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BACKGROUND: Polymyositis/dermatomyositis (PM/DM) is an autoimmune disease that is sometimes complicated with rapidly progressive interstitial lung disease (RPILD). However, serum and lung biomarkers that can predict RPILD development remain unclear. OBJECTIVES: To determine potential serum and lung biomarkers that can predict RPILD development in patients with PM/DM-ILD. METHODS: In total, 49 patients with PM/DM-ILD were enrolled. We measured the serum levels of 41 cytokines/chemokines, ferritin and anti-MDA5 antibody, compared them between the RPILD (n = 23) and non-RPILD (n = 26) groups, and ranked them by their importance through random forest analysis. To distinguish the two groups, we determined biomarker combinations by logistic regression analysis. We also measured the bronchoalveolar lavage fluid (BALF) levels of 41 cytokines/chemokines. Using immunohistochemistry, we examined IL-15 expression in lung tissues. The IL-15 production was also investigated using A549 and BEAS-2B cells. RESULTS: The RPILD group had significantly higher IL-15, IL-1RA, IL-6, CXCL10, VCAM-1, anti-MDA5 antibody and ferritin serum levels than the non-RPILD group, but it had a significantly low CCL22 level. Meanwhile, anti-MDA5 antibody, IL-15, CXCL8, CCL22, IL-1RA and ferritin were the best combination to distinguish the two groups. IL-15 and CCL22 were also predictive marker for RPILD development in anti-MDA5 antibody-positive patients. Additionally, the RPILD group had significantly high IL-15 levels in BALF. The lung tissues expressed IL-15, which increased after cytokine stimulation in the A549 cells. CONCLUSION: This study identified a combination of biomarkers predicting PM/DM-RPILD progression, and IL-15 is an important cytokine for predicting RPILD development and reflecting ILD severity.
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Dermatomiositis/complicaciones , Interleucina-15/inmunología , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/inmunología , Biomarcadores , Líquido del Lavado Bronquioalveolar/química , Quimiocinas/inmunología , Citocinas/inmunología , Progresión de la Enfermedad , Femenino , Ferritinas/inmunología , Humanos , Japón , MasculinoRESUMEN
BACKGROUND: Antimelanoma differentiation-associated protein (anti-MDA)5 antibodies are associated with rapidly progressive interstitial lung disease (RP-ILD) in patients with clinically amyopathic dermatomyositis (CADM) or dermatomyositis (DM). OBJECTIVES: We aimed to evaluate the relevance of monitoring anti-MDA5 antibody levels for the management of RP-ILD in patients with CADM or DM. METHODS: Twelve patients with CADM (n = 10) or DM (n = 2) accompanied by RP-ILD were included. Baseline characteristics and outcomes were recorded. Serial measurements of anti-MDA5 antibody levels were measured. All patients were treated with corticosteroids, tacrolimus and intravenous cyclophosphamide. RESULTS: All patients achieved RP-ILD remission after combined immunosuppressive therapy for a mean of 6·8 months, with significant decreases noted in the mean anti-MDA5 antibody levels at remission. Six (50%) patients became anti-MDA5 antibody negative after therapy. After a mean follow-up of 31 months, RP-ILD relapse was observed in four (33%) patients in both the anti-MDA5 antibody sustained positive group and the negative conversion group. However, relapsed patients in the sustained positive group relapsed earlier than those in the negative conversion group. Thus, a decrease in anti-MDA5 antibody levels during remission was associated with longer remission. Relapses were associated with a reincrease of anti-MDA5 antibody levels in four of four (100%) patients. In contrast, none of the patients without reincrease in anti-MDA5 antibody exhibited symptoms of relapse during follow-up. Therefore, reincrease in anti-MDA5 antibody levels was associated with relapse. CONCLUSIONS: The anti-MDA5 antibody level is a novel parameter for monitoring and a good predictor of RP-ILD relapse in patients with CADM or DM.
