THE PATHOGENESIS OF AUTOIMMUNITY IN A MURINE MODEL OF PRIMARY BILIARY CIRRHOSIS

摘要重症胆汁性肝硬变(PBC)是一种神秘的、肝脏特异的自身免疫性疾病，其特征是抗胆汁性肝硬变。 线粒体抗体和进行性肝内胆管破坏。从来没有一种动物 PBC的模型和研究依赖于人类临床标本，这一问题因 疾病发病的隐蔽性，使患者无法在早期阶段被发现。在其他自身免疫疾病中 对于疾病，提供信息的动物模型为免疫过程的剖析提供了便利。我们 提出一个联合方法，利用三个校区的优势来研究两个新的小鼠模型 在自身免疫性胆道疾病中，具有B6/B10衍生区的NOD.c3c4同源小鼠 3号和4号染色体，以及一种名为2445的新菌株。2445线显著降低了B6/B10 在3号和4号染色体上与NOD.C3C4进行比较，这将有助于基因的定位克隆 与疾病密切相关。两种品系的小鼠都会出现进行性门脉淋巴细胞性浸润性病变，肉芽肿， 抗线粒体抗体与终末期胆道疾病。我们的目标是执行一项详细的 对免疫系统进行个体发育分析，以确定特定谱系参与的动力学 利用NOD.C3C4、2445菌株和对照的疾病过程。将进行的研究是那些 镜像人类PBC，包括分析包括肝脏在内的先天、体液和细胞免疫系统 淋巴亚群和免疫组织化学鉴定发育阶段各成分 与疾病的发病机制有关。我们还将对导致肝脏的关键基因进行定位克隆 使用目前可用的同源菌株以及将产生的新的同源菌株感染疾病。 根据这些数据，使用NOD.C3C4和2445-SCID接受者的采用转移战略将定义 肝脏疾病发展所需的致病效应细胞。我们认为这一型号提供了 这不仅有助于增进我们对PBC的了解，而且有助于提高对自身免疫的总体认识。中国人民银行 是一种典型的自身免疫性疾病，具有组织特异性影响，但始终是非组织特异性的 自动反应性，在这个模型中紧密复制的特征。最后，因为PBC的小鼠模型是 在病理学和免疫学上与人类PBC相似，它为鉴别分析提供了可能性 启动事件，并最终研究治疗干预措施。

rimary biliary cirrhosis (PBC) is an enigmatic, liver specific, autoimmune disease characterized by antimito- chondrial antibodies and progressive destruction of intrahepatic bile ducts. There has not been an animal model of PBC and studies are dependent on human clinical specimens, a problem compounded by the cryptic nature of disease onset that prevents identification of patients in early stages. In other autoimmune diseases, the dissection of the immune process has been facilitated by informative animal models. We propose a consortium approach utilizing the strengths of three campuses to study two novel murine models of autoimmune biliary disease, the NOD.c3c4 congenic mouse with B6/B10 derived regions on chromosomes 3 and 4 as well as a new strain, called 2445. Line 2445 has significantly reduced B6/B10 ntervals on chromosome 3 and 4 compared to NOD.c3c4, which will facilitate positional cloning of genes ntegral to disease. Both strains of mice develop progressive portal tract lymphocytic infiltrates, granulomas, anti-mitochondrial antibodies and terminal biliary disease. Our objectives are to perform a detailed ontogenetic analysis of the immune system to define the kinetics by which specific lineages contribute to disease process utilizing NOD.c3c4, strain 2445, and controls. The studies to be performed are those which mirror human PBC, including analysis of the innate, humoral and cellular immune systems, including liver lymphoid subpopulations and immunohistochemistry to identify the developmental stage each component contributes to disease pathogenesis. We will also positionally clone the genes critical for causing liver disease using currently available congenic strains as well as novel congenic strains that will be generated. Based upon these data, adoptive transfer strategies using NOD.c3c4- and 2445-scid recipients will define the pathogenic effector cells required for the development of liver disease. We submit that this model offers significant potential for not only enhancing our understanding of PBC, but also autoimmunity in general. PBC is the prototypic autoimmune disease with a tissue specific impact, but a constant non-tissue specific autoreactivity, features closely reproduced in this model. Finally, because this murine model of PBC is pathologically and immunologieally similar to human PBC, it opens the possibility of discriminative analysis of initiating events and eventually study of therapeutic interventions.