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清楚，但目前认为是由于不适当的CD 4？介导易感个体对空气传播的过敏原的炎症反应。尽管进行了广泛的研究，但在哮喘个体中引发Th 2（IL-13）免疫应答的确切机制尚不清楚。Th 2免疫应答的启动和维持依赖于气道表面树突状细胞的特异性活化。最近的证据表明，树突状细胞（DC）的特定亚群是过敏性气道反应的启动至关重要的，并在驱动免疫（骨髓，mDC）或耐受（浆细胞样，pDC）吸入抗原的重要作用。然而，特异性DC亚群被募集到肺中并响应于过敏原暴露而被激活的机制尚不清楚。我们的初步数据共同支持新的假设，即常见的过敏原，屋尘螨，触发快速释放的未成熟的树突状细胞的化学引诱物，CCL 20，从其存储网站上的细胞外基质分子syndecan-1，通过激活dectin-1，模式识别分子，识别β-葡聚糖。CCL 20一旦释放，驱动免疫原性骨髓树突状细胞亚群的优先募集和活化，这反过来又指导Th 2细胞分化和过敏性炎症的发展。此外，IL-13本身可以诱导CCL 20从气道上皮释放，为持续的Th 2细胞因子产生提供扩增环。驱动上皮细胞CCL 20从多配体蛋白聚糖释放的分子机制、CCL 20/多配体蛋白聚糖-1优先募集和激活mDC的机制、IL-13诱导CCL 20释放并使树突状细胞募集进入肺的机制以及这些途径对变应原诱导的气道高反应性和气道炎症的确切贡献尚不清楚。因此，我们提出了以下具体目标来验证这一假设并确定过敏原诱导的Th 2细胞因子产生的分子机制：1）确定dectin-1信号通路在HDM诱导的气道上皮细胞表面syndecan-1/CCL 20复合物释放中的作用; 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使免疫原性DC亚群的募集和进一步的Th 2细胞因子产生永久化的机制。总的来说，这些研究的结果应该提供驱动Th 2（IL-13）细胞因子产生的机制的更好的理解，并可能导致新的哮喘治疗的发展，这是疾病的修改，而不是改善。公共卫生相关性：哮喘是一种慢性肺部疾病，近几十年来呈上升趋势。由于IL-13已被证明是过敏性炎症的中心介质，因此本提案中的研究旨在阐明导致肺中产生IL-13的途径。识别启动这些反应的特定途径可能会导致开发用于治疗这种不断增加的疾病的新的有效疗法。

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.