Translational studies of autoimmune-mediated lung disease

描述（由申请人提供）：间质性肺病（ILD）是一种复杂的异质性疾病，通常与自身免疫综合征相关;然而，尽管ILD与自身免疫之间存在联系，但研究尚未确定自身免疫应答特异性靶向ILD患者肺部的致病机制。随着我们发现靶向自身免疫介导的ILD的新型小鼠和人肺抗原（BPIFB 1），我们已经将自身免疫应答与肺特异性蛋白BPIFB 1和临床ILD联系起来。我们在Aire翻译模型中的研究已经证明了肺自身抗原在ILD发病机制中的关键作用。AIRE基因缺陷的患者由于免疫耐受的明确破坏而发展为人类自身免疫多腺体综合征1型（APS 1），其包括肺自身免疫。重要的是，该模型中的肺自身免疫显示出与更常见形式的自身免疫相关ILD相关，因为Aire缺陷的患者和小鼠发生自身免疫ILD，其在病理学上与自身免疫结缔组织疾病（如RA）的ILD相同。引人注目的是，一部分非APS 1自身免疫性ILD患者携带BPIFB 1自身抗体，BPIFB 1是我们在模型中鉴定的主要人类抗原。这些结果有力地表明，Aire模型代表了一种新的理想系统，用于研究肺特异性自身免疫在ILD发病机制中的作用。我们假设，针对自身抗原的自身反应性T细胞反应是自身免疫性疾病中激发间质性肺炎症和纤维化的重要机制。我们的目标是发展对疾病机制的更深入的了解，以允许靶向细胞因子或细胞干预来预防肺自身免疫和肺纤维化。为此，我们将：（1）确定BPIFB 1作为肺自身免疫中的主要肺自身抗原的作用;（2）确定TH 17细胞在自身免疫性肺纤维化中的作用;（3）开发用于改善ILD患者诊断和疾病监测的工具。随着拟定研究的完成，我们将准备对自身免疫介导的ILD的相关抗原靶点和效应机制进行深入研究。通过证明对肺特异性抗原的自身耐受性丧失有助于已知或未识别自身免疫性患者亚组中的ILD，我们将确定这些机制在自身免疫性肺损伤和肺纤维化进展中的作用。随着敏感性和抗原特异性检测方法的发展，我们希望在早期阶段更准确地诊断自身免疫相关ILD，允许对高危患者进行监测或进行更特异性的免疫靶向干预，以改变ILD的破坏性病程和由此产生的肺纤维化。

DESCRIPTION (provided by applicant): Interstitial lung disease (ILD) is a complex and heterogeneous disorder that is often associated with autoimmune syndromes; however, despite the connection between ILD and autoimmunity, studies have yet to identify a pathogenic mechanism whereby an autoimmune response specifically targets the lung within ILD patients. With our discovery of novel mouse and human lung antigens (BPIFB1) targeted in autoimmune- mediated ILD, we have linked an autoimmune response to the lung-specific protein BPIFB1 and clinical ILD. Our studies in the Aire translational model have demonstrated a critical role for lun autoantigens in ILD pathogenesis. Patients with defects in the AIRE gene develop the human Autoimmune Polyglandular Syndrome Type 1 (APS1), which includes lung autoimmunity, due to a well-defined breakdown in immune tolerance. Importantly, lung autoimmunity in this model shows relevance to more common forms of autoimmune-associated ILD, as patients and mice with defects in Aire develop autoimmune ILD that is pathologically identical to the ILD of autoimmune connective tissue disorders such as in RA. Strikingly, a subset of non-APS1 patients with autoimmune ILD harbor autoantibodies to BPIFB1, the major human antigen we identified in our model. These results strongly suggest that the Aire model represents a novel ideal system for studying the role of lung-specific autoimmunity in ILD pathogenesis. We hypothesize that autoreactive T cell responses targeting self-antigens in the lung are an important mechanism for inciting interstitial lung inflammation and fibrosis in autoimmune disease. We aim to develop improved insights into disease mechanisms to allow targeted cytokine or cellular interventions in preventing lung autoimmunity and lung fibrosis. To this end we will: (1) define the role of BPIFB1 as a major lung autoantigen in lung autoimmunity; (2) define the role of TH17 cells in autoimmune lung fibrosis; and (3) develop tools for improved diagnosis and disease monitoring in ILD patients. With completion of the proposed studies, we will be poised to gain significant insight into the relevant antigenic targets and effector mechanisms of autoimmune-mediated ILD. By demonstrating that loss of self-tolerance to lung-specific antigens contributes to ILD in a subset of patients with known or unrecognized autoimmunity, we will establish the role of these mechanisms in autoimmune lung injury and progression to lung fibrosis. With development of sensitive and antigen-specific assays, we hope to more accurately diagnosis autoimmune-associated ILD at earlier stages, allowing at risk patients to be monitored or undergo more specific immune-targeted interventions to alter the devastating course of ILD and resultant lung fibrosis.