Study on the Pathogenesis of Type 1 Diabetes Mellitus

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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.