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Dermatomiositis/inmunología , Enfermedades Pulmonares Intersticiales/inmunología , Corticoesteroides/uso terapéutico , Autoanticuerpos/metabolismo , Ciclofosfamida/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Dermatomiositis/tratamiento farmacológico , Quimioterapia Combinada , Femenino , Humanos , Inmunosupresores/uso terapéutico , Helicasa Inducida por Interferón IFIH1/inmunología , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Recurrencia , Resultado del TratamientoRESUMEN
OBJECTIVES: To clarify the prevalence of anti-signal recognition particle (anti-SRP) antibody in connective tissue diseases (CTDs) and investigate the clinical characteristics of patients without inflammatory myopathy. METHOD: Sera from 6180 patients with CTD were examined by immunoprecipitation (IPP) assays, and the records of patients positive for anti-SRP antibody were reviewed retrospectively. The antibody against the 54-kDa protein of SRP (SRP54) was quantified by enzyme-linked immunosorbent assay (ELISA) in patients with anti-SRP antibody. RESULTS: Of the 28 patients positive for anti-SRP antibody, nine (32.1%) did not have inflammatory myopathy. The clinical diagnoses and characteristics of those patients varied considerably. In patients with inflammatory myopathy, the index of anti-SRP54 was much higher than in those without myopathy (1.15 vs. 0.46; p = 0.036). CONCLUSIONS: The prevalence of anti-SRP antibody was 0.5% in a cohort of Japanese patients with CTD, and one-third of them did not have inflammatory myopathy. Sera from patients with inflammatory myopathy recognized SRP54 more strongly than in those without myopathy.
RESUMEN
OBJECTIVES: To evaluate the roles of circulating B cells in the pathogenic process of systemic lupus erythematosus (SLE) by measuring the expression of chemokines and their receptors. METHODS: Peripheral-blood mononuclear cells were obtained from 17 active, 21 inactive SLE patients, and 13 healthy controls. The expression of CXCR4, CXCR5, and CCR7 on CD19+ B cells was determined by flow cytometry, serum concentration of CXCL12 was measured by enzyme-linked immunosorbent assay, and the chemotactic responsiveness of B cells toward CXCL12 was evaluated. B or plasma cells expressing CXCR4 in renal biopsy specimens were detected using immnofluorescent staining. RESULTS: Flow cytometric analysis revealed that expression level of CXCR4 on circulating B cells was significantly higher in patients with active disease than in those with inactive disease or controls. Serum CXCL12 concentration was not different between these groups. In addition, the migratory ability of B cells toward CXCL12 was enhanced in active SLE patients. Finally, CXCR4-expressing B cells were more frequently observed in the renal biopsy specimens of lupus nephritis. CONCLUSIONS: Up-regulated CXCR4 expression on circulating B cells in active SLE may enhance their chemotactic response toward CXCL12, which may promote infiltration of these cells into inflamed renal tissue and contribute to the development of SLE.
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Linfocitos B/inmunología , Quimiocina CXCL12/inmunología , Lupus Eritematoso Sistémico/inmunología , Nefritis Lúpica/inmunología , Receptores CXCR4/inmunología , Adulto , Anciano , Humanos , Inmunohistoquímica , Riñón/inmunología , Riñón/patología , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Nefritis Lúpica/etiología , Nefritis Lúpica/patología , Masculino , Persona de Mediana Edad , Gravedad del Paciente , Estadística como Asunto , Regulación hacia ArribaAsunto(s)
Ciclofosfamida/administración & dosificación , Inmunosupresores/administración & dosificación , Lupus Eritematoso Sistémico/tratamiento farmacológico , Esclerodermia Sistémica/tratamiento farmacológico , Ciclofosfamida/efectos adversos , Relación Dosis-Respuesta a Droga , Humanos , Inmunosupresores/efectos adversos , Ácido Micofenólico/uso terapéuticoRESUMEN
BACKGROUND AND PURPOSE: There is no general consensus as to whether autoimmune myasthenia gravis (MG) is associated with heart diseases, despite the fact that myocarditis, a serious cardiac involvement treatable by immunotherapy, is a complication of MG. It has been observed previously that MG patients with clinically suspected myocarditis had anti-Kv1.4 antibodies. The purpose of this study was to disclose the association between anti-Kv1.4 antibodies and cardiac involvements in MG patients. METHODS: Anti-Kv1.4 antibody was detected by an immunoprecipitation assay using (35) S-labeled rhabdomyosarcome cellular extract as the antigen source. Cardiac findings including electrocardiography (ECG) and clinical features of clinically suspected myocarditis in MG patients with anti-Kv1.4 antibodies were investigated. Ultrasound echocardiography (UCG) of ex vivo chick embryos was performed to determine the suppressive effects of sera with or without anti-Kv1.4 antibodies on heart muscle functions. RESULTS: Seventy (10.8%) of 650 MG patients had anti-Kv1.4 antibodies and 60% of them had abnormal ECG findings with high frequencies of T-wave abnormality and QT prolongation. Clinically suspected myocarditis was found in eight MG patients with anti-Kv1.4 antibodies but in none of the MG patients without anti-Kv1.4 antibodies. Most patients showed rapid deterioration with lethal arrhythmias such as ventricular tachycardia, sick sinus syndrome, or complete atrial ventricular block and severe heart failure. It was concluded using UCG of ex vivo chick embryos that MG serum with anti-Kv1.4 antibodies suppressed heart muscle functions. CONCLUSION: It has been demonstrated that anti-Kv1.4 antibodies are possible markers for cardiac involvements in MG patients.
