RESUMEN
Type-1 diabetes (T1D) is a heterogeneous autoimmune disease, and there are pathogenetic differences between young- and adult-onset T1D patients. We hypothesized that the expressions of genes involved in costimulatory immune system pathways in peripheral blood are differently regulated in young- and adult-onset T1D. Study group I consisted of 80 children, adolescents, and young adults (age range 1.4-21.4 y; 31 controls and 49 T1D patients). Study group II consisted of 48 adults (age range 22.0-78.4 y; 30 controls and 18 T1D patients). The mRNA expression levels of CD86, CD28, CD25, CD226, CD40, BTLA, GITR, PDCD1, FoxP3, TGF-ß, ICOS, sCTLA4, flCTLA4, and CD80 were measured in peripheral blood. Genetic polymorphisms (HLA haplotypes; rs231806, rs231775, and rs3087243 in CTLA4; rs763361 in CD226; and rs706778 in CD25) and T1D-associated autoantibodies were analyzed. In group I, there was significantly lower expression of CD226 in T1D patients than in the controls. In group II, there were significantly higher expression levels of CD86 and TGF-ß in T1D patients than in the controls. In the T1D patients in group I, the upregulated CD80 expression correlated with the expression of both CTLA4 splice variants (sCTLA4 and flCTLA4). In contrast, in group II, upregulated CD86 correlated with TGF-ß and CD25. In group I, the inhibitory CD80-CTLA4 pathway was activated, whereas, in group II, the activation CD86-CD28 pathway and TGF-ß production were activated. These results emphasize the differences between young-onset and adult-onset T1D in the regulation of costimulatory pathways. These differences should be considered when developing novel treatments for T1D.
Asunto(s)
Antígenos B7/sangre , Antígenos CD28/sangre , Diabetes Mellitus Tipo 1/sangre , Adolescente , Adulto , Anciano , Antígenos B7/genética , Antígenos CD28/genética , Estudios de Casos y Controles , Niño , Preescolar , Diabetes Mellitus Tipo 1/diagnóstico , Femenino , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Transcriptoma , Adulto JovenRESUMEN
Type 1 diabetes (T1D) is an autoimmune disease that is thought to be triggered by environmental factors in genetically susceptible individuals. Enteroviruses have been mentioned as the most probable induction component of the disease. Nevertheless, the literature is controversial regarding the association of T1D with viral infection and first-line antiviral defence components, for example type I interferons (IFNs). Our aim was to test the hypothesis that an abnormality in IFN-stimulated gene patterns may cause a failure in immunological tolerance and, thereby, initiate T1D as an autoimmune disorder. We studied material from 64 T1D and 36 control subjects, divided into two age groups: <10 years and ≥10 years old. Using a relative gene expression method, we observed a lower expression of interferon-induced helicase 1 (IFIH1) and other type I IFN-induced genes in the blood cells of T1D subjects, especially subjects under 10 years old, in spite of their higher IFN levels as measured by the pSTAT1-inducing capacity of their sera. Likewise, freshly purified CpG-stimulated cells from T1D patients showed significantly lower upregulation of IFN-induced genes, that is IFIH1 and CXCL10, compared to cells from the control group. The identified dysregulation in the IFN-α-induced antiviral response in T1D patients, especially in early childhood, could be one of the factors affecting T1D development.