Division of Paediatrics & Diabetes Research Centre, Department of Molecular & Clinical Medicine, Linköping University, Linköping, Sweden.
Diabetes Metab Res Rev. 2012 Jan;28(1):84-96. doi: 10.1002/dmrr.1286.
High levels of soluble cytotoxic T-lymphocyte antigen 4 (soluble CTLA-4), an alternative splice form of the regulatory T-cell (Treg) associated CTLA-4 gene, have been associated with type 1 diabetes (T1D) and other autoimmune diseases, such as Grave's disease and myasthenia gravis. At the same time, studies have shown soluble CTLA-4 to inhibit T-cell activation through B7 binding. This study aimed to investigate the role of soluble CTLA-4 in relation to full-length CTLA-4 and other Treg-associated markers in T1D children and in individuals with high or low risk of developing the disease.
T1D children were studied at 4 days, 1 and 2 years after diagnosis in comparison to individuals with high or low risk of developing the disease. Isolated peripheral blood mononuclear cells were stimulated with the T1D-associated glutamic acid decarboxylase 65 and phytohaemagglutinin. Subsequently, soluble CTLA-4, full-length CTLA-4, FOXP3 and TGF-β mRNA transcription were quantified and protein concentrations of soluble CTLA-4 were measured in culture supernatant and sera.
Low protein concentrations of circulating soluble CTLA-4 and a positive correlation between soluble CTLA-4 mRNA and protein were seen in T1D, in parallel with a negative correlation in healthy subjects. Further, low levels of mitogen-induced soluble CTLA-4 were accompanied by low C-peptide levels. Interestingly, low mitogen-induced soluble CTLA-4 mRNA and low TGF-β mRNA expression were seen in high risk individuals, suggesting an alteration in activation and down-regulating immune mechanisms during the pre-diabetic phase.
高水平的可溶性细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4），一种调节性 T 细胞（Treg）相关 CTLA-4 基因的替代剪接形式，与 1 型糖尿病（T1D）和其他自身免疫性疾病，如格雷夫斯病和重症肌无力有关。与此同时，研究表明可溶性 CTLA-4 通过与 B7 结合抑制 T 细胞活化。本研究旨在探讨可溶性 CTLA-4 与全长 CTLA-4 及其他 Treg 相关标志物在 T1D 患儿及高危和低危个体中的作用。
在诊断后 4 天、1 年和 2 年时，对 T1D 患儿与高危和低危个体进行比较。用与 T1D 相关的谷氨酸脱羧酶 65 和植物血凝素刺激分离的外周血单核细胞。随后，定量检测可溶性 CTLA-4、全长 CTLA-4、FOXP3 和 TGF-β 的 mRNA 转录，测量培养上清液和血清中可溶性 CTLA-4 的蛋白浓度。
T1D 患儿中循环可溶性 CTLA-4 蛋白浓度较低，与健康个体呈负相关，可溶性 CTLA-4 mRNA 与蛋白呈正相关。此外，诱导的可溶性 CTLA-4 水平较低与 C 肽水平较低相关。有趣的是，高危个体中诱导的可溶性 CTLA-4 mRNA 和 TGF-β mRNA 表达水平较低，提示在糖尿病前期阶段，激活和下调免疫机制发生改变。
