RESUMO
The glucocorticoid-induced tumour necrosis factor (TNF)-receptor (GITR) affects the functions of regulatory T (T(reg)) and effector T (T(eff)) cells, but the significance of this phenomenon is still unclear. To examine the association of single nucleotide polymorphisms (SNPs) in the GITR gene with the expression of GITR molecules on T cells and with the pathological conditions in patients with autoimmune thyroid disease (AITD), we examined the frequencies of four candidate SNPs in AITD patients and healthy volunteers by restriction enzyme analysis and direct sequence analyses. We also analysed the GITR expression on peripheral T(reg) and T(eff) cells in AITD patients by three-colour flow cytometry. The CC genotype in the rs3753348 C/G SNP was significantly more frequent in patients with mild Hashimoto's disease (HD) than in those with severe HD [P = 0·0117, odds ratio (OR) = 3·13]. The AA genotype in the rs2298213 A/G SNP was significantly more frequent in patients with mild HD than in patients with severe HD (P = 0·010, OR = 4·43). All patients and healthy individuals had the GG genotype in rs60038293 A/G and rs11466696 A/G SNPs. The proportions of GITR(+) cells in T(reg) and T(eff) cells were significantly higher in AITD patients with the CC genotype of the rs3753348 SNP than in those with the GG genotype (P = 0·004 and P = 0·011, respectively). In conclusion, the rs3753348 C/G SNP in the GITR is associated with HD prognosis and expression on T(reg) and T(eff) cells.
Assuntos
Proteína Relacionada a TNFR Induzida por Glucocorticoide/genética , Doença de Graves/genética , Doença de Hashimoto/genética , Polimorfismo de Nucleotídeo Único , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Adulto , Sequência de Bases , Feminino , Citometria de Fluxo , Frequência do Gene , Genótipo , Proteína Relacionada a TNFR Induzida por Glucocorticoide/biossíntese , Doença de Graves/imunologia , Doença de Hashimoto/diagnóstico , Doença de Hashimoto/imunologia , Humanos , Masculino , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Prognóstico , Mapeamento por Restrição , Análise de Sequência de DNA , Linfócitos T Reguladores/patologiaRESUMO
The severity of Hashimoto's disease (HD) and intractability (or inducibility to remission) of Graves' disease (GD) varies among patients. Forkhead box P3 (FoxP3) is a crucial regulatory factor for the development and function of regulatory T (T(reg) ) cells, and deficiency of the FoxP3 gene (FOXP3) suppresses the regulatory function of T(reg) cells. To clarify the association of the functional polymorphisms of the FOXP3 with the prognosis of GD and HD, we genotyped -3499A/G, -3279C/A and -2383C/T polymorphisms in FOXP3 gene obtained from 38 patients with severe HD, 40 patients with mild HD, 65 patients with intractable GD, in whom remission was difficult to induce, 44 patients with GD in remission and 71 healthy volunteers. The -3279CA genotype was more frequent in patients with GD in remission than in patients with intractable GD, and the -3279AA genotype, which correlates to defective transcription of FOXP3, was absent in patients with GD in remission. The -2383CC genotype was more frequent in patients with severe HD than in those with mild HD. In conclusion, the -3279A/C polymorphism is related to the development and intractability of GD and the -2383CC genotype to the severity of HD.