原发性胆汁性肝硬化的细胞免疫学发病机制

Cellular mechanism of immunopathogenesis of primary biliary cirrhosis

原发性胆汁性肝硬化(PBC)是一种器官特异性的进行性自身免疫疾病,常见于女性,以肝脏门脉周围的淋巴细胞浸润,胆管上皮细胞特异性损伤以及血清中高滴度抗线粒体抗体(AMA)为主要特征。最新的PBC研究采用了CD4启动子控制下的TGFβ受体2显性失活(dnTGFβRⅡ)小鼠模型,这种小鼠模型很好地模拟了PBC患者的典型特征。在这种小鼠的基因背景下,通过分别敲除Rag1,μ以及CD1d基因建立了多种双基因缺陷鼠,通过研究发现T细胞,B细胞以及CD1d限制的NKT细胞等对肝脏淋巴细胞浸润,胆管上皮细胞损伤以及AMA的产生发挥着重要的作用。一系列的细胞免疫学实验结果显示,是CD8+T细胞而非CD4+T细胞在肝脏损伤过程中起着决定性的作用,而B细胞除分泌抗自身抗体之外,还具有抑制PBC发生的免疫调节作用。这些机制的研究为揭示人类PBC疾病的细胞免疫学致病机理提供了有力的证据和依托。

Primary biliary cirrhosis（PBC） is a progressive,organ-specific autoimmune disease that predominantly affects woman and is characterized by lymphocytic infiltration in portal tracts,immune-mediated destruction of small intrahepatic small bile ducts,and the presence of high titers of serum anti-mitochondrial Abs（AMAs）.A murine model of PBC,generated by expressing a dominant-negative form of TGFβ receptor type Ⅱ（dnTGFβRⅡ） under the direction of the CD4 promoter,demonstrates several key features of human PBC and has been applied in previous PBC studies.Experimental data from Rag1-/-,μ-/-and CD1d-/-mice on a dnTGFβRⅡ background indicated that T cells,B cells and CD1d-restricted NKT cells plays critical roles in liver injury.Moreover,based on a rigorous series of cellular immunological studies,it is concluded that CD8＋,but not CD4＋ T cells,play a prominent role in mediating pathogenesis,and that B cells can have a suppressive regulatory effect on the infiammatory response besides just secreting auto-antibodies.These studies provide substantial evidence for a cellular mechanism in human primary biliary cirrhosis pathogenesis