Local B cell memory in airway hypersensitivity.

项目摘要/摘要 过敏性哮喘是一种慢性呼吸道炎症性疾病，目前尚无治愈方法。生产 吸入性变应原的免疫球蛋白E(IgE)可促进炎症和变态反应 哮喘。超过一半的患者在呼吸道粘膜表现出过敏原特异性的IgE，但不是系统性的 循环，说明了在当地生产免疫球蛋白E的重要性。然而，促进和发展的机制 维持局部致病的IgE反应尚不清楚。使用呼吸道过敏的小鼠模型， 我们已经确定了一组记忆B细胞，它们在反复吸入后定位于肺部 过敏原。这些位于肺部的记忆B细胞对过敏原表现出特异性，在解决 炎症，随着局部过敏原特异性IgE的增加而在再次激发时扩大。我们假设组织- 常驻记忆B细胞是哮喘肺部局部反应的主要来源，负责维持 呼吸道长期过敏。在这个提案中，我们将阐明维持细胞环境的 记忆B细胞在哮喘肺内的滞留及其在呼吸道超敏反应中的作用 具体地说，在目标1中，我们将使用体内循环细胞耗竭和异种共生实验来验证 记忆B细胞在哮喘肺中的组织驻留。我们将确定肺局部的潜在利基环境 记忆B细胞，并检查负责维持它们在肺部的细胞环境 尖端成像技术。在目标2中，我们将在重新挑战期间抑制循环B细胞的招募 并对组织驻留记忆B细胞进行过继细胞转移，以描绘组织驻留的功能 记忆B细胞与呼吸道超敏反应总而言之，我们的目标是阐明 记忆呼吸道中的B细胞，并揭示它们在呼吸道过敏中的作用。这项研究可能会揭示 一个关键的细胞群体，可以作为治疗或预防人类过敏性哮喘进展的靶点。 这笔奖学金将为申请者成为一名独立调查员提供至关重要的支持。 在免疫学方面。

Project Summary/Abstract Allergic asthma is a chronic inflammatory disease of the airway that currently has no cure. Production of immunoglobulin E (IgE) to inhaled allergens drives inflammation and the allergic response seen in allergic asthma. Over half of patients exhibit allergen-specific IgE at the respiratory mucosa but not systemically in circulation, illustrating the importance of local production of IgE. However, the mechanisms that promote and maintain local pathogenic IgE responses are not understood. Using a mouse model of airway hypersensitivity, we have identified a population of memory B cells that localize to the lungs after repeated exposures to inhaled allergens. These lung-localized memory B cells exhibit specificity for allergens, persist after the resolution of inflammation, expand upon re-challenge with increase of local allergen-specific IgE. We hypothesize that tissue- resident memory B cells are the major source of local responses in asthmatic lungs, responsible for maintaining long-term hypersensitivity in the airway. In this proposal, we will elucidate the cellular environment that maintains lung residency of memory B cells in asthmatic lungs and investigate their functions in airway hypersensitivity. Specifically, in Aim 1, using in vivo depletion of circulating cells and parabiosis experiments we will verify the tissue-residency of memory B cells in asthmatic lungs. We will identify the potential niches of lung-localized memory B cells and examine the cellular environment responsible for their maintenance in the lungs using cutting-edge imaging technologies. In Aim 2, we will inhibit recruitment of circulating B cells during re-challenge and perform adoptive cell transfer of tissue-resident memory B cells to delineate the function of tissue-resident memory B cells in airway hypersensitivity. In summary, we aim to shed light on the fundamental biology of memory B cells in the respiratory tract and reveal their functions in airway hypersensitivity. This study may reveal a crucial cell population that can be targeted to treat or prevent the progression of allergic asthma in humans. This fellowship will provide the crucial support for the applicant to pursue a career as an independent investigator in immunology.