TLR9 Mediated Dendritic Cell Responses in Hypersensitivity Pneumonitis

描述（由申请人提供）：过敏性肺炎（HP）是一种炎症性肺部疾病，在反复暴露于吸入颗粒抗原后发生。HP的流行病学在很大程度上仍然是未知的。HP的特点是Th1（或1型）介导的强烈免疫反应，既往研究表明Th1细胞因子如IL-12和IFN-y在HP的发病过程中起重要作用。Stachybotrys chartarum （SC）是一种二态真菌，与许多呼吸系统疾病有关，包括“病态建筑综合征”、哮喘和HP。在初步研究中，我们发现在致敏小鼠中吸入SC分生孢子会导致肺部超敏反应的发生。此外，在细胞内toll样受体TLR9缺失的小鼠中，SC诱导的肉芽性炎症显著减少。在TLR9缺陷小鼠中观察到的肉芽肿反应改变的机制尚未明确，这是本提案中概述的研究重点。基于这些初步研究，我们假设树突状细胞（DC）是sc诱导HP发展过程中促进Th1应答的必需抗原提呈细胞，DC促进肉芽肿炎症是由TLR9介导的。目的1)确定SC分生孢子对体外DC效应反应的影响，确定SC介导的DC激活是否需要TLR9；目的2)确定TLR9在sc诱导的肺肉芽肿炎症中的作用；目的3)确定tlr9介导的DC反应在sc诱导HP中肉芽肿性炎症的产生中的作用。该建议将作为我迄今为止所做的研究TLR9介导的肺部抗菌免疫反应的工作的自然延伸。所概述的培训计划旨在提供必要的技术和知识基础，以成功完成所概述的研究，并提供发展成为一名成功的独立医生-科学家所需的工具。相关性（见说明书）：过敏性肺炎是一种具有不同强度和临床表现的复杂综合征，约占总人口的9%。该疾病的机制、病因和进展尚不清楚。该项目将为TLR9介导的树突状细胞反应在肉芽肿炎症产生中的作用提供机制见解。

DESCRIPTION (provided by applicant): Hypersensitivity pneumonitis (HP) is an inflammatory lung disease that develops following repeated exposure to inhaled particulate antigen. The epidemiology of HP remains largely unknown. HP is characterized by a vigorous Th1 (or type 1) mediated immune response and previous studies suggest that Th1 cytokines such as IL-12 and IFN-y play an important role in the pathogenesis of HP. Stachybotrys chartarum (SC) is a dimorphic fungus that has been implicated in a number of respiratory illnesses, including "sick building syndrome", asthma, and HP. In preliminary studies, we have found that inhalation of SC conidia in sensitized mice results in the development of a pulmonary hypersensitivity response. Moreover, granulmatous inflammation induced by SC is substantially reduced in mice deficient in the intracellular toll- like receptor, TLR9. Mechanisms accounting for the altered granulomatous response observed in TLR9- deficient mice have not been defined and are the focus of this studies outlined in this proposal. Based on these preliminary studies, we hypothesize that the dendritic cell (DC) is the essential antigen presenting cell that promotes Th1 responses during the development of SC-induced HP, and the promotion of granulomatous inflammation by DC is mediated by TLR9. The following Specific Aims are designed to test this hypothesis: Aim 1) To determine the effect of SC conidia on DC effector responses in vitro, and determine if TLR9 is required for SC-mediated DC activation; Aim 2) To determine the contribution of TLR9 to SC-induced pulmonary granulomatous inflammation in vivo; Aim 3) To determine the contribution of TLR9-mediated DC responses in the generation of granulamatous inflammation in SC-induced HP. This proposal will serve as a natural extension of work I have performed to date investigating TLR9- mediated responses in lung antibacterial immunity. The training program outlined has been designed to provide the necessary techniques and knowledge base to successfully complete the studies outlined and the tools required to develop into a successful independent physician-scientist. RELEVANCE (See instructions): Hypersensitivity pneumontis is a complex syndrome of varying intensity and clinical presentation affecting approximately 9% of the general population. Mechanisms underlying cause and progression of the disease are still unknown. This project will provide mechanistic insight into the role of TLR9 mediated dendritic cell responses on the generation of granulomatous inflammation.