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.

摘要自身免疫性肝炎（AIH）是一种病因不明的炎症性肝病。的 炎症反应被认为是由识别肝脏自身免疫的CD 4 + T淋巴细胞协调的。 抗原人类HLA-DRB 1（*0401和 *0301）等位基因的检测 白细胞抗原（HLA）区域提示这些等位基因错误抗原呈递， 细胞活化可能在AIH的发病机制中起一定作用。我们最近做了一个小鼠模型， Traf 6 BTEC，由于胸腺髓质细胞的耗竭，在胸腺中显示受损的抗原呈递。 上皮细胞（mTECs）。mTEC表达组织限制性抗原（TRAs）并呈递 这些胸腺细胞自身抗原导致自身反应性T细胞的消除， 自身免疫性Traf 6 β TEC小鼠中mTEC的条件性耗竭与自发性 自身免疫性肝炎（AIH）的发展， 人类AIH的免疫学标志。最近我们发现抗生素治疗可以减少AIH Traf 6 ESTTEC小鼠的组织病理学表明肠道微生物群参与AIH发展。我们还发现 调节性T细胞和表达肠道归巢受体CCR 4、CCR 7和CCR 9的T细胞的产生增加 在Traf 6 ETEC小鼠的肠道和肝脏中，伴随着内皮细胞粘附表达的增加， 分子和趋化因子。这些结果建立了肠道微生物群 和AIH在该小鼠模型中的发展，并另外概括了在 其他肝脏自身免疫性疾病的临床背景。根据我们迄今为止的研究结果，我们提出以下建议 假设：mTEC耗竭导致产生自身反应性T细胞，其归巢至肝脏并启动 炎症通过肝脏自身抗原的异常识别。基因敲除后微生物群的变化 在动物中，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 为了验证这一假设，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，并鉴定自身反应性T细胞靶向的肝脏自身抗原 2）阐明肠介导的AIH诱导和/或加重的机制;和3）定义 Traf 6微生物群特征及其与正常微生物群的不同并识别特征/细菌 与AIH病理学相关的物种。阐明AIH的调节机制 发展可能导致急需的新的治疗策略，以更好地管理，也许治疗 这种疾病。这些实验也可能定义一个共同的机制， 其他肝脏自身免疫性疾病，无论其最终的细胞靶点。