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于Th2极化的免疫反应对其他明显无害的环境蛋白造成的。为什么特定的蛋白质在易感宿主中驱动如此不适应的免疫反应还不清楚。我们的实验室和其他人已经提出，这些蛋白质和先天性免疫系统之间的直接、(Dys)功能相互作用是过敏的分子基础的核心。以屋尘螨变应原Der p 2为例，我们的数据表明它往往是获得性免疫反应的目标，因为它具有内在的佐剂活性，因为它具有分子模拟MD-2，TLR4复合体的内毒素结合亚单位。在无MD-2和存在MD-2的情况下，DER-2可以分别重建和增强TLR4信号。此外，Der p2在小鼠的呼吸道中驱动TLR4依赖、MD-2非依赖的Th2极化炎症。最近的数据表明，TLR4信号在推动Th2炎症中起重要作用的相关基因涉及通过气道上皮细胞(AECs)的TLR4信号，AECs通过产生趋化因子和细胞因子来调节肺树突状细胞的功能，从而调节空气过敏反应的发展。依赖MD-2的TLR4信号涉及MAL/MyD88和TRIF/TRAM信号转导通路的激活。依赖于Der p2的TLR4信号转导的分子机制尚不清楚。根据初步数据，我们假设：(A)与MD-2一样，Der p2通过两条途径驱动TLR4信号；但(B)Der p 2的过敏性主要取决于TRIF/TRAM信号。拟议的实验将确定依赖于Der p2的TLR4刺激在遗传上易处理的细胞系中激活的信号通路；确定由Der p 2驱动的TLR4信号在原代AEC中驱动的Th2极化细胞反应(和潜在的信号通路)；以及使用遗传小鼠模型确定TLR4驱动的信号通路对Der p 2的体内过敏性至关重要。这项建议的长期目标是确定Der p 2激活的信号通路及其对空气过敏的生物学后果，以设计新的过敏性哮喘预防和/或治疗策略。 公共卫生相关性：过敏性哮喘通常是一种使人衰弱的慢性肺部疾病，在发达国家的患病率急剧上升。该项目的目标是了解过敏原如何导致过敏性哮喘的发生，以便开发新的预防和/或治疗措施。

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.