ROLE OF CD40-CD40 LIGAND IN PRIMARY BILIARY CIRRHOSIS

说明(改编自应用程序) 摘要原发性胆汁性肝硬变是一种慢性自身免疫性肝病。 通过炎性破坏中小型肝内胆管， 导致胆汁淤积，然后是纤维化、肝硬变及其并发症。 虽然病因不明，但胆小管周围的T细胞 胆管破坏的可能中介物。中的其他单元格类型 门脉浸润，包括巨噬细胞和B细胞，可能有助于 这一自身免疫过程。然而，这些细胞的通信方式 而合作造成胆管损伤的原因还不清楚。的假说 这个提议的项目是T细胞协调免疫攻击 胆管细胞通过CD40配体向肝内其他细胞传递信号。 活化的T细胞在肝脏中表达CD40配体 刺激B细胞增加免疫球蛋白的产生；激活 巨噬细胞产生IL-12，这导致T辅助细胞向 Th1表型和随后产生的IL-2和干扰素-γ；以及诱导 胆管细胞的凋亡率增加。这一假说将 CD40配体表达水平的相关性分析 PBC患者肝脏中CD40-CD40的潜在影响 配基相互作用；如免疫球蛋白和细胞因子的上调 胆管细胞的产生和凋亡。CD40和CD40配体的表达 将通过免疫组织化学定位于肝脏。这些 以患者为中心的研究将由设计的体外实验补充 目的：研究CD40配体诱导的胆管细胞凋亡。这些研究将 深入了解T细胞在PBC发病机制中的作用，并提供 对开发新的治疗方式有用的信息。

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.