TLR9 Mediated Dendritic Cell Responses in Hypersensitivity Pneumonitis

描述（由申请方提供）：过敏性肺炎（HP）是一种炎症性肺病，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未知。HP以Th 1（或1型）介导的免疫应答为特征，先前的研究表明Th 1细胞因子如IL-12和IFN-γ在HP的发病机制中起重要作用。Chartarum（SC）是一种二型真菌，与许多呼吸道疾病有关，包括“病态建筑综合征”，哮喘和HP。在初步研究中，我们发现，吸入SC分生孢子在致敏小鼠的结果在肺过敏反应的发展。此外，由SC诱导的肉芽肿性炎症在细胞内Toll样受体TLR 9缺陷的小鼠中显著减少。解释TLR 9缺陷小鼠中观察到的肉芽肿反应改变的机制尚未确定，并且是本提案中概述的本研究的重点。基于这些初步研究，我们假设树突状细胞（DC）是在SC诱导的HP的发展过程中促进Th 1应答的必需抗原呈递细胞，并且DC促进肉芽肿性炎症是由TLR 9介导的。本论文的主要目的是：1）在体外研究SC分生孢子对DC效应子应答的影响，并确定SC介导的DC活化是否需要TLR 9; 2）在体内研究TLR 9对SC诱导的肺肉芽肿性炎症的作用;目的3）探讨TLR 9介导的DC反应在SC诱导的HP肉芽肿性炎症中的作用。这个提议将作为我迄今为止研究TLR 9介导的肺抗菌免疫反应的工作的自然延伸。概述的培训计划旨在提供必要的技术和知识基础，以成功完成概述的研究和发展成为成功的独立医生-科学家所需的工具。相关性（参见说明）：过敏性肺炎是一种复杂的综合征，其严重程度和临床表现各不相同，影响约9%的一般人群。该病的病因和进展机制尚不清楚。该项目将为TLR 9介导的树突状细胞反应在肉芽肿性炎症产生中的作用提供机制上的见解。

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.