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Autoanticuerpos/sangre , Cardiopatías/inmunología , Canal de Potasio Kv1.4/inmunología , Miastenia Gravis/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Electrocardiografía , Femenino , Corazón/fisiopatología , Cardiopatías/sangre , Cardiopatías/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Miastenia Gravis/sangre , Miastenia Gravis/complicaciones , Adulto JovenRESUMEN
OBJECTIVES: Recent genome-wide association studies disclosed that several single nucleotide polymorphisms (SNPs), including tumour necrosis factor (TNF) receptor-associated factor 1 (TRAF1) (+16860A/G), are associated with the pathophysiology of rheumatoid arthritis (RA). We assessed the usefulness of TRAF1 genotyping as a genetic predictor of the response to anti-TNF treatment in Japanese RA patients. METHODS: TRAF1 (+16860A/G) was genotyped using the TaqMan SNP genotyping assay in 101 Japanese RA patients treated with anti-TNF drugs for >24 weeks. We retrospectively analysed the association between SNP and the clinical response to treatment. TRAF1 mRNA and protein expression was also evaluated in CD4+, CD8+, CD14+, or CD19+ cells from 25 healthy subjects using quantitative polymerase chain reaction and intracellular staining flow cytometry, respectively. RESULTS: No statistical difference in DAS28-ESR at baseline was observed between the patient groups with the AA, AG, or GG genotype. The GG genotype was more frequent in non-responders than in good or moderate responders [odds ratio (OR) 7.4, 95% confidence interval (CI) 1.5-37.5]. The non-responders possessed the G allele more frequently than the good or moderate responders (OR 3.5, 95% CI 1.4-9.0). TRAF1 protein expression increased significantly in CD14+ monocytes from healthy subjects with the GG genotype compared with that in subjects with the AA or AG genotype. CONCLUSIONS: TRAF1 (+16860A/G) may be useful for predicting the clinical response to anti-TNF treatment and may contribute to resistance to treatment in RA patients with the GG genotype by increasing the TRAF1 expression in circulating inflammatory cells.
