Study on the Pathogenesis of Type 1 Diabetes Mellitus

The pathogenic role of abnormal expression of major histocompatiManagement complex （MHC） antigens on pancreatic beta cells was studed using molecular biological techniques。We first tested which cytokines could induce MHC antigen expression on rat inoma cell line RINm5F。通过北方分析测试了I类和II类MHC分子的信使RNA。结果显示，在细胞因子的缺失中， 1）第一类MHC抗原mRNA被合理地表达，但2）第二类MHC mRNA在RINm 5 F细胞中未被检测到。I类mRNA对任何干扰素-伽马（IFNgamma）或IFNgamma加肿瘤坏死因子-α（TNFalpha）的反应都有所增加。在对任何细胞因子的挑战之后，发现了第二类mRNA。在另一方面，胰岛素mRNA在每个IFN γ或IFN γ + TNalpha的存在中被降解，我们第二次研究了MHC抗原表达对beta细胞功能的影响，一个名为胰岛素保密能力的影响。RINm 5 F细胞被转染为人类MHC类I抗原（HLA-Cw 2）基因和十二克隆，具有不同程度的表达的转染。胰岛素保密能力的克隆人在反应中与葡萄糖的数量负相关，这些结果表明，MHC抗原在beta细胞中的表达是由各种细胞因子控制的，而胰岛素保密能力是由MHC抗原在beta细胞中的表达所抵消的。这一建议是MHC抗原表达在1型糖尿病中的重要性。

The pathogenic role of abnormal expression of major histocompatibility complex (MHC) antigens on pancreatic beta cells was studied using molecular biological techniques.We first tested which cytokines could induce MHC antigen expression on rat insulinoma cell line RINm5F. Messenger RNAs of class I and class II MHC molecules were examined by Northern analysis. The result showed that, in the absence of cytokines, 1) class I MHC antigen mRNA was constitutively expressed but 2) class II MHC mRNA was not detected in RINm5F cells. Class I mRNA was increased in response to either interferonーgamma (IFNgamma) or IFNgamma plus tumor necrosis factorーalpha (TNFalpha). However, no class II mRNA was detected after the challenge of any cytokines. On the other hand, insulin mRNA was decreased in the presence of either IFNgamma or IFNgamma+TNFalpha.We secondly examined the effect of MHC antigen expression on beta cell function, namely insulin secreting capacity. RINm5F cells were transfected with human MHC class I antigen (HLA-Cw2) gene and twelve clones with different degrees of expression of the transfectant were obtained. Insulin secreting capacity of the clones in response to glucose was negatively correlated with the amount of class I MHC antigen expressed.These results indicate that the expression of MHC antigen in beta cells is controlled by various cytokines and that insulin secreting capacity is impaired by the expression of MHC antigens in beta cells. This suggests the importance of MHC antigen expression in the pathogenesis of Type 1 diabetes mellitus.