IMMUNE-RESPONSE TO GLUTAMIC-ACID DECARBOXYLASE CORRELATES WITH INSULITIS IN NONOBESE DIABETIC MICE
IMMUNE-RESPONSE TO GLUTAMIC-ACID DECARBOXYLASE CORRELATES WITH INSULITIS IN NONOBESE DIABETIC MICE
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DOI：
10.1038/366072a0
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发表时间：
1993-11-04
期刊：
影响因子：
64.8
通讯作者：
MCDEVITT, HO
中科院分区：
文献类型：
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作者：
TISCH, R;YANG, XD;MCDEVITT, HO
了解器官特异性自身免疫性疾病的自身抗原靶点对于了解其发病机制至关重要。胰岛素依赖型糖尿病（IDDM）是一种自身免疫性疾病，其特征为胰岛淋巴细胞浸润（胰岛炎）和分泌胰岛素的胰腺β细胞破坏1。几种β细胞蛋白已被鉴定为自身抗原，但它们在糖尿病发生过程中的重要性尚不清楚2。非肥胖糖尿病（NOD）小鼠是自发性IDDM 3的鼠模型。 在这里，我们确定的时间序列的T-细胞和抗体反应NOD小鼠的一组五个鼠β-细胞抗原，并发现特异性的谷氨酸脱羧酶（GAD）的两种亚型的抗体和T-细胞反应，首先检测到4周龄的NOD小鼠。这种GAD特异性反应与对胰岛提取物的最早可检测反应以及胰岛炎的发作相一致。此外，接受胸腺内注射GAD 65的NOD小鼠除了保持无糖尿病之外，还表现出对GAD和该组的其余部分的T细胞增殖应答显著降低。这些结果表明，对β细胞抗原的自发反应在生命的早期就出现了，并且抗GAD免疫反应在此期间的疾病过程中起着关键作用。
KNOWING the autoantigen target(s) in an organ-specific autoimmune disease is essential to understanding its pathogenesis. Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease characterized by lymphocytic infiltration of the islets of Langerhans (insulitis) and destruction of insulin-secreting pancreatic beta-cells1. Several beta-cell proteins have been identified as autoantigens, but their importance in the diabetogenic process is not known2. The non-obese diabetic (NOD) mouse is a murine model for spontaneous IDDM3. Here we determine the temporal sequence of T-cell and antibody responses in NOD mice to a panel of five murine beta-cell antigens and find that antibody and T-cell responses specific for the two isoforms of glutamic acid decarboxylase (GAD) are first detected in 4-week-old NOD mice. This GAD-specific reactivity coincides with the earliest detectable response to an islet extract, and with the onset of insulitis. Furthermore, NOD mice receiving intrathymic injections of GAD65 exhibit markedly reduced T-cell proliferative responses to GAD and to the rest of the panel, in addition to remaining free of diabetes. These results indicate that the spontaneous response to beta-cell antigens arises very early in life and that the anti-GAD immune response has a critical role in the disease process during this period.