Mechanisms and Antigen Identification in a Novel Model of Autoimmune Lung Disease

描述（由申请人提供）： 肺部疾病是系统性自身免疫性疾病的常见并发症，通常需要使用大剂量免疫抑制剂或肺移植进行积极治疗。尽管有显著的临床影响，但对自身免疫性疾病中肺部疾病的发病机制知之甚少。作为加州大学旧金山分校弗朗西斯科的一名肺病和重症监护医生，Anthony Shum博士正在将自己确立为自身免疫介导的肺病机制的研究者。凭借备受推崇的免疫学培训计划和国际认可的指导团队，UCSF为Shum博士朝着他作为医生科学家的职业生涯的长期目标发展所需的批判性研究和强化培训提供了理想的环境。主要导师Mark安德森博士是中枢免疫耐受方面的领先专家，共同导师Harold Chapman博士是肺科教授兼主任，是肺损伤和组织重塑方面的著名权威。肺自身免疫研究的一个主要障碍是缺乏研究疾病发病机制的动物模型。使用Aire（自身免疫调节器）缺陷小鼠，Shum博士的研究提供了在已知人类自身免疫综合征的新模型中定义自身免疫性肺病基本机制的独特机会。自身免疫性多腺综合征1（APS 1）由AIRE基因突变引起，与人类相似，AIRE缺陷小鼠由于中枢免疫耐受的严重破坏而对多个器官（包括肺）产生自身免疫。重要的是，Aire缺陷小鼠自发地以与APS 1患者惊人相似的模式发展间质性肺病。此外，Shum博士在Aire缺陷小鼠中发现了一种新的肺自身抗原，可能是引发疾病的关键。因此，我们假设，在Aire KO小鼠的肺部疾病是由于未能耐受胸腺细胞的一个关键的肺抗原，导致自身反应性T细胞逃逸的目标和损伤肺。为了解决这一假设，提出的具体目的是：（1）确定介导Aire KO小鼠肺部疾病的细胞群;（2）确定我们的肺抗原在小鼠模型肺部疾病发病机制中的作用;（3）确定我们的抗原的人同源物的作用，并证明APS 1和ILD患者的免疫反应性。

DESCRIPTION (provided by applicant): Pulmonary disease is a frequent complication of systemic autoimmune diseases, often requiring aggressive treatment with high dose immunosuppression or lung transplantation. Despite the significant clinical impact, little is understood about the pathogenesis of lung disease in autoimmune conditions. As a pulmonary and critical care physician at the University of California, San Francisco, Dr. Anthony Shum is establishing himself as an investigator in the mechanisms of autoimmune-mediated lung disease. With the highly regarded Immunology Training Program and an internationally recognized mentoring team, UCSF provides the ideal environment for the critical studies and intensive training necessary for Dr. Shum's development towards his long-term goal of a career as a physician-scientist. The primary mentor, Dr. Mark Anderson, is a leading expert in central immune tolerance, and co-mentor, Dr. Harold Chapman, Professor and Chief of the Pulmonary Division, is a renowned authority on lung injury and tissue remodeling. A major barrier to research on lung autoimmunity has been the lack of animal models in which to study disease pathogenesis. Using the Aire (Autoimmune Regulator) deficient mouse, Dr. Shum's research presents the unique opportunity to define basic mechanisms of autoimmune lung disease in a novel model of a known human autoimmune syndrome. Autoimmune Polyglandular Syndrome 1 (APS1) arises from mutations in the AIRE gene and like their human counterparts, Aire deficient mice develop autoimmunity to multiple organs, including the lung, due to a critical breakdown in central immune tolerance. Importantly, Aire deficient mice develop interstitial lung disease spontaneously in a pattern strikingly similar to APS1 patients. Furthermore, Dr. Shum has identified a novel lung autoantigen in the Aire deficient mouse that may be the key to initiating disease. Thus, we hypothesize that pulmonary disease in Aire KO mice is due to a failure to tolerize thymocytes to a critical lung antigen, resulting in the escape of autoreactive T cells that target and injure the lung. To address this hypothesis, the proposed specific aims are to: (1) determine the cell populations that mediate lung disease in Aire KO mice; (2) establish the role of our lung antigen in the pathogenesis of pulmonary disease in the mouse model; and (3) establish the role of the human homolog of our antigen and demonstrate APS1 and ILD patient immunoreactivity.