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Anticuerpos Monoclonales Humanizados/farmacología , Artritis Reumatoide , Factor 1 Asociado a Receptor de TNF/genética , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto , Anciano , Antirreumáticos/farmacología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/genética , Pueblo Asiatico/genética , Femenino , Técnicas de Genotipaje , Humanos , Japón , Masculino , Persona de Mediana Edad , Farmacogenética/métodos , Polimorfismo de Nucleótido Simple , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Although the HLA region contributes to one-third of the genetic factors affecting rheumatoid arthritis (RA), there are few reports on the association of the disease with any of the HLA loci other than the DRB1. In this study we examined the association between RA and the alleles of the six classical HLA loci including DRB1. Six HLA loci (HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1) of 1659 Japanese subjects (622 cases; 488 anti-cyclic citrullinated peptides (CCP) antibody (Ab) positive (82.6%); 103 anti-CCP Ab negative (17.4%); 31 not known and 1037 controls) were genotyped. Disease types and positivity/negativity for CCP autoantibodies were used to stratify the cases. Statistical and genetic assessments were performed by Fisher's exact tests, odds ratio, trend tests and haplotype estimation. None of the HLA loci were significantly associated with CCP sero-negative cases after Bonferroni correction and we therefore limited further analyses to using only the anti CCP-positive RA cases and both anti-CCP positive and anti-CCP negative controls. Some alleles of the non-DRB1 HLA loci showed significant association with RA, which could be explained by linkage disequilibrium with DRB1 alleles. However, DPB1*02:01, DPB1*04:01 and DPB1*09:01 conferred RA risk/protection independently from DRB1. DPB1*02:01 was significantly associated with the highly erosive disease type. The odds ratio of the four HLA-loci haplotypes with DRB1*04:05 and DQB1*04:01, which were the high-risk HLA alleles in Japanese, varied from 1.01 to 5.58. C*07:04, and B*15:18 showed similar P-values and odds ratios to DRB1*04:01, which was located on the same haplotype. This haplotype analysis showed that the DRB1 gene as well as five other HLA loci is required for a more comprehensive understanding of the genetic association between HLA and RA than analyzing DRB1 alone.
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Artritis Reumatoide/genética , Antígenos HLA/genética , Artritis Reumatoide/inmunología , Autoanticuerpos/metabolismo , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Prueba de Histocompatibilidad , Humanos , Japón , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Polimorfismo GenéticoRESUMEN
Antibodies against double-stranded DNA (dsDNA) are widely used to diagnose systemic lupus erythematosus (SLE) and evaluate its activity in patients. This study was undertaken to examine the clinical utility of circulating anti-dsDNA antibody-secreting cells for evaluating SLE patients. Anti-dsDNA antibody-secreting cells quantified using an enzyme-linked immunospot assay were detected in the spleen, bone marrow and peripheral blood from MRL/lpr but not in control BALB/c mice. Circulating anti-dsDNA antibody-secreting cells were detected in 29 (22%) of 130 patients with SLE, but in none of 49 with non-SLE connective-tissue disease or 18 healthy controls. The presence of circulating anti-dsDNA antibody-secreting cells was associated with persistent proteinuria, high SLE disease activity index and systemic lupus activity measures, and a high serum anti-dsDNA antibody titre measured with an enzyme-linked immunosorbent assay. The positive predictive value for active disease was 48% for circulating anti-dsDNA antibody-secreting cells versus 17% for serum anti-dsDNA antibodies. A prospective cohort of patients with circulating anti-dsDNA antibodies and inactive SLE showed that the cumulative disease flare-free rate was significantly lower in patients with than without circulating anti-dsDNA antibody-secreting cells (p < 0.001). Circulating anti-dsDNA antibody-secreting cells are a useful biomarker for assessing disease activity in SLE patients.
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Células Productoras de Anticuerpos/inmunología , Autoanticuerpos/inmunología , ADN/inmunología , Lupus Eritematoso Sistémico/inmunología , Adulto , Animales , Biomarcadores/metabolismo , Estudios de Casos y Controles , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Ensayo de Immunospot Ligado a Enzimas , Femenino , Humanos , Lupus Eritematoso Sistémico/fisiopatología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos MRL lpr , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Estudios Retrospectivos , Índice de Severidad de la EnfermedadAsunto(s)
Glucocorticoides/administración & dosificación , Metotrexato/administración & dosificación , Músculo Esquelético/patología , Enfermedades Musculares , Partícula de Reconocimiento de Señal/inmunología , Tacrolimus/administración & dosificación , Edad de Inicio , Autoanticuerpos/sangre , Biopsia/métodos , Niño , Esquema de Medicación , Quimioterapia Combinada/métodos , Humanos , Masculino , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/tratamiento farmacológico , Enfermedades Musculares/inmunología , Enfermedades Musculares/fisiopatología , Necrosis , Resultado del TratamientoRESUMEN
The reactivities to individual U1 small nuclear ribonucleoprotein (snRNP) components and their relationship to clinical features in patients with anti-U1 snRNP antibodies were examined. We evaluated 114 patients with connective tissue disease whose sera were positive for anti-U1 snRNP antibodies, but negative for anti-Sm antibodies. Antibodies to the U1 snRNP polypeptides 70K, A, and C were detected using subunit-specific enzyme-linked immunosorbent assays and antibodies to U1 small nuclear RNA (snRNA) were identified by an immunoprecipitation assay using deproteinized HeLa cell extracts. The clinical features were retrospectively obtained by chart review and prospectively collected after study entry. The pattern of antibody reactivities to U1 snRNP components varied among patients. The frequency of anti-70K, anti-A, anti-C, and anti-U1 snRNA antibodies was 60%, 86%, 74%, and 46%, respectively. There was no relationship between each reactivity and the clinical findings, but the presence of reactivities to increasing numbers of U1 snRNP components was correlated with sclerodactyly, shortness of the sublingual frenulum, esophageal dysfunction, and a lack of persistent proteinurea (p < 0.05 for all comparisons). The detection of autoantibody reactivities to individual components of the U1 snRNP particle is potentially useful for predicting the clinical course in patients with connective tissue disease and anti-U1 snRNP antibodies.
