Trained Immunity in the Airway Mucosa Differentiates Asthma from Allergy Alone

气道粘膜经过训练的免疫力可将哮喘与单纯过敏区分开来

• 批准号: 10673238
• 负责人: Benjamin David Medoff
• 金额: $ 25.2万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673238
• 关键词: Allergens; Allergic; Allergic rhinitis; Antioxidants; Asthma; Binding Sites; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Bronchoscopy; Cell Line; Cell Separation; Cells; Cellular Assay; Characteristics; Chromatin; Chromatin Structure; Coculture Techniques; Communicable Diseases; DNA; Development; Disease; Economic Burden; Environmental Exposure; Epigenetic Process; Epithelial Cells; Exposure to; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genetic Transcription; Glycolysis; Health; Healthcare Systems; Homeostasis; Hypersensitivity; Immune; Immune response; Immunity; Immunologic Memory; Individual; Infection; Inflammation Mediators; Inflammatory; Inflammatory Response; Link; Lower respiratory tract structure; Lung; Lung diseases; Maps; Measurement; Measures; Metabolic; Metabolic Pathway; Modification; Mononuclear; Nose; Pathogenesis; Pathogenicity; Pathway Analysis; Pathway interactions; Patients; Persons; Phagocytes; Phenotype; Publishing; Pyroglyphidae; Reaction; Regulation; Regulator Genes; Respiratory Mucosa; Risk; Risk Factors; Role; Sampling; Signal Transduction; Spectrometry, Mass, Electrospray Ionization; Structure of mucous membrane of nose; Symptoms; Therapeutic Agents; Time; Tissue-Specific Gene Expression; Tissues; Training; Transposase; United States; airway epithelium; airway inflammation; asthmatic; asthmatic airway; curative treatments; effective therapy; genomic locus; insight; metabolic profile; metabolomics; morphogens; new therapeutic target; pathogen; programs; response; theories; therapeutic target; transcription factor

Project Summary Despite the widespread availability of therapeutic agents, more than half of the 300 million people worldwide with asthma have inadequate control of their disease resulting in an increased risk of exacerbations and a large economic burden to the United States health care system. More effective and curative therapies are clearly needed and will best be identified by increasing our understanding of the pathogenic mechanisms of asthma. Allergy is a risk factor for the development of asthma, and most cases of asthma are allergic in origin. However, not all individuals with systemic allergen sensitization develop asthma symptoms upon allergen exposure. These allergic non-asthmatic individuals may develop allergic rhinitis in response to an allergen but do not have the lower respiratory tract symptoms characteristic of asthma. Interestingly, many allergic non-asthmatic patients will develop asthma symptoms over time, suggesting that the pathogenic mechanisms leading to asthma may be incremental and reversible. Thus, determination of factors that differentiate the asthma phenotype in allergic individuals could provide important insights into asthma pathogenesis and identify therapeutic targets. In health, airway epithelial cells (AEC) and airway mononuclear phagocytes (MNP) help to maintain tissue homeostasis and defend against pathogens. However, in asthma, AEC generate pro-inflammatory signals in response to allergens that then initiates and propagates a type 2 immune response in the lung via activation of MNP. Our published and preliminary studies demonstrate that the AEC and MNP have profoundly different reactions to allergens in allergic asthmatics (AA) compared to allergic non-asthmatic controls (AC), including differential gene expression and regulation of metabolic pathways, and an enhanced inflammatory response in allergic asthmatics. These studies suggest that AEC and MNP can undergo epigenetic modifications and metabolic reprogramming leading to a lasting immunological memory and enhanced response towards subsequent exposures. This functional reprogramming is called trained immunity, and while it has been studied in the context of infectious diseases, it has not been explored in the context of pulmonary inflammatory diseases such as asthma. Our hypothesis is that AEC and airway MNP cells in allergic asthmatic individuals have a trained immune response to allergens which drives the asthma phenotype. The specific aims are to: 1) Determine the transcriptional accessibility of gene loci in AEC and airway MNP from allergic subjects with and without asthma.; and 2) Compare the metabolic profile of AEC and airway MNP from allergic subjects with and without asthma. We will utilize nasal brushings and bronchoscopy to directly sample AEC and MNP and bronchoalveolar lavage fluid from AA and AC airways for single cell Assay for Transposase-Accessible Chromatin sequencing (scATAC- seq) and metabolomics to determine if there are fundamental differences in the gene regulatory and metabolic landscape of AEC and MNP between these groups.

项目概要 尽管治疗药物广泛可用，但全球 3 亿人中仍有一半以上患有此病 哮喘患者对其疾病的控制不足，导致病情恶化的风险增加，并且大量 给美国医疗保健系统带来经济负担。显然更有效和治愈的疗法 需要并且最好通过增加我们对哮喘致病机制的了解来识别。 过敏是哮喘发生的危险因素，大多数哮喘病例都是过敏性的。然而， 并非所有具有全身过敏原致敏的个体在接触过敏原后都会出现哮喘症状。这些 过敏性非哮喘个体可能因过敏原而出现过敏性鼻炎，但没有 下呼吸道症状是哮喘的特征。有趣的是，许多过敏性非哮喘患者 随着时间的推移会出现哮喘症状，这表明导致哮喘的致病机制可能是 是增量且可逆的。因此，确定区分过敏性哮喘表型的因素 个人可以提供有关哮喘发病机制的重要见解并确定治疗靶点。在健康方面， 气道上皮细胞（AEC）和气道单核吞噬细胞（MNP）有助于维持组织稳态 并防御病原体。然而，在哮喘中，AEC 会产生促炎信号以响应 然后通过 MNP 的激活在肺部启动并传播 2 型免疫反应。我们的 已发表的研究和初步研究表明，AEC 和 MNP 对这一问题的反应截然不同 过敏性哮喘患者 (AA) 与过敏性非哮喘对照 (AC) 的过敏原，包括差异基因 代谢途径的表达和调节，以及过敏性炎症反应的增强 哮喘患者。这些研究表明 AEC 和 MNP 可以经历表观遗传修饰和代谢 重新编程导致持久的免疫记忆并增强对后续反应的反应 曝光。这种功能性重编程被称为训练免疫，虽然它已经在上下文中进行了研究 传染病方面，尚未在肺部炎症性疾病的背景下进行探索，例如 哮喘。我们的假设是，过敏性哮喘个体中的 AEC 和气道 MNP 细胞经过训练 对过敏原的免疫反应会导致哮喘表型。具体目标是： 1) 确定 患有和不患有哮喘的过敏受试者的 AEC 和气道 MNP 中基因位点的转录可及性。 2) 比较患有和不患有哮喘的过敏受试者的 AEC 和气道 MNP 代谢特征。 我们将利用鼻刷和支气管镜直接采样 AEC 和 MNP 以及支气管肺泡灌洗液 来自 AA 和 AC 气道的液体，用于转座酶可及染色质测序的单细胞测定 (scATAC- seq）和代谢组学，以确定基因调控和代谢是否存在根本差异 这些群体之间 AEC 和 MNP 的情况。