Mechanism of autoimmune hepatitis development in a novel mouse model

新型小鼠模型中自身免疫性肝炎发生的机制

• 批准号: 9516717
• 负责人: KONSTANTINA ALEXANDROPOULOS
• 金额: $ 38.03万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-20 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9516717
• 关键词: Affinity; Alleles; Animals; Antibiotic Therapy; Antibiotics; Antibodies; Antigen Presentation; Antigen Targeting; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Hepatitis; Autoimmune Responses; Autoimmunity; Bacteria; Binding; CCR9 gene; CD4 Positive T Lymphocytes; Cell Adhesion Molecules; Clinical; Data; Development; Disease; Endothelial Cells; Etiology; Exhibits; Functional disorder; Germ-Free; Gnotobiotic; HLA Antigens; Hepatitis; Histologic; Histopathology; Home environment; Homing; Human; Human Characteristics; Immune; Immune response; Immunize; Immunodeficient Mouse; Immunoglobulins; Immunologics; Impairment; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Infiltrate; Inflammatory Response; Interphase; Knockout Mice; Lead; Liver; Liver diseases; Lobular; Maintenance; Major Histocompatibility Complex; Mediating; Methods; Modeling; Mucous Membrane; Mus; Pathogenesis; Pathology; Patients; Peripheral; Plasma Cells; Play; Population; Predisposition; Primary biliary cirrhosis; Process; Production; Proteins; Regulatory T-Lymphocyte; Relapse; Role; Self Tolerance; Sequence Homology; Steroids; Stromal Cells; Structure of thymic cortex; Surface; Symptoms; T-Cell Activation; T-Lymphocyte; T-cell diversity; Testing; Thymic epithelial cell; Thymus Gland; Time; Tissues; To autoantigen; Up-Regulation; autoreactive T cell; base; cellular targeting; central tolerance; chemokine; experimental study; gut microbiota; insight; intrahepatic; knockout animal; liver inflammation; liver transplantation; microbial; microbiota; microbiota profiles; mouse model; normal microbiota; novel; novel therapeutics; peripheral tolerance; primary sclerosing cholangitis; receptor; recruit; response; screening; thymocyte; ubiquitin ligase

SUMMARY. Autoimmune hepatitis (AIH) is an inflammatory liver disease of unknown etiology. The inflammatory response is thought to be orchestrated by CD4+ T lymphocytes recognizing liver self- antigens. The identification of susceptibility HLA-DRB1 (*0401 and *0301) alleles within the human leukocyte antigen (HLA) region suggested that faulty antigen presentation by these alleles and ensuing T cell activation may play a role in the pathogenesis of AIH. We recently generated a mouse model, Traf6TEC, displaying impaired antigen presentation in the thymus due to depletion of medullary thymic epithelial cells (mTECs). Expression of tissue restricted antigens (TRAs) by mTECs and presentation of these self-antigens to developing thymocytes leads to elimination of autoreactive T cells and suppression of autoimmunity. Conditional depletion of mTECs in Traf6TEC mice associated with spontaneous development of autoimmune hepatitis (AIH) that recapitulated the known histopathological and immunological hallmarks of human AIH. More recently we found that antibiotic treatment reduced AIH histopathology in Traf6TEC mice implicating the gut microbiota in AIH development. We also found increased production of regulatory T cells and T cells expressing the gut-homing receptors 47 and CCR9 in the gut and liver of Traf6TEC mice accompanied by increased expression of endothelial-cell adhesion molecules and chemokines in the liver. These results establish a connection between the gut microbiota and development of AIH in this mouse model and additionally recapitulate similar evidence observed in the clinical setting of other liver autoimmune diseases. Based on our results to date, we propose the following hypothesis: mTEC depletion leads to production of autoreactive T cells that home to the liver and initiate inflammation through aberrant recognition of liver self-antigens. Changes in the microbiota of knockout animals lead to increased production of mucosal T cells that circulate to the liver and exacerbate AIH. To examine this hypothesis we will: 1) Determine the contributions of autoreactive T cells vs. the gut microbiota in AIH development/maintenance and identify liver self-antigens targeted by autoreactive T cells; 2) Elucidate the mechanism of gut-mediated induction and/or exacerbation of AIH; and 3) Define the microbiota profile of Traf6TEC and how it differs from normal microbiota and identify a signature/bacterial species that associate with AIH pathology. Elucidation of the mechanisms that regulate of AIH development may lead to much-needed novel therapeutic strategies to better manage and perhaps treat this disease. These experiments may also define a common mechanism underling the development of other liver autoimmune diseases irrespective of their ultimate cellular targets.

概括。自身免疫性肝炎（AIH）是一种病因不明的炎症性肝病。这 炎症反应被认为是由识别肝脏自身免疫的 CD4+ T 淋巴细胞精心策划的。 抗原。人类易感性 HLA-DRB1（*0401 和 *0301）等位基因的鉴定 白细胞抗原 (HLA) 区域表明这些等位基因的抗原呈递错误以及随后的 T 细胞活化可能在 AIH 的发病机制中发挥作用。我们最近生成了一个小鼠模型， Traf6TEC，由于胸腺髓质耗竭而导致胸腺中抗原呈递受损 上皮细胞（mTEC）。 mTEC 表达组织限制性抗原 (TRA) 以及呈递 这些针对正在发育的胸腺细胞的自身抗原会导致自身反应性 T 细胞的消除和抑制 自身免疫。 Traf6TEC 小鼠中 mTEC 的条件性消耗与自发性相关 自身免疫性肝炎（AIH）的发展概括了已知的组织病理学和 人类 AIH 的免疫学特征。最近我们发现抗生素治疗可减少 AIH Traf6TEC 小鼠的组织病理学表明肠道微生物群与 AIH 的发生有关。我们还发现 调节性 T 细胞和表达肠道归巢受体 47 和 CCR9 的 T 细胞的产生增加 在 Traf6TEC 小鼠的肠道和肝脏中，伴随内皮细胞粘附表达增加 肝脏中的分子和趋化因子。这些结果建立了肠道微生物群之间的联系 以及该小鼠模型中 AIH 的发展，并另外概括了在 其他肝脏自身免疫性疾病的临床情况。根据我们迄今为止的结果，我们提出以下建议 假设：mTEC 消耗导致自身反应性 T 细胞产生，这些细胞归巢于肝脏并启动 由于肝脏自身抗原的异常识别而引起炎症。基因敲除后微生物群的变化 动物会导致粘膜 T 细胞的产生增加，这些 T 细胞循环到肝脏并加剧 AIH。到 检查这个假设，我们将： 1) 确定自身反应性 T 细胞与肠道的贡献 微生物群在 AIH 发展/维持中的作用，并识别自身反应性 T 靶向的肝脏自身抗原 细胞； 2) 阐明肠道介导的AIH诱发和/或加重的机制； 3) 定义 Traf6TEC 的微生物群概况及其与正常微生物群的差异以及识别特征/细菌的方式 与 AIH 病理相关的物种。 AIH 调节机制的阐明 发展可能会带来急需的新治疗策略，以更好地管理和治疗 这种病。这些实验还可能定义一个共同的机制，支持开发 其他肝脏自身免疫性疾病，无论其最终细胞目标是什么。