TLR9 Mediated Dendritic Cell Responses in Hypersensitivity Pneumonitis

描述(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。幽门螺杆菌的流行病学在很大程度上仍不清楚。幽门螺杆菌具有强烈的Th1(或1型)免疫应答的特点，以往的研究表明Th1细胞因子如IL-12和干扰素-γ在幽门螺杆菌的发病机制中起重要作用。水苏打菌(SC)是一种二相性真菌，与多种呼吸道疾病有关，包括“病态建筑综合症”、哮喘和幽门螺杆菌。在初步研究中，我们发现吸入SC分生孢子会导致致敏小鼠出现肺过敏反应。此外，在缺乏细胞内Toll样受体TLR9的小鼠中，SC引起的肉芽肿炎症显著减少。在TLR9缺陷小鼠中观察到的肉芽肿反应改变的机制尚未确定，这是本提案中概述的这项研究的重点。在这些初步研究的基础上，我们假设树突状细胞(DC)是在SC诱导的HP形成过程中促进Th1反应的基本抗原提呈细胞，DC促进肉芽肿炎症的作用是由TLR9介导的。目的1)确定SC分生孢子在体外对DC效应的影响，并确定TLR9是否是SC介导的DC激活所必需的；目的2)确定TLR9在SC诱导的体内肺肉芽肿性炎症中的作用；目的3)确定TLR9介导的DC应答在SC诱导的HP肉芽肿炎症中的作用。这项提议将作为我迄今为止研究TLR9介导的肺部抗菌免疫反应的工作的自然延伸。概述的培训方案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一名成功的独立内科科学家所需的工具。相关性(见说明)：过敏性肺炎是一种复杂的综合征，具有不同的强度和临床表现，影响大约9%的普通人群。该病的病因和进展的潜在机制仍不清楚。这个项目将提供对TLR9介导的树突状细胞反应在肉芽肿炎症发生中的作用的机械性见解。

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.