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.

项目摘要 尽管治疗剂的可用性广泛，但全球3亿人中有一半以上 哮喘对疾病的控制不足，导致患病风险增加，并且很大 美国卫生保健系统的经济负担。更有效和治愈的疗法显然是 需要，最好通过增加我们对哮喘致病机制的理解来确定。 过敏是哮喘发育的危险因素，大多数哮喘病例的起源是过敏的。然而， 并非所有具有系统性过敏原敏化的人在过敏原暴露时会出现哮喘症状。这些 过敏性的非心血管个体可能会因过敏原而出现过敏性鼻炎，但没有 哮喘的下呼吸道症状特征。有趣的是，许多过敏性非心脏病患者 会随着时间的推移发展哮喘症状，表明导致哮喘的致病机制可能 递增和可逆。因此，确定分化过敏性哮喘表型的因素 个体可以为哮喘发病机理提供重要的见解并确定治疗靶标。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 并防止病原体。但是，在哮喘中，AEC响应于 然后通过MNP激活在肺中引发并传播2型免疫反应并传播2型免疫反应的过敏原。我们的 发表和初步研究表明，AEC和MNP对 与过敏性非心律对照（AC）相比，过敏性哮喘患者（AA）中的过敏原（AA），包括差异基因 代谢途径的表达和调节，过敏性炎症反应增强 哮喘患者。这些研究表明，AEC和MNP可以进行表观遗传修饰和代谢 重新编程，导致持久的免疫记忆和对随后的反应增强 暴露。该功能重编程称为受过训练的免疫力，虽然已在上下文中进行了研究 在传染病中，尚未在肺部炎症性疾病（例如 哮喘。我们的假设是，过敏性哮喘患者中的AEC和​​气道MNP细胞具有训练有素的 对驱动哮喘表型的过敏原的免疫反应。具体目的是：1）确定 AEC中基因基因座的转录可访问性来自有或没有哮喘的过敏受试者的气道MNP。 2）比较有和没有哮喘的过敏受试者的AEC和​​气道MNP的代谢谱。 我们将利用鼻刷和支气管镜直接品尝AEC，MNP和支气管肺泡灌洗 来自AA和AC气道的流体进行单细胞测定，用于转座酶可访问的染色质测序（scatac-- SEQ）和代谢组学确定基因调节和代谢中是否存在基本差异 这些群体之间的AEC和​​MNP的景观。