Translational studies of autoimmune-mediated lung disease

自身免疫介导的肺部疾病的转化研究

• 批准号: 8818509
• 负责人: Anthony Shum
• 金额: $ 38.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8818509
• 关键词: Adoptive Transfer; Affect; Animal Model; Animals; Antigens; Asthma; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; B-Lymphocyte Epitopes; B-Lymphocytes; Biological Assay; Cells; Cicatrix; Clinical; Complex; Connective Tissue Diseases; Data; Defect; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Early Diagnosis; Early Intervention; Epitopes; Fibrosis; Genes; Goals; Health; Human; Immune; Immune Targeting; Immune Tolerance; Immune response; Inflammatory Response; Interferons; Interleukin-17; Interstitial Lung Diseases; Interstitial Pneumonia; Intervention; Kinetics; Knock-in Mouse; Lead; Link; Lung; Lung diseases; Maps; Mediating; Mediator of activation protein; Modeling; Monitor; Mus; Outcome; Pathogenesis; Patient risk; Patients; Peptide/MHC Complex; Peptides; Predisposition; Proteins; Pulmonary Pathology; Reporter; Rheumatoid Arthritis; Role; Scleroderma; Self Tolerance; Sensitivity and Specificity; Staging; Syndrome; System; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Th1 Cells; Time; Transgenic Mice; Translating; Work; autoreactive T cell; central tolerance; cytokine; disease diagnosis; improved; insight; lung development; lung injury; mortality; novel; prevent; public health relevance; response; risk variant; tool; translational study

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.

描述（由申请人提供）：间质性肺病（ILD）是一种复杂且异质性的疾病，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反应特异性针对 ILD 患者肺部的致病机制。随着我们发现针对自身免疫介导的 ILD 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性蛋白 BPIFB1 和临床 ILD 联系起来。我们在 Aire 转化模型中的研究证明了 lun 自身抗原在 ILD 发病机制中的关键作用。 AIRE 基因缺陷的患者会出现 1 型人类自身免疫性多腺体综合征 (APS1)，其中包括肺自身免疫性，这是由于免疫耐受性明显下降所致。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 的相关性，因为患有 Aire 缺陷的患者和小鼠会发展出自身免疫性 ILD，其病理学上与自身免疫性结缔组织疾病（例如 RA）的 ILD 相同。引人注目的是，患有自身免疫性 ILD 的非 APS1 患者亚群含有 BPIFB1 自身抗体，BPIFB1 是我们在模型中识别的主要人类抗原。这些结果强烈表明，Aire 模型代表了研究肺特异性自身免疫在 ILD 发病机制中的作用的新的理想系统。我们假设，针对肺部自身抗原的自身反应性 T 细胞反应是引发自身免疫性疾病中间质性肺炎症和纤维化的重要机制。我们的目标是更好地了解疾病机制，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）定义BPIFB1作为主要肺自身抗原在肺自身免疫中的作用； (2)明确TH17细胞在自身免疫性肺纤维化中的作用； (3) 开发工具以改进 ILD 患者的诊断和疾病监测。随着拟议研究的完成，我们将能够深入了解自身免疫介导的 ILD 的相关抗原靶点和效应机制。通过证明对肺特异性抗原的自我耐受性丧失会导致已知或未识别的自身免疫性患者的 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。随着敏感和抗原特异性检测方法的发展，我们希望能够在早期更准确地诊断与自身免疫相关的 ILD，从而对高危患者进行监测或接受更特异性的免疫靶向干预措施，以改变 ILD 的破坏性进程和由此产生的肺纤维化。