Epithelial Regulation of Th2 Immune Responses in the Lung

描述(申请人提供)：过敏性哮喘是一种慢性疾病，近几十年来呈上升趋势。虽然哮喘的病因还不是很清楚，但目前认为它是由于易感个体对空气传播的过敏原的不适当的CD4？介导性炎症反应所致。尽管进行了广泛的研究，但哮喘患者启动Th2(IL-13)免疫反应的确切机制尚不清楚。Th2免疫应答的启动和维持依赖于呼吸道表面树突状细胞的特异性激活。最近的证据表明，树突状细胞(DC)的特定亚群在启动过敏性呼吸道反应中起关键作用，并在驱动免疫(髓系，MDCS)或对吸入性抗原的耐受(浆细胞，PDCs)方面发挥重要作用。然而，特定的DC亚群被招募到肺并在过敏原暴露下被激活的机制尚不清楚。我们的初步数据共同支持这一新的假设，即常见的过敏原房屋尘螨通过激活识别β-葡聚糖的模式识别分子Dectin-1，触发未成熟的树突状细胞趋化物质CCL20从其在细胞外基质分子syndecan-1上的存储位置快速释放。CCL20一旦释放，就会驱动免疫原性髓系树突状细胞亚群的优先招募和激活，进而指导Th2细胞的分化和过敏性炎症的发展。此外，IL-13本身可以诱导呼吸道上皮细胞释放CCL20，为Th2细胞因子的持续产生提供一个扩增环。驱动上皮细胞CCL20从Syndecan释放的分子机制，CCL20/syndecan-1优先募集和激活MDCs的机制，IL-13诱导CCL20释放并使树突状细胞持续募集到肺内的机制，以及这些途径在变应原诱导的气道高反应性和气道炎症中的确切作用尚不清楚。因此，我们提出以下特定的目的来验证这一假说，并确定变应原诱导Th2细胞因子产生的分子机制：1)确定Dectin-1信号通路在HDM诱导的呼吸道上皮细胞表面释放Syndecan-1/CCL20复合体中的作用；2)确定Syndecan-1在体外和体内调节树突状细胞调节T细胞IL-13产生的机制；3)确定IL-13维持免疫原性DC亚群的招募和进一步Th2细胞因子产生的机制。总而言之，这些研究的结果应该能更好地理解驱动Th2(IL-13)细胞因子产生的机制，并可能导致新的哮喘疗法的开发，这些疗法是改善而不是改善疾病的。与公共卫生相关：哮喘是一种慢性肺部疾病，近几十年来一直在上升。由于IL-13已被证明是过敏性炎症的中心介质，本提案中的研究旨在阐明导致IL-13在肺中产生的途径。识别启动这些反应的特定途径可能会导致开发新的、有效的疗法来治疗这种日益增长的疾病。

DESCRIPTION (provided by applicant): Allergic asthma is a chronic disease which has been on the rise in recent decades. Although the etiology of asthma is not well understood, it is currently thought to arise as a result of inappropriate CD4?mediated inflammatory responses to airborne allergens in susceptible individuals. Despite extensive investigation, the exact mechanisms responsible for the initiation of Th2 (IL-13) immune responses in asthmatic individuals are unknown. The initiation and maintenance of Th2 immune responses are dependent upon specific activation of dendritic cells at the airway surface. Recent evidence suggests that specific subsets of dendritic cells (DCs) are critical for the initiation of allergic airway responses and play an important role in driving either immunity (myeloid, mDCs) or tolerance (plasmacytoid, pDCs) to inhaled antigens. However, the mechanisms by which specific DC subsets are recruited to the lung and activated in response to allergen exposure are unknown. Our preliminary data collectively support the novel hypothesis that the common allergen, house dust mite, triggers the rapid release of the immature dendritic cell chemoattractant, CCL20, from its storage sites on the extracellular matrix molecule syndecan-1, through the activation of dectin-1, a pattern recognition molecule which recognizes beta-glucans. CCL20 once released drives the preferential recruitment and activation of the immunogenic myeloid dendritic cell subset which in turn directs Th2 cell differentiation and the development of allergic inflammation. Moreover, IL-13 itself can induce the release of CCL20 from the airway epithelium providing an amplication loop for continued Th2 cytokine production. The molecular mechanisms driving epithelial CCL20 release from syndecan, the mechanisms of preferential recruitment and activation of mDCs by CCL20/syndecan-1, the mechanisms by which IL-13 induces CCL20 release and perpetuates dendritic cell recruitment into the lung, and the exact contributions of these pathways to allergen-induced airway hyperresponsiveness and airway inflammation are unknown. Thus we propose the following specific aims to test this hypothesis and define the molecular mechanisms underlying allergen-induced induction of Th2 cytokine production: 1)To determine the role of dectin-1 signaling pathways in the HDM-induced release of syndecan-1/CCL20 complexes from the surface of airway epithelial cells; 2) To determine the mechanism by which syndecan-1 regulates dendritic cell conditioning of T cell IL- 13 production in vitro and in vivo; 3)To determine the mechanisms by which IL-13 perpetuates the recruitment of immunogenic DC subsets and further Th2 cytokine production. Collectively, the results of these studies should provide a better understanding of the mechanisms driving Th2 (IL-13) cytokine production and may lead to the development of novel asthma therapies which are disease modifying rather than ameliorative. PUBLIC HEALTH RELEVANCE: Asthma is a chronic disease of the lung which has been on the rise in recent decades. As IL-13 has been shown to be a central mediator of allergic inflammation, studies in this proposal aim to elucidate the pathways leading to the generation of IL-13 in the lung. The identification of specific pathways initiating these responses may lead to the development of novel, effective therapies for the treatment of this ever-increasing disease.