Role of thymocyte differentiation in the progression of primary biliary cirrhosis

原发性胆汁性肝硬变(PBC)是一种自身免疫性肝病，以非增生性破坏性胆管炎为特征，可导致肝硬变和肝功能衰竭。这种疾病在40岁以上的女性中相当常见。在我们之前的研究中，更年期的变化被认为是对各种器官产生自身免疫反应的最重要的触发因素之一。我们认为，血浆雌激素水平的突然下降可能会对这种疾病的进展产生很大影响。因此，在这项研究中，我们探讨了雌激素缺乏小鼠胸腺细胞的发育情况，并证实了CD4+CD8+CD25+胸腺细胞的发育受损。高强度的胸腺细胞受体β的发育障碍可能与自身免疫的发展有关，因为这些细胞足以抑制B细胞的增殖。在为期两年的项目中，我们发现B细胞在雌激素缺乏的小鼠的骨髓和肝脏中的增殖更加显著，外源性雌激素能够显著地抑制B细胞的增殖。因此，我们将同种异体脾细胞移植到雌激素缺乏的小鼠，并诱导慢性胆管炎，以评估胆管上皮的破坏性变化和炎症变化。雌激素缺乏受者的破坏性改变和炎性细胞浸润明显比野生型受者严重。外源性雌激素能有效减轻胆管上皮损伤。根据这些观察结果，我们推测绝经后雌激素缺乏可通过免疫机制严重恶化胆管上皮的破坏。

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.