Department of Immunology, Institute of Biomedicine, University of Tartu, Ravila 19, Tartu 50411, Estonia; Centre for Translational Medicine, University of Tartu, Ravila 19, Tartu 50411, Estonia.
Hum Immunol. 2013 Oct;74(10):1251-7. doi: 10.1016/j.humimm.2013.07.007. Epub 2013 Jul 31.
Type-1 diabetes (T1D) is caused by T-cell mediated autoimmune reaction directed against the insulin-secreting beta cells. We hypothesized that in addition to antigen/MHC recognition the co-stimulatory B7 and CD28 pathway is also strongly affected in T1D. CD80, CD86, CD28, CTLA4, ICOS and CD25 mRNA expression was characterized in 49 newly diagnosed young T1D patients (mean age 11 ± 5 years, 25 male/24 women) and 31 controls (mean age 14 ± 7 years, 14 male/17 women). In addition, polymorphisms in CTLA4 (rs231806, rs231775, rs3087243) were genotyped and soluble CTLA4 plasma levels measured by ELISA. T1D patients presented with higher peripheral blood expression levels of CD80 (Mann-Whitney U-test, p=0.0001) and lower ICOS levels compared to healthy controls (Glm adjusted for age, p=0.0004). CD80 expression in T1D patients correlated with expression of two CTLA4 splice variants (Spearman's rank correlation, rho=0.56, p=0.0002 for sCTLA4; rho=0.61, p<0.0001 for flCTLA4). In controls, CD80 expression correlated with CD25 expression (Spearman's rank correlation, rho=0.57, p=0.002). A strong correlation was observed between sCTLA4 and flCTLA4 (Spearman's rank correlation, rho=0.94, p<0.0001). We also found a tendency that the CTLA4 +49A/G polymorphism influenced sCTLA4 mRNA expression in T1D individuals and was lowest in individuals with the GG genotype (Mann-Whitney U-test, p=0.039). However, we could not identify associations between gene expression and plasma levels of sCTLA4. To summarize, we expect that newly diagnosed T1D among children and adolescents is associated with activation of CD80 and CTLA4 in peripheral blood. Additional studies will be needed to elucidate the role of CD80/CTLA4 signaling in T1D.
1 型糖尿病（T1D）是由针对胰岛素分泌β细胞的 T 细胞介导的自身免疫反应引起的。我们假设，除了抗原/MHC 识别之外，共刺激 B7 和 CD28 途径在 T1D 中也受到强烈影响。在 49 名新诊断的年轻 T1D 患者（平均年龄 11 ± 5 岁，25 名男性/24 名女性）和 31 名对照者（平均年龄 14 ± 7 岁，14 名男性/17 名女性）中，我们对 CD80、CD86、CD28、CTLA4、ICOS 和 CD25 mRNA 的表达进行了特征描述。此外，通过 ELISA 测定了 CTLA4（rs231806、rs231775、rs3087243）的多态性和可溶性 CTLA4 血浆水平。与健康对照组相比，T1D 患者外周血中 CD80 的表达水平更高（Mann-Whitney U 检验，p=0.0001），而 ICOS 水平更低（Glm 调整年龄，p=0.0004）。T1D 患者的 CD80 表达与两种 CTLA4 剪接变体的表达相关（Spearman 秩相关，rho=0.56，p=0.0002 用于 sCTLA4；rho=0.61，p<0.0001 用于 flCTLA4）。在对照组中，CD80 表达与 CD25 表达相关（Spearman 秩相关，rho=0.57，p=0.002）。sCTLA4 和 flCTLA4 之间存在很强的相关性（Spearman 秩相关，rho=0.94，p<0.0001）。我们还发现 CTLA4 +49A/G 多态性倾向于影响 T1D 个体中 sCTLA4 mRNA 的表达，并且 GG 基因型个体的 sCTLA4 表达最低（Mann-Whitney U 检验，p=0.039）。然而，我们无法确定基因表达与 sCTLA4 血浆水平之间的关联。总之，我们预计儿童和青少年新诊断的 T1D 与外周血中 CD80 和 CTLA4 的激活有关。需要进一步的研究来阐明 CD80/CTLA4 信号在 T1D 中的作用。
