptococcal infection is not apparent. The clinical manifestations of poststreptococcal syndromes are highly variable, and the diagnosis of concomitant PSRA and PSGN should be considered when patients present with glomerulonephritis and inflammatory arthritis. Factors from both the host and the pathogen are probably important in determining disease expression in poststreptococcal syndromes.
Assuntos
Artrite Reativa/complicações , Artrite Reativa/microbiologia , Glomerulonefrite/complicações , Infecções Estreptocócicas/complicações , Corticosteroides/uso terapêutico , Adulto , Antibacterianos/uso terapêutico , Artrite Reativa/tratamento farmacológico , Biópsia por Agulha , Quimioterapia Combinada , Seguimentos , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/patologia , Humanos , Imuno-Histoquímica , Masculino , Medição de Risco , Infecções Estreptocócicas/diagnóstico , Infecções Estreptocócicas/tratamento farmacológico , Resultado do Tratamento , UrináliseRESUMO
The methyl-accepting chemotaxis protein, McpB, is the sole receptor mediating asparagine chemotaxis in Bacillus subtilis. In this study, we show that wild-type B. subtilis cells contain approximately 2,000 copies of McpB per cell, that these receptors are localized polarly, and that titration of only a few receptors is sufficient to generate a detectable behavioural response. In contrast to the wild type, a cheB mutant was incapable of tumbling in response to decreasing concentrations of asparagine, but the cheB mutant was able to accumulate to low concentrations of asparagine in the capillary assay, as observed previously in response to azetidine-2-carboxylate. Furthermore, net demethylation of McpB is logarithmically dependent on asparagine concentration, with half-maximal demethylation of McpB occurring when only 3% of the receptors are titrated. Because the corresponding methanol production is exponentially dependent on attractant concentration, net methylation changes and increased turnover of methyl groups must occur on McpB at high concentrations of asparagine. Together, the data support the hypothesis that methylation changes occur on asparagine-bound McpB to enhance the dynamic range of the receptor complex and to enable the cell to respond to a negative stimulus, such as removal of asparagine.