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Autoanticuerpos/inmunología , Enfermedades del Tejido Conjuntivo/inmunología , Ribonucleoproteína Nuclear Pequeña U1/inmunología , Adulto , Anciano , Enfermedades del Tejido Conjuntivo/fisiopatología , Ensayo de Inmunoadsorción Enzimática , Femenino , Células HeLa , Humanos , Inmunoprecipitación/métodos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estudios Retrospectivos , Adulto JovenRESUMEN
To examine the role of genetic factors in development of immune thrombocytopenic purpura (ITP) in association with Helicobacter pylori infection, gene polymorphisms within the loci for human leukocyte antigen class II, interleukin (IL)-1beta (-511), tumor necrosis factor-beta (+252), immunoglobulin (Ig)G1 heavy chain (+643), and Igkappa light chain (+573) were determined in 164 adults with ITP and 75 healthy controls. Of these gene polymorphisms, the IL-1beta (-511) T allele was less frequently detected in H. pylori-infected than in H. pylori-uninfected (58% vs 81%, P = 0.01, odds ratio = 0.31) ITP patients diagnosed before age 50. These findings suggest that a single nucleotide polymorphism within the IL-1beta (-511) may affect susceptibility to early-onset ITP associated with H. pylori infection.
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Infecciones por Helicobacter/genética , Helicobacter pylori/patogenicidad , Interleucina-1beta/genética , Polimorfismo de Nucleótido Simple , Púrpura Trombocitopénica Idiopática/genética , Adolescente , Adulto , Femenino , Predisposición Genética a la Enfermedad , Infecciones por Helicobacter/etiología , Humanos , Interleucina-1beta/inmunología , Persona de Mediana Edad , Púrpura Trombocitopénica Idiopática/complicaciones , Púrpura Trombocitopénica Idiopática/inmunología , Adulto JovenRESUMEN
OBJECTIVE: Patients with systemic sclerosis (SSc) complicated by severe gastrointestinal tract (GIT) dysmotility at an early stage are difficult to treat and mortality is high. To clarify the pathogenesis of GIT involvement, the occurrence of autoantibody was investigated for muscarinic-3 acetylcholine receptor (M3R) in patients with SSc. METHODS: Fourteen patients with severe GIT involvement (malabsorption syndrome and/or pseudo-obstruction) within 2 years of SSc onset (group 1) were enrolled in the present study. Sixty-two patients with SSc without severe GIT involvement within 2 years of onset (group 2) were also recruited, along with 70 healthy control subjects. Using an established enzyme immunoassay (EIA) system detecting autoantibody against the second loop domain of M3R, the presence of an anti-M3R antibody was examined in SSc patients. RESULTS: The mean optical density (OD) titres of group 1 were significantly higher than those of group 2 (0.65 (SD 0.58) vs 0.066 (SD 0.13), p<0.001). The positivity of anti-M3R antibody was significantly higher in group 1 than in group 2 (9/14 vs 3/62, p = 2.5 x 10(-6) by Fisher's exact test). The cutoff OD was calculated from the EIA reaction of the 70 healthy controls (the mean value plus 2 SD was 0.295). CONCLUSION: The findings indicated that anti-M3R antibody very frequently appears in patients with SSc, which is accompanied by severe GIT involvement, suggesting that M3R-mediated enteric cholinergic neurotransmission may provide a pathogenic mechanism for GIT dysmotility in SSc.
