IFNβ accelerates autoimmune type 1 diabetes in nonobese diabetic mice and breaks the tolerance to β cells in nondiabetes-prone mice
IFNβ accelerates autoimmune type 1 diabetes in nonobese diabetic mice and breaks the tolerance to β cells in nondiabetes-prone mice
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DOI：
10.4049/jimmunol.173.11.6667
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发表时间：
2004-12-01
影响因子：
4.4
通讯作者：
Vives-Pi, M
中科院分区：
文献类型：
--
作者：
Alba, A;Puertas, MC;Vives-Pi, M
遗传和环境因素是决定1型糖尿病的病因。已经提出病毒作为触发环境事件，并且已经报道了一些证据：1型IFN存在于糖尿病患者的胰腺中，并且在β细胞中表达这些细胞因子的转基因小鼠发展糖尿病。为了确定IFN β在糖尿病中的作用，我们研究了在β细胞中表达人IFN β的转基因小鼠。发现自身免疫特征：MHC I类胰岛高表达，T和B细胞浸润胰岛和淋巴细胞转移疾病。此外，β 2-微球蛋白、前胰岛素原和胰高血糖素在胸腺中的表达不受IFN β的影响，因此表明该疾病是由IFN β的局部作用引起的，其强度足以打破外周对β细胞的耐受性。这是第一次报告的一代NOD（自发性自身免疫性糖尿病模型）和nonobese-resistant（其同源抗性）转基因小鼠表达的I型干扰素的胰岛：转基因NOD和nonobese-resistant小鼠发展加速自身免疫性糖尿病的发病率高。这些结果表明，抗病毒细胞因子IFN β破坏了对β细胞的外周耐受，影响了胰岛炎的进展，并有助于糖尿病和非糖尿病易感小鼠的自身免疫。
Genetic and environmental factors are decisive in the etiology of type 1 diabetes. Viruses have been proposed as a triggering environmental event and some evidences have been reported: type 1 IFNs exist in the pancreata of diabetic patients and transgenic mice expressing these cytokines in beta cells develop diabetes. To determine the role of IFNbeta in diabetes, we studied transgenic mice expressing human IFNbeta in the beta cells. Autoimmune features were found: MHC class I islet hyperexpression, T and B cells infiltrating the islets and transfer of the disease by lymphocytes. Moreover, the expression of beta(2)-microglobulin, preproinsulin, and glucagon in the thymus was not altered by IFNbeta, thus suggesting that the disease is caused by a local effect of IFNbeta, strong enough to break the peripheral tolerance to beta cells. This is the first report of the generation of NOD (a model of spontaneous autoimmune diabetes) and nonobese-resistant (its homologous resistant) transgenic mice expressing a type I IFN in the islets: transgenic NOD and nonobese-resistant mice developed accelerated autoimmune diabetes with a high incidence of the disease. These results indicate that the antiviral cytokine IFNbeta breaks peripheral tolerance to beta cells, influences the insulitis progression and contributes to autoimmunity in diabetes and nondiabetes- prone mice.