Regional B Cells Modulate Airway Th2 Responses

描述（由申请人提供）：哮喘是一种气道炎症性疾病，涉及抗原提呈细胞、T淋巴细胞、肥大细胞和嗜酸性粒细胞。传统上认为B淋巴细胞是Th2细胞因子的靶细胞；然而，新出现的证据表明，在炎症条件下可以诱导调节性B细胞（Breg），这些Breg细胞可以抑制炎症和/或增强耐受性。致敏小鼠表现出对抗原的双期反应，急性暴露引起过敏性气道疾病，慢性暴露导致局部吸入耐受性（LIT），气道和肺部炎症消退，但全身过敏性致敏持续存在。LIT的一个一致特征是淋巴细胞持续存在于支气管肺泡灌洗液、肺组织和肺门淋巴结（HLN）中。这些淋巴细胞中的一些是调节性T细胞（Treg），但其他的是B细胞。根据我们的初步数据，我们假设一种新的调节性b细胞表型在局部组织的LIT发育过程中分化，并且这种细胞调节局部免疫反应。我们建议确定促进LIT发展的B细胞亚群及其机制，具有以下具体目的：1)评估抑制性HLN LIT B细胞亚群的表型和功能特征；2)确定LIT HLN b细胞介导诱导Treg细胞的机制；3)确定这种抑制性Breg是否代表先前存在的细胞类型被募集到hln中，或者是从先前存在的B细胞亚群转化而来。从我们提出的研究中获得的见解可能阐明LIT的重要机制，并最终可能帮助我们了解如何类似地关闭人类哮喘患者的气道炎症。此外，上述研究的结果将产生关于b细胞调节t细胞功能的新的基本免疫学见解，这可能会产生远远超出哮喘的影响。公共卫生相关性：过敏小鼠能够关闭它们的哮喘。它们似乎产生了一种特殊类型的B淋巴细胞，这种B淋巴细胞能够产生抑制气道炎症的调节性T淋巴细胞。更好地了解小鼠的这一过程可能有助于我们学习如何类似地关闭人类哮喘患者的气道炎症。

DESCRIPTION (provided by applicant): Asthma is an inflammatory disease of the airways, involving antigen-presenting cells, T lymphocytes, mast cells and eosinophils. B lymphocytes have traditionally been viewed as target cells for Th2 cytokines; however, emerging evidence suggests that regulatory types of B cells (Breg) can be induced under inflammatory conditions and that these Breg cells can suppress inflammation and/or enhance tolerance. Sensitized mice demonstrate a biphasic response to antigen, with acute exposure eliciting allergic airway disease but chronic exposure resulting in local inhalational tolerance (LIT), with resolution of airway and lung inflammation but persistence of systemic allergic sensitization. A consistent feature of LIT is the persistence of lymphocytes in bronchoalveolar lavage, lung tissue, and hilar lymph nodes (HLN). Some of these lymphocytes are regulatory T cells (Treg), but others are B cells. Based on our preliminary data, we hypothesize that a novel regulatory B-cell phenotype differentiates during the development of LIT in regional tissues, and that this cell regulates local immunologic responses. We propose to identify the B cell subset(s) and their mechanisms that contribute to the development of LIT with the following Specific Aims: 1) Assess phenotypic and functional characteristics of suppressive HLN LIT B cell subset(s); 2) Determine the mechanism(s) underlying LIT HLN B-cell-mediated induction of Treg cells; and 3) Determine if this inhibitory Breg represents recruitment of a pre-existing cell type into the HLNs or conversion from a pre-existing B cell subset. Insights gained from our proposed studies may elucidate important mechanisms underlying LIT and, ultimately, may help us learn how to similarly turn off airway inflammation in human asthmatics. Moreover, results of the above studies will yield new fundamental immunologic insights regarding B-cell regulation of T-cell function, which may have ramifications that extend well beyond asthma. PUBLIC HEALTH RELEVANCE: Allergic mice are able to turn off their asthma. They appear to make a specific type of B lymphocyte that is capable of creating regulatory T lymphocytes, which inhibit airway inflammation. Better understanding of this process in mice may help us to learn how to similarly turn off airway inflammation in human asthmatics.