RESUMEN
OBJECTIVE: T cell receptor (TCR) diversity determines the autoimmune responses in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and is closely associated with autoimmune diseases prognosis and prevention. However, the characteristics of variations in TCR diversity and their clinical significance is still unknown. Large series of patients must be studied in order to elucidate the effects of these variations. METHODS: Peripheral blood from 877 SLE patients, 206 RA patients and 439 healthy controls (HC) were amplified for the TCR repertoire and sequenced using a high-throughput sequencer. We have developed a statistical model to identify disease-associated TCR clones and diagnose autoimmune diseases. RESULTS: Significant differences were identified in variable (V), joining (J) and V-J pairing between the SLE or RA and HC groups. These differences can be utilised to discriminate the three groups with perfect accuracy (V: area under receiver operating curve > 0.99). One hundred ninety-eight SLE-associated and 53 RA-associated TCRs were identified and used for diseases classification by cross validation with high specificity and sensitivity. Disease-associated clones showed common features and high similarity between both autoimmune diseases. SLE displayed higher TCR heterogeneity than RA with several organ specific properties. Furthermore, the association between clonal expansion and the concentration of disease-associated clones with disease severity were identified, and pathogen-related TCRs were enriched in both diseases. CONCLUSIONS: These characteristics of the TCR repertoire, particularly the disease-associated clones, can potentially serve as biomarkers and provide novel insights for disease status and therapeutical targets in autoimmune diseases.
Asunto(s)
Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Adulto , Análisis de Varianza , Artritis Reumatoide/sangre , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Autoinmunidad , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lupus Eritematoso Sistémico/sangre , Masculino , Persona de Mediana Edad , Receptores de Antígenos de Linfocitos T/metabolismo , Valores de Referencia , Medición de Riesgo , Estadísticas no ParamétricasRESUMEN
MicroRNAs (miRNAs) play important roles in the pathogenesis of systemic lupus erythematosus (SLE). Here, we investigated the serum miRNAs expression profiles in the serum of SLE and healthy controls, and identified the potential serum biomarkers for SLE. We screened and identified the differentially expressed miRNAs such as miR-371b-5p, miR-5100, miR-146a-5p among active SLE, inactive SLE and healthy controls based on the miRNAs expression array. Furthermore, the results of RT-qPCR confirmed that miR-371b-5p and miR-5100 expression was different among active SLE, inactive SLE and healthy controls. Moreover, we performed in a large cohort which we validated that expression of miR-371b-5p and miR-5100 was increased significantly in the serum of SLE compared with healthy controls and rheumatoid arthritis (RA), and was also higher in active SLE than that in inactive SLE. In addition, we found the associations between the expression levels of miR-371b-5p and miR-5100 and these clinical parameters of SLE. These results suggested that miR-371b-5p and miR-5100 may act as serum biomarkers for SLE.
Asunto(s)
Lupus Eritematoso Sistémico/metabolismo , MicroARNs/metabolismo , Adulto , Artritis Reumatoide/genética , Artritis Reumatoide/metabolismo , Biomarcadores/metabolismo , Estudios de Casos y Controles , Femenino , Humanos , Lupus Eritematoso Sistémico/genética , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
OBJECTIVE: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease with limited reliable diagnostic biomarkers. We investigated whether gene methylation could meet sensitivity and specificity criteria for a robust biomarker. METHODS: IFI44L promoter methylation was examined using DNA samples from a discovery set including 377 patients with SLE, 358 healthy controls (HCs) and 353 patients with rheumatoid arthritis (RA). Two independent sets including 1144 patients with SLE, 1350 HCs, 429 patients with RA and 199 patients with primary Sjögren's syndrome (pSS) were used for validation. RESULTS: Significant hypomethylation of two CpG sites within IFI44L promoter, Site1 (Chr1: 79â 085â 222) and Site2 (Chr1: 79â 085â 250; cg06872964), was identified in patients with SLE compared with HCs, patients with RA and patients with pSS. In a comparison between patients with SLE and HCs included in the first validation cohort, Site1 methylation had a sensitivity of 93.6% and a specificity of 96.8% at a cut-off methylation level of 75.5% and Site2 methylation had a sensitivity of 94.1% and a specificity of 98.2% at a cut-off methylation level of 25.5%. The IFI44L promoter methylation marker was also validated in an European-derived cohort. In addition, the methylation levels of Site1 and Site2 within IFI44L promoter were significantly lower in patients with SLE with renal damage than those without renal damage. Patients with SLE showed significantly increased methylation levels of Site1 and Site2 during remission compared with active stage. CONCLUSIONS: The methylation level of IFI44L promoter can distinguish patients with SLE from healthy persons and other autoimmune diseases, and is a highly sensitive and specific diagnostic marker for SLE.