ROLE OF CD40-CD40 LIGAND IN PRIMARY BILIARY CIRRHOSIS

描述（改编自应用程序） 原发性胆汁性肝硬化是一种慢性自身免疫性肝病， 通过小的和中等大小的肝内胆管的炎性破坏， 导致胆汁淤积，然后是纤维化、肝硬化及其并发症。 虽然病因不明，但胆管周围的T细胞是 胆管破坏的可能介质。其他细胞类型 门静脉浸润，包括巨噬细胞和B细胞，可能有助于 自身免疫过程然而，这些细胞的交流方式 并共同导致胆管病变的原因尚不清楚。的假设 这个计划是T细胞协调免疫攻击， 胆管细胞通过CD 40配体向肝脏中的其他细胞发出信号。 具体地，通过肝脏中活化的T细胞表达CD 40配体， 刺激B细胞以增加免疫球蛋白的产生;激活 巨噬细胞产生IL-12，这导致T辅助细胞转移到 Th 1表型和随后的IL-2和IFN-γ产生;并诱导 胆管细胞以增加的速率进行凋亡。这一假设将 通过CD 40配体表达水平的相关性分析进行检测 PBC患者肝脏中CD 40-CD 40的潜在后果 配体相互作用;如免疫球蛋白和细胞因子的上调 产生和胆管细胞凋亡。表达cd 40和cd 40 l 将通过放射学定位于肝脏。这些 以患者为导向的研究将辅以体外实验， 研究CD 40配体诱导胆管细胞凋亡的作用。这些研究将 提供对T细胞在PBC发病机制中的作用的深入了解，并提供 有助于开发新的治疗方法。

DESCRIPTION (adapted from the application) Primary biliary cirrhosis is a chronic autoimmune liver disease characterized by inflammatory destruction of small and medium sized intrahepatic bile ducts, leading to cholestasis, then fibrosis, cirrhosis, and its complications. Although the etiology is unknown, T cells that surround the bile ductules are the likely mediators of bile duct destruction. Other cell types within the portal infiltrate, including macrophages and B cells, probably contribute to this autoimmune process. However, the manner in which these cells communicate and collaborate to cause bile duct lesions is not understood. The hypothesis of this proposed project is that T cells orchestrate the immune attack on cholangiocytes via signaling to other cells in the liver through CD40 ligand. Specifically, expression of CD40 ligand by activated T cells in the liver stimulates B cells to increase production of immunoglobulins; activates macrophages to produce IL-12, which leads to a shift of T helper cells to the Th1 phenotype and subsequent IL-2 and IFN-gamma production; and induces cholangiocytes to undergo apoptosis at an increased rate. This hypothesis will be tested by a correlative analysis of the level of expression of CD40 ligand in the liver of PBC patients with the potential consequences of CD40-CD40 ligand interaction; such as upregulation of immunoglobulin and cytokine production, and apoptosis of cholangiocytes. Expression of CD40 and CD40 ligand will be localized in the liver with immunohistochernistry. These patient-oriented studies will be supplemented by in vitro experiments designed to study CD40-ligand induced apoptosis in cholangiocytes. These studies will provide insight into the role of T cells in the pathogenesis of PBC and provide information useful in developing new treatment modalities.