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Autoanticuerpos/sangre , Enfermedades Gastrointestinales/inmunología , Motilidad Gastrointestinal/inmunología , Receptor Muscarínico M3/inmunología , Esclerodermia Sistémica/complicaciones , Adulto , Anciano , Anticuerpos Antinucleares/sangre , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/fisiopatología , Femenino , Estudios de Seguimiento , Enfermedades Gastrointestinales/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Esclerodermia Sistémica/inmunología , Esclerodermia Sistémica/fisiopatologíaRESUMEN
OBJECTIVES: To validate the association of a single nucleotide polymorphism (SNP) of the connective tissue growth factor gene (CTGF) with susceptibility to systemic sclerosis (SSc) in the Japanese population. METHODS: 395 Japanese patients with SSc, 115 patients with rheumatoid arthritis and 269 healthy Japanese volunteers were enrolled in the study. An SNP (rs6918698) at -945 bp from the start codon in the promoter region of the CTGF gene was determined by allelic discrimination with the use of a specific TaqMan probe. RESULTS: The G allele showed a significantly higher frequency in patients with SSc than in controls (p<0.001; odds ratio 1.5; 95% confidence interval 1.2 to 1.9). In particular, the clinical subsets of SSc showed a more significant association between the G allele and diffuse cutaneous SSc (p<0.001) and the presence of interstitial lung disease (p<0.001), the presence of anti-topoisomerase I antibody (p<0.001) and anti-U1RNP antibody (p = 0.010). Association analyses using the genotype of the SNP yielded results similar to those of analyses using the allele. CONCLUSIONS: This study confirms the association between an SNP in the CTGF gene and susceptibility to SSc, especially in the presence of diffuse cutaneous SSc, interstitial lung disease and anti-topoisomerase I antibody. The results strongly suggest that this SNP may be a powerful indicator of severe skin and lung involvement in patients with SSc.
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Factor de Crecimiento del Tejido Conjuntivo/genética , Polimorfismo de Nucleótido Simple , Esclerodermia Sistémica/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/genética , Autoanticuerpos/análisis , Niño , Femenino , Fibrosis/etiología , Fibrosis/genética , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Japón , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/genética , Masculino , Persona de Mediana Edad , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/inmunología , Piel/patología , Adulto JovenRESUMEN
OBJECTIVE: To determine the association of distinct clinical subsets with myositis-specific autoantibodies (MSAs) towards anti-155/140-kDa polypeptides [anti-155/140 antibodies (Abs)], anti-140-kDa polypeptides (anti-140 Abs), and anti-aminoacyl tRNA synthetases (ARS Abs) in Japanese patients with dermatomyositis (DM). METHODS: We compared the clinical features and short-term prognoses of 30 DM patients whose serological status included these MSAs. The MSAs were determined by immunoprecipitation. RESULTS: Anti-155/140 Abs (n = 5), anti-140 Abs (n = 8), and anti-ARS Abs (n = 7) did not overlap each other. All of the anti-155/140 Ab-positive patients (n = 5) were complicated by malignancies, as were all of the anti-140 Ab-positive patients (n = 8), who showed rapidly progressive interstitial lung disease (ILD). The survival rate at 6 months from the diagnosis of DM was significantly lower in the anti-140 Ab-positive patients than in the other patients. CONCLUSION: This is the first study to report, in a single cohort of DM patients, that distinct clinical subsets are distributed in an anti-155/140 Ab-positive group, an anti-140 Ab-positive group, or an anti-ARS Ab-positive group. Our data also confirm previous evidence that anti-155/140 Abs are involved in malignancies and that anti-140 Abs are involved in rapidly progressive ILD.
