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

描述(由申请人提供)： 肺部疾病是全身性自身免疫性疾病的常见并发症，通常需要大剂量免疫抑制或肺移植的积极治疗。尽管有重大的临床影响，但对自身免疫条件下肺部疾病的发病机制知之甚少。作为加州大学旧金山分校的一名肺部和重症监护内科医生，安东尼·申博士正在确立自己在自身免疫介导的肺部疾病机制方面的研究人员的地位。凭借备受推崇的免疫学培训计划和国际公认的指导团队，加州大学旧金山分校为沈博士向他作为内科科学家职业生涯的长期目标发展所必需的关键研究和强化培训提供了理想的环境。主要导师Mark Anderson博士是中枢免疫耐受方面的领先专家，共同导师、教授兼肺科主任Harold Chapman博士是肺损伤和组织重塑方面的知名权威。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。利用Aire(自身免疫调节因子)缺陷小鼠，沈博士的研究提供了一个独特的机会，在一种已知的人类自身免疫综合征的新模型中确定自身免疫性肺病的基本机制。自身免疫性多腺体综合征1(APS1)由AIRE基因突变引起，与人类同龄人一样，AIRE缺陷小鼠由于中枢免疫耐受严重崩溃而对包括肺在内的多个器官产生自身免疫。重要的是，Aire缺陷小鼠自发地发展为间质性肺疾病，其模式与APS1患者惊人地相似。此外，沈博士还在Aire缺陷小鼠身上发现了一种新的肺自身抗原，这可能是引发疾病的关键。因此，我们假设Aire KO小鼠的肺部疾病是由于胸腺细胞不能耐受一种关键的肺抗原，导致靶向肺并损伤肺的自身反应性T细胞逃逸。为了解决这一假设，拟议的具体目标是：(1)确定介导Aire KO小鼠肺部疾病的细胞群；(2)在小鼠模型中确定我们的肺抗原在肺部疾病发病机制中的作用；以及(3)确定我们的抗原的人类同源物的作用，并证明APS1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.