Der p 2-driven TLR4 signaling in allergic asthma

描述（由申请人提供）：过敏性哮喘被认为是由th2极化免疫反应引起的，否则显然是无害的环境蛋白。为什么特定的蛋白质在易感宿主中驱动这种适应性不良的免疫反应尚不清楚。我们的实验室和其他人已经提出，这些蛋白质与先天免疫系统之间的直接（天）功能相互作用是致敏性的分子基础的核心。对于主要的尘螨过敏原Der p2，我们的数据表明，它往往是适应性免疫反应的目标，因为它具有内在的佐剂活性，这是由于它的分子模拟MD-2， TLR4复合体的lps结合亚基。在MD-2缺失和MD-2存在的情况下，Der p2分别可以重建和增强TLR4信号。此外，Der p2在小鼠气道中驱动tlr4依赖性、MD- 2非依赖性的th2极化炎症。最近的数据表明，TLR4信号通路的相关位点对驱动气道Th2炎症很重要，涉及气道上皮细胞（AECs）的TLR4信号通路，其通过产生趋化因子和细胞因子来调节气道过敏反应的发展，这些趋化因子和细胞因子招募和调节肺树突状细胞的功能。md -2依赖性TLR4信号通路涉及Mal/MyD88和TRIF/TRAM信号转导通路的激活。Der p2依赖性TLR4信号的分子机制仍有待明确。基于初步数据，我们假设：(a)与MD-2一样，Der p2通过两种途径驱动TLR4信号传导；但(b) Der p2的致敏性主要取决于TRIF/TRAM信号。本实验将确定基因易感性细胞系中受Der p2依赖性TLR4刺激激活的信号通路；确定原发性aec中由Der p2驱动的TLR4信号驱动的th2极化细胞反应（以及潜在的信号通路）；并使用遗传小鼠模型确定tlr4驱动的信号通路对Der p2的体内致敏性至关重要。本提案的长期目标是明确由Der p2激活的信号通路及其对空气过敏的生物学影响，以便制定新的预防和/或治疗过敏性哮喘的策略。

DESCRIPTION (provided by applicant): Allergic asthma is thought to result from Th2-polarized immune responses to otherwise apparently innocuous environmental proteins. Why specific proteins drive such maladaptive immune responses in susceptible hosts has been unclear. Our lab and others have suggested that direct, (dys)functional interactions between such proteins and the innate immune system are central to the molecular basis of allergenicity. In the case of Der p 2, a major house dust mite allergen, our data indicate that it tends to be a target of adaptive immune responses because it has intrinsic adjuvant activity due to its molecular mimicry of MD-2, the LPS-binding subunit of the TLR4 complex. Der p 2 can reconstitute and augment TLR4 signaling in the absence and presence of MD-2, respectively. In addition, Der p 2 drives TLR4-dependent, MD- 2-independent Th2-polarized inflammation in the airways of mice. Recent data suggest that the relevant locus of TLR4 signaling important for driving Th2 inflammation in the airway involves TLR4 signaling by airway epithelial cells (AECs), which regulate the development of aeroallergic responses via the production of chemokines and cytokines that recruit and regulate the function of lung dendritic cells. MD-2-dependent TLR4 signaling involves activation of both Mal/MyD88 and TRIF/TRAM pathways of signal transduction. The molecular mechanisms underlying Der p 2-dependent TLR4 signaling remain to be defined. Based on preliminary data, we hypothesize that: (a) like MD-2, Der p 2 drives TLR4 signaling via both pathways; but (b) the allergenicity of Der p 2 is depends primarily on TRIF/TRAM signaling. The proposed experiments will define the signaling pathways activated by Der p 2-dependent TLR4 stimulation in genetically tractable cell lines; determine the Th2-polarizing cellular responses (and underlying signaling pathways) driven by Der p 2-driven TLR4 signaling in primary AECs; and define the TLR4-driven signaling pathways essential to the in vivo allergenicity of Der p 2 using genetic mouse models. The long-term goal of this proposal is to define the signaling pathways activated by Der p 2 and their biological consequences for aeroallergy, in order to devise new preventive and/or therapeutic strategies for allergic asthma. PUBLIC HEALTH RELEVANCE: Allergic asthma is often a debilitating chronic lung disease that has undergone a dramatic increase in prevalence in the developed world. The goal of this project is to understand how allergens induce the development of allergic asthma so that new preventive and/or therapeutic measures can be developed.