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Aminoacil-ARNt Sintetasas/inmunología , Autoanticuerpos/inmunología , Dermatomiositis/diagnóstico , Dermatomiositis/inmunología , ARN de Transferencia/inmunología , Adulto , Anciano , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Inmunoprecipitación , Japón , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Péptidos/inmunología , Probabilidad , Estadísticas no ParamétricasRESUMEN
OBJECTIVE: To characterize autoreactive T cells against myeloperoxidase (MPO) by generating antigen-specific T-cell clones from patients with microscopic polyangiitis (MPA) and healthy individuals. METHODS: Peripheral blood T cells from five patients with MPA and MPO-anti-neutrophil cytoplasmic antibodies (ANCAs) and from three healthy donors were used to establish MPO-specific T-cell clones by repeated stimulation with recombinant MPO fragments, followed by limiting dilution. The MPO-specific T-cell clones were subjected to analyses for CD4/CD8 phenotype, human leukocyte antigen (HLA) class II restriction, T-cell receptor (TCR) Beta-chain gene usage, complementarity-determining region 3 (CDR3) amino acid sequences, and cytokine expression profiles. RESULTS: We successfully generated seven MPO-specific T-cell clones, five from the patients and two from healthy donors. Two clones recognized the light chain of MPO and five recognized the heavy chain. All the clones were HLA-DR-restricted CD4(+)CD8(-) helper T cells. The T-cell clones shared TCR Beta CDR3 amino acid motifs, depending on their MPO epitope: AGXiXiN was used by clones recognizing the light chain and TGXiS or QGXiE by those recognizing the heavy chain, whether the cells were derived from MPA patients or healthy subjects. However, the cytokine expression profiles of the patients' clones were skewed towards the Th1 phenotype, whereas the healthy individuals' clones remained Th0. CONCLUSIONS: We have characterized MPO-reactive T cells in detail. This information may be useful for elucidating the mechanism of ANCA production and for developing selective therapeutic strategies for MPO-ANCA-associated vasculitis.
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Autoantígenos/inmunología , Poliangitis Microscópica/inmunología , Peroxidasa/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Autoinmunidad , Estudios de Casos y Controles , Línea Celular , Citocinas/metabolismo , Humanos , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
OBJECTIVE: Auto-antibodies to signal recognition particle (SRP) are known to be specific to PM among rheumatic disorders, but the specificity in myopathic diseases remains unclear. The clinical utility of anti-SRP antibody in the differential diagnosis of myopathies has not been studied. The aim of the present study was to elucidate whether detection of anti-SRP antibody can discriminate of PM from muscular dystrophy (MD). METHODS: We report a patient with a childhood onset myopathy, in whom it was clinically difficult to make a differential diagnosis of PM or MD for 21 yrs, despite repeated muscle biopsies. Myositis-specific auto-antibodies to RNA-associated antigens were screened in this particular case as well as in 105 serum samples from various types of MD and 84 from PM patients using RNA immunoprecipitation. The MD and PM serum samples were obtained from different institutions. The presence of anti-SRP antibody was confirmed by RNA immunoprecipitation combined with immunodepletion of SRP from the antigen. RESULTS: Anti-SRP antibody was positive in the present patient, supporting the diagnosis of PM. Anti-SRP antibody was detected in seven (8.3%) patients with PM, but in none of the patients with MD. Myositis-specific auto-antibodies were not detected in any of the patients with MD. CONCLUSION: Anti-SRP antibody is useful for discriminating PM from MD among patients with myopathies.
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Autoanticuerpos/sangre , Distrofias Musculares/diagnóstico , Polimiositis/diagnóstico , Partícula de Reconocimiento de Señal/inmunología , Adulto , Biomarcadores/sangre , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Polimiositis/patologíaRESUMEN
OBJECTIVE: To investigate whether single-nucleotide polymorphisms (SNPs) within the estrogen receptor (ER) alpha and Beta genes are associated with disease susceptibility and clinical presentation in Japanese patients with systemic sclerosis (SSc). METHODS: Three SNPs, ERalpha PvuII T/C, ERalpha XbaI A/G, and ERBeta RsaI G/A, were genotyped using polymerase-chain reaction combined with restriction fragment length polymorphisms in 103 patients with SSc and 56 race-matched healthy controls. The distribution of the individual ER SNPs in SSc patients with or without SSc-related organ involvement and serum antinuclear antibodies was determined. RESULTS: The frequency of the ERalpha XbaI GG phenotype was significantly lower in SSc patients than in healthy controls (2% vs. 13%, p=0.005, odds ratio=0.14, 95%CI 0.03-0.69), and no significant association was detected for the other SNPs. Except in the case of heart involvement accompanying SSc, there was no significant association of the ER SNPs with SSc-related individual organ involvement or with antinuclear antibody profiles. Specifically, the ERalpha PvuII CC phenotype was significantly more frequent among patients with heart involvement compared with those without it (75% vs. 14%, p=0.0001, odds ratio=17.4, 95%CI 3.2-94.8). CONCLUSION: SNPs located within the ERalpha gene may contribute to disease susceptibility and to certain clinical manifestations of SSc patients.
