Expression-Based Genome-Wide Association Study Links Vitamin D-Binding Protein With Autoantigenicity in Type 1 Diabetes.
Expression-Based Genome-Wide Association Study Links Vitamin D-Binding Protein With Autoantigenicity in Type 1 Diabetes.
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作者：
Kodama K;Zhao Z;Toda K;Yip L;Fuhlbrigge R;Miao D;Fathman CG;Yamada S;Butte AJ;Yu L
1型糖尿病（T1 D）是由识别胰岛抗原并破坏产生胰岛素的β细胞的自身反应性T细胞引起的。这种攻击是由于对自身抗原耐受性的破坏，这是由胸腺和胰腺淋巴结（PLN）中的异位抗原表达控制的。已知涉及的自身抗原包括一组胰岛蛋白，如胰岛素、GAD 65、IA-2和ZnT 8。在试图确定额外的抗原蛋白，我们进行了基于表达的全基因组关联研究，使用来自T1 D小鼠胸腺和PLN的118个阵列的微阵列数据。我们根据发现重复差异表达的可能性和胰岛的组织特异性程度对所有16，089个蛋白质编码基因进行了排名。维生素D结合蛋白（VDBP）是最重要的自身抗原候选者。与对照刺激相比，T细胞增殖测定显示出对VDBP更强的T细胞反应性。T1 D患者（n = 331）的血清抗VDBP自身抗体（VDBP-Ab）水平和频率高于健康对照受试者（n = 77）。血清维生素D水平与VDBP抗体水平呈负相关，其中T1 D在冬季发展的患者。免疫组织化学定位显示VDBP特异性表达于胰岛α细胞。我们认为VDBP可能是T1 D的自身抗原。
Type 1 diabetes (T1D) is caused by autoreactive T cells that recognize pancreatic islet antigens and destroy insulin-producing β-cells. This attack results from a breakdown in tolerance for self-antigens, which is controlled by ectopic antigen expression in the thymus and pancreatic lymph nodes (PLNs). The autoantigens known to be involved include a set of islet proteins, such as insulin, GAD65, IA-2, and ZnT8. In an attempt to identify additional antigenic proteins, we performed an expression-based genome-wide association study using microarray data from 118 arrays of the thymus and PLNs of T1D mice. We ranked all 16,089 protein-coding genes by the likelihood of finding repeated differential expression and the degree of tissue specificity for pancreatic islets. The top autoantigen candidate was vitamin D–binding protein (VDBP). T-cell proliferation assays showed stronger T-cell reactivity to VDBP compared with control stimulations. Higher levels and frequencies of serum anti-VDBP autoantibodies (VDBP-Abs) were identified in patients with T1D (n = 331) than in healthy control subjects (n = 77). Serum vitamin D levels were negatively correlated with VDBP-Ab levels in patients in whom T1D developed during the winter. Immunohistochemical localization revealed that VDBP was specifically expressed in α-cells of pancreatic islets. We propose that VDBP could be an autoantigen in T1D.