Regional B Cells Modulate Airway Th2 Responses

描述(申请人提供)：哮喘是一种呼吸道炎症性疾病，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，B淋巴细胞被认为是Th2细胞因子的靶细胞；然而，新的证据表明，调节型B细胞(Breg)可以在炎症条件下诱导，这些Breg细胞可以抑制炎症和/或增强耐受性。致敏小鼠对抗原表现出双相反应，急性暴露引起过敏性呼吸道疾病，而慢性暴露导致局部吸入耐受(LIT)，呼吸道和肺部炎症消退，但全身性变态反应持续。LIT的一个一贯特征是淋巴细胞在支气管肺泡灌洗液、肺组织和肺门淋巴结(HLN)中持续存在。这些淋巴细胞中有一些是调节性T细胞(Treg)，但也有一些是B细胞。根据我们的初步数据，我们假设在局部组织LIT的发展过程中，一种新的调节性B细胞表型分化，并且该细胞调节局部免疫反应。我们建议确定B细胞亚群(S)及其促进LIT发展的机制，具体目的如下：1)评估抑制性HLN LIT B细胞亚群(S)的表型和功能特征；2)确定LIT B细胞介导的Treg细胞诱导的机制(S)；3)确定这种抑制性Breg是否代表着一种预先存在的细胞类型重新聚集到HLN中或从先前存在的B细胞亚群转化为HLN。从我们提出的研究中获得的见解可能会阐明LIT背后的重要机制，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呼吸道炎症。此外，上述研究的结果将对B细胞对T细胞功能的调节产生新的基本免疫学见解，这可能会产生远远超出哮喘的影响。与公共卫生相关：过敏性小鼠能够治愈哮喘。它们似乎能产生一种特殊类型的B淋巴细胞，这种B淋巴细胞能够产生调节性T淋巴细胞，从而抑制呼吸道炎症。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呼吸道炎症。

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.