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Receptor alfa de Estrógeno/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Esclerodermia Sistémica/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Receptor beta de Estrógeno/genética , Femenino , Frecuencia de los Genes , Humanos , Japón , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Adulto JovenRESUMEN
OBJECTIVE: To evaluate the activation status of circulating CD4+, CD8+, and gammadelta T cells in patients with active and inactive Behçet's disease (BD). METHODS: We studied 11 subjects with active BD, 28 with inactive BD, and 13 healthy controls. The expression of CD4, CD8, pan-gammadelta, Vdelta1, and Vdelta2 along with the early activation marker CD69 was analyzed by 3-color flow cytometry. RESULTS: Proportions of activated CD8+ and gammadelta T cells were significantly greater in patients with active BD than in those with inactive BD or healthy control subjects, but the proportion of activated CD4+ T cells did not differ among these 3 groups. In addition, significantly greater proportions of the Vdelta1+ and Vdelta2+ gammadelta T-cell subsets were activated in patients with active BD than in those with inactive BD or healthy controls; in active BD, the balance of activation between these subsets favored the Vdelta1+ T cells. No significant differences in these proportions were found between subjects with inactive BD and healthy controls. These findings were observed exclusively in patients with HLA-B51. A comparison of samples from 5 patients taken during active BD and after resolution of BD-related symptoms showed the proportions of activated CD8+ and gammadelta T cells dropped when the patients' BD became inactive. CONCLUSION: CD8+ and gammadelta T cells, rather than CD4+ T cells, were activated in vivo in patients with active BD and HLA-B51, but not in those with inactive BD, suggesting that these potentially cytotoxic T cells play a critical role in BD flares.
Asunto(s)
Síndrome de Behçet/inmunología , Linfocitos T CD8-positivos/inmunología , Antígenos HLA-B/inmunología , Subgrupos de Linfocitos T/inmunología , Adulto , Linfocitos T CD4-Positivos/inmunología , Estudios de Casos y Controles , Femenino , Citometría de Flujo , Antígeno HLA-B51 , Humanos , Activación de Linfocitos , Masculino , Persona de Mediana EdadRESUMEN
T cell proliferative responses to platelet membrane GPIIb-IIIa were examined in 14 patients with chronic immune thrombocytopenic purpura (ITP), 7 systemic lupus erythematosus (SLE) patients with or without thrombocytopenia, and 10 healthy donors. Although peripheral blood T cells from all subjects failed to respond to the protein complex in its native state, reduced GPIIb-IIIa stimulated T cells from three ITP patients and one SLE patient with thrombocytopenia, and tryptic peptides of GPIIb-IIIa stimulated T cells from nearly all subjects. The specificity of the responses for GPIIb-IIIa was confirmed by activation of GPIIb-IIIa-primed T cells by a recombinant GPIIbalpha fragment in secondary cultures. Characterization of T cell response induced by modified GPIIb-IIIa showed that the response was restricted by HLA-DR, the responding T cells had a CD4(+) phenotype, and the proliferation was accelerated only in ITP patients, suggesting in vivo activation of these T cells. In vitro IgG anti-GPIIb-IIIa synthesis in PBMC cultures was induced by modified GPIIb-IIIa specifically in ITP patients with platelet-associated anti-GPIIb-IIIa antibody. Anti-GPIIb-IIIa antibody produced in supernatants was absorbed by incubation with normal platelets. In summary, CD4(+) and HLA-DR-restricted T cells to GPIIb-IIIa are involved in production of anti-platelet autoantibody in ITP patients and are related to the pathogenic process in chronic ITP.