Immunogenetic control of autoimmune biliary disease

原发性胆汁性胆管炎（PBC）是一种无法治愈的自身免疫性胆道疾病（“ABD”），其中 免疫系统通过靶向胆管细胞破坏胆管。许多免疫基础 治疗方法已应用于PBC，但没有一种是成功的， 目前无法治愈。寻找PBC新疗法的进展受阻，因为 疾病的临床症状通常在疾病开始后多年出现;因此数据来源于 从人类患者的研究还没有允许对免疫发病机制的基本见解， 这种疾病能够产生新的治疗靶点的基本新见解需要 PBC最早发病机制的信息，必须来自动物模型， 疾病我们开发了第一个自发性PBC动物模型：NOD.ABD小鼠， 发生与人类非常相似的自身免疫性胆道疾病，包括1）抗线粒体 对人PBC高度特异性的抗体; 2）可由自身反应性T细胞转移的疾病;和 3)PBC免疫组织病理学特征性表现为肉芽肿形成、T细胞浸润 以及破坏性胆管炎最近我们发现了一种新的基因突变 在NOD ABD。了解这种新的遗传系统如何控制异常的胆管细胞： 驱动ABD的免疫系统相互作用是当前资助的目标。这里我们有 构建了一种新的同源小鼠（NOD.Abd3），使我们能够机械地分析 最早的疾病基础。我们还表明，遗传背景，增强 自身免疫（NOD遗传背景，易患许多自身免疫性疾病） 包括T1 D、Sjogren综合征和甲状腺炎在内的疾病）必须存在。这个复杂 遗传病因与人类疾病相似。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 目的：目的1：明确NOD自身免疫性胆道疾病的遗传基础。我们表明 在同源NOD.Abd3小鼠中，这种疾病需要1号染色体上的一个区域“Abd 3”， 包括1.0 Mb B6区间（“B6-Abd 3”）以及其上游的突变的Pkhd 1del 36 -67。 假设胆管细胞中异常Pkhd 1的早期表达破坏免疫 对胆管细胞的耐受性。我们可以通过复杂的遗传学方法来证明/反驳这一假设。 接近。目的2：确定早期胆管细胞“导管反应”在肝硬化中的作用。 NOD.Abd3发病机制。到4周龄时，NOD.Abd3胆管显示出大量的免疫反应， 浸润，然后上升到肝内胆管。我们的假设是 免疫应答是由于NOD.Abd3胆管细胞的早期“小管反应”， 刺激先天免疫系统目的3：髓源性的机制作用 在NOD.Abd3和人PBC中的抑制细胞（MDSC）和活化的巨噬细胞 发病机制在我们的模型中，临床ABD需要免疫系统。我们假设 Abd 3基因区域改变巨噬细胞功能/亚群比率。我们将测试 在鼠疾病和人PBC肝脏样品中的巨噬细胞中。 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， 由于肝脏免疫/炎症在许多肝脏中起着中心作用， 疾病（如酒精性肝炎，丙型肝炎）是常见的退伍军人群体。我们 研究将深入了解自身免疫性胆管炎和肝脏的基础生物学， 炎症/耐受，并确定这些难治性疾病的新治疗靶点。

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.