Immunogenetic control of autoimmune biliary disease

原发性胆管炎(PBC)是一种无法治愈的自身免疫性胆道疾病。 免疫系统通过攻击胆管细胞来破坏胆管。许多基于免疫的 治疗方法已经应用于PBC，但都没有成功，这种疾病是 目前是无法治愈的。寻找PBC新疗法的进展受阻，因为 疾病的临床症状通常在发病多年后出现；因此，数据来源于 不允许对免疫发病机制有基本的了解。 这种疾病。能够产生新的治疗靶点的根本新见解需要 关于PBC最早发病机制的信息，必须来自动物模型 疾病。我们建立了第一个自发的PBC：NOD.ABD小鼠动物模型， 发生与人类极其相似的自身免疫性胆道疾病，包括1)抗线粒体 高度特异的人类PBC抗体；2)可由自身反应性T细胞转移的疾病；以及 3)免疫组织病理学特征：PBC伴肉芽肿形成，T细胞浸润 胆道衬里和破坏性胆管炎。最近我们发现了一种新的基因突变 在点头和阿布德。了解这种新的遗传系统是如何控制异常的胆管细胞的： 推动ABD的免疫系统相互作用是目前赠款的目标。这就是我们的 构建了一种新的同源小鼠(NOD.Abd3)，使我们能够从机制上分析 最早的疾病基础。我们还展示了一种基因背景，它增强了 自身免疫(NOD遗传背景，这是许多自身免疫的易感性 必须存在包括T1D、干燥综合征和甲状腺炎在内的疾病。这个建筑群 遗传病因学与人类疾病相似。因此，我们独特的模型提供了新的见解 与人类PBC和其他胆管疾病相关的基础免疫病理学。我们建议3个 目的：目的1：确定NOD自身免疫性胆道疾病的遗传学基础。我们展示了 在同基因的NOD.Abd3小鼠中，这种疾病需要1号染色体上的一个区域，“abd3”，它 包括1.0Mb的B6间隔(“B6-abd3”)以及其上游突变的Pkhd1del36-67。我们的 假设胆管细胞早期表达异常的Pkhd1破坏免疫 对胆管细胞的耐受。我们可以通过复杂的基因来证明/反驳这一假设 接近了。目的2：探讨早期胆管细胞“导管反应”在胆管损伤中的作用。 NOD.Abd3发病机制。4周龄时，NOD.Abd3胆管表现出大量免疫 浸润性，然后上升到肝内胆管。我们的假设是，反常的 免疫反应是由于NOD.Abd3胆管细胞早期的“管状反应”，这是 刺激先天免疫系统。目的3：髓系细胞的机制作用 NOD.Abd3和人PBC中抑制细胞(MDSCs)和激活的巨噬细胞 发病机制。在我们的模型中，临床ABD需要免疫系统。我们假设 Abd3基因区域改变巨噬细胞功能/亚群比率。我们将测试它的作用 小鼠疾病和人类PBC肝脏样本中的巨噬细胞。 这些研究与影响退伍军人的特定的、不可治愈的胆道疾病有关，并且 由于肝脏免疫/炎症在许多肝脏中起中心作用，这一点也很重要 退伍军人中常见的疾病(如酒精性肝炎、丙型肝炎)。我们的 研究将对自身免疫性胆管炎和肝脏的基本生物学有深入的了解 炎症/耐受性，并为这些棘手的疾病确定新的治疗靶点。

Primary biliary cholangitis (PBC) is an incurable autoimmune biliary disease (“ABD”) in which the immune system destroys bile ducts by targeting cholangiocytes. Many immune based therapies have been applied to PBC, but none have been successful and the disease is currently incurable. Progress in finding new therapies for PBC has been blocked because the clinical symptoms of disease often arise many years after initiation of disease; thus data derived from human patients has not permitted fundamental insights into the immunopathogenesis of the disease. Fundamental new insights that can generate new therapeutic targets require information about the earliest pathogenesis of PBC, which must come from animal models of disease. We developed the first spontaneous animal model of PBC: NOD.ABD mice that develop autoimmune biliary disease remarkably similar to human including 1) anti-mitochondrial antibodies highly specific for human PBC; 2) disease transferable by autoreactive T cells; and 3) immunohistopathology highly characteristic of PBC with granuloma formation, T cell infiltrates in the biliary lining, and destructive cholangitis. Recently we discovered a novel genetic mutation in NOD ABD. Understanding how this novel genetic system controls the aberrant cholangiocyte: immune system interaction which drives ABD is the goal of the current grant. Here we have constructed a novel congenic mouse (NOD.Abd3) that allows us to mechanistically analyze the very earliest basis of disease. We also show that a genetic background which enhances autoimmunity (the NOD genetic background, which predisposes to many autoimmune conditions including T1D, Sjogren’s syndrome, and thyroiditis) must be present. This complex genetic etiology is similar to human disease. Therefore our unique model offers new insights into basic immunopathology relevant to human PBC and other cholangiopathies. We propose 3 aims: Aim 1: Determine the genetic basis of NOD autoimmune biliary disease. We show that disease in congenic NOD.Abd3 mice requires a region on chromosome 1, “Abd3”, which includes a 1.0 Mb B6 interval (“B6-Abd3”) as well as mutated Pkhd1del36-67 upstream of it. Our hypothesis is that early expression of aberrant Pkhd1 in cholangiocytes breaks immune tolerance to cholangiocytes. We can prove/disprove this hypothesis by sophisticated genetic approaches. Aim 2: Determine the role of early cholangiocyte “ductular reaction” in NOD.Abd3 pathogenesis. By 4 weeks of age, NOD.Abd3 bile ducts show massive immune infiltration which then ascends into intrahepatic bile ducts. Our hypothesis is that the aberrant immune response is due to an early “ductular reaction” of NOD.Abd3 cholangiocytes, which stimulates the innate immune system. Aim 3: Mechanistic role of myeloid derived suppressor cells (MDSCs) and activated macrophages in NOD.Abd3 and human PBC pathogenesis. The immune system is required for clinical ABD in our model. We hypothesize that the Abd3 genetic region alters macrophage function/subset ratios. We will test the role of macrophages in both murine disease and human PBC liver samples. These studies are relevant to specific, incurable biliary diseases that affect Veterans, and are also important due to the central role hepatic immunity/inflammation plays in many liver diseases (e.g. alcoholic hepatitis, hepatitis C) that are common in Veteran populations. Our studies will produce insights into the basic biology of autoimmune cholangitis and liver inflammation/tolerance, and identify new therapeutic targets for these intractable conditions.