Translational studies of autoimmune-mediated lung disease

描述(申请人提供)：间质性肺病(ILD)是一种复杂和异质性的疾病，通常与自身免疫综合征有关；然而，尽管ILD和自身免疫之间存在联系，但研究尚未确定一种致病机制，即ILD患者体内的自身免疫反应特异性地针对肺。随着我们发现了以自身免疫介导的ILD为靶点的新型小鼠和人类肺抗原(BPIFB1)，我们将自身免疫反应与肺特异蛋白BPIFB1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LUN自身抗原在ILD发病机制中的关键作用。AIRE基因缺陷的患者会患上人类自身免疫性多腺体综合征1型(APS1)，其中包括肺自身免疫，这是由于免疫耐受性的明确崩溃。重要的是，在这个模型中，肺自身免疫与更常见的自身免疫相关的ILD相关，因为Aire缺陷的患者和小鼠发展成与自身免疫性结缔组织疾病(如RA)的ILD在病理上相同的自身免疫性ILD。值得注意的是，患有自身免疫性ILD的非APS1患者的一部分患者体内存在针对BPIFB1的自身抗体，BPIFB1是我们在模型中发现的主要人类抗原。这些结果有力地表明，Aire模型是研究肺特异性自身免疫在ILD发病机制中作用的一种新的理想系统。我们假设，针对肺中自身抗原的自身反应性T细胞反应是在自身免疫性疾病中激发肺间质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好的见解，以允许有针对性的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BPIFB1在肺自身免疫中的主要肺自身抗原的作用；(2)确定TH17细胞在自身免疫性肺纤维化中的作用；(3)开发改进ILD患者的诊断和疾病监测的工具。随着拟议研究的完成，我们将对自身免疫介导的ILD的相关抗原靶点和效应机制有重要的了解。通过证明对肺特异性抗原的自身耐受性丧失在已知或未知自身免疫的患者亚群中导致ILD，我们将确定这些机制在自身免疫性肺损伤和进展为肺纤维化中的作用。随着敏感和抗原特异性分析的发展，我们希望在早期阶段更准确地诊断自身免疫相关的ILD，允许对高危患者进行监测或接受更具体的免疫靶向干预，以改变ILD和由此导致的肺纤维化的破坏性过程。

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.