Epithelial Regulation of Th2 Immune Responses in the Lung

描述（由申请人提供）：过敏性哮喘是一种近几十年来呈上升趋势的慢性疾病。虽然哮喘的病因尚不清楚，但目前认为是由于不适当的CD4？易感个体对空气中过敏原介导的炎症反应。尽管进行了广泛的研究，但哮喘个体启动Th2 （IL-13）免疫反应的确切机制尚不清楚。Th2免疫反应的启动和维持依赖于气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）的特定亚群对于过敏性气道反应的启动至关重要，并在驱动对吸入抗原的免疫（髓细胞，mDCs）或耐受性（浆细胞样细胞，pDCs）中发挥重要作用。然而，特异性DC亚群被招募到肺部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了一种新的假设，即常见的过敏原，屋尘螨，通过激活dectin-1（一种识别β -葡聚糖的模式识别分子），触发未成熟树突状细胞化学引诱剂CCL20从细胞外基质分子syndecan-1上的存储位点快速释放。CCL20一旦释放，就会驱动免疫原性骨髓树突状细胞亚群的优先招募和激活，进而指导Th2细胞分化和过敏性炎症的发展。此外，IL-13本身可以诱导CCL20从气道上皮释放，为Th2细胞因子的持续产生提供了一个扩增回路。驱动上皮细胞从syndecan释放CCL20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募集进入肺部的机制，以及这些途径在过敏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，我们提出以下具体目标来验证这一假设，并确定过敏原诱导Th2细胞因子产生的分子机制：1)确定dectin-1信号通路在hdm诱导的气道上皮细胞表面syndecan-1/CCL20复合物释放中的作用；2)体外和体内研究syndecan-1调控树突状细胞调节T细胞IL- 13生成的机制；3)确定IL-13持续募集免疫原性DC亚群和进一步产生Th2细胞因子的机制。总的来说，这些研究的结果应该提供更好地理解驱动Th2 （IL-13）细胞因子产生的机制，并可能导致新的哮喘治疗方法的发展，这些治疗方法是改善而不是改善疾病。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，本提案的研究旨在阐明导致IL-13在肺部产生的途径。确定启动这些反应的特定途径可能会导致开发新的有效疗法来治疗这种不断增加的疾病。

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.