Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice
Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice
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DOI：
10.1038/nature03523
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发表时间：
2005-05-12
期刊：
影响因子：
64.8
通讯作者：
Eisenbarth, GS
中科院分区：
文献类型：
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作者：
Nakayama, M;Abiru, N;Eisenbarth, GS
关于自发性自身免疫性糖尿病发病机制的一个基本问题是是否存在主要自身抗原。对于1型糖尿病，很明显在人类和动物模型中多种胰岛分子是自身免疫的靶点（1,2）。目前尚不清楚这些靶点分子中是否有任何一种对胰岛β细胞的破坏是必不可少的。在此我们表明，胰岛素原/胰岛素分子具有一个序列，它是导致非肥胖糖尿病（NOD）小鼠糖尿病的自身免疫的主要靶点。我们在NOD小鼠中创建了胰岛素1和胰岛素2基因敲除小鼠，并结合一个突变的胰岛素原转基因（其中B链上的第16位残基被改变为丙氨酸）。这种突变消除了一系列主要的胰岛素自身反应性NOD T细胞克隆的T细胞刺激（3）。与含有至少一个天然胰岛素基因拷贝的小鼠相反，仅具有改变的胰岛素的雌性小鼠没有产生胰岛素自身抗体、胰岛炎或自身免疫性糖尿病。我们认为胰岛素原是NOD小鼠的一种主要自身抗原，并推测具有明显的主要组织相容性复合体（MHC）疾病限制性的器官特异性自身免疫疾病可能具有特定的主要自身抗原。
A fundamental question about the pathogenesis of spontaneous autoimmune diabetes is whether there are primary autoantigens. For type 1 diabetes it is clear that multiple islet molecules are the target of autoimmunity in man and animal models(1,2). It is not clear whether any of the target molecules are essential for the destruction of islet beta cells. Here we show that the proinsulin/ insulin molecules have a sequence that is a primary target of the autoimmunity that causes diabetes of the non-obese diabetic ( NOD) mouse. We created insulin 1 and insulin 2 gene knockouts combined with a mutated proinsulin transgene ( in which residue 16 on the B chain was changed to alanine) in NOD mice. This mutation abrogated the T-cell stimulation of a series of the major insulin autoreactive NOD T-cell clones(3). Female mice with only the altered insulin did not develop insulin autoantibodies, insulitis or autoimmune diabetes, in contrast with mice containing at least one copy of the native insulin gene. We suggest that proinsulin is a primary autoantigen of the NOD mouse, and speculate that organ-restricted autoimmune disorders with marked major histocompatibility complex (MHC) restriction of disease are likely to have specific primary autoantigens.