Role of thymocyte differentiation in the progression of primary biliary cirrhosis

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Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized with nonsuprative destructive cholangitis that results in liver cirrhosis and liver failure. This disease is rather frequent in female older than 40s. In our previous study, menopausal changes were suggested as one of the most important trigger for the development of autoimmune responses to a variety of organs. Abrupt decrease in plasma estrogen levels may affect so much on the progression of this disease, we believe. Thus in this study, we inquired the development of thymocytes in estrogen deficient mice and proved impaired development of CD4+CD8+CD25+ thymocytes. Impaired development of thymocytes with TCR β in high intensity could be involved in the development of autoimmunity as these cells are potent enough to suppress B cell proliferation.In the two-year project, we showed B cell are more prominently proliferating in bone marrow and in the liver in estrogen deficient mice and exogeneous estrogens are able to attenuate B cell proliferation significantly. Therefore, we transferred allogeneic spleen cells to estrogen deficient mice and induced chronic cholangitis for assessing destructive changes of biliary epithelium and inflammatory changes. Destructive changes and inflammatory cell infiltration were apparently more severe in estrogen-deficient recipients than in wild type recipients. Exogenously administered estrogens were very potent to attenuate damages of biliary epithelium. From these observations we deduce that destruction of biliary epithelium via immunological mechanism could be deteriorated profoundly by estrogen deficiency in postmenopausal stage.