DENDRITIC CELLS IN ATOPIC AND VIRUS-INDUCED AIRWAY DISEASE

描述（由申请方提供）：现代化世界中，过敏性疾病的患病率正在增加，严重的呼吸道病毒感染会大大增加哮喘和过敏性（特应性）疾病的风险。病毒性和过敏性疾病诱导IgE的产生，尽管抗病毒IgE没有已知的功能作用。树突状细胞（DC）是启动适应性免疫应答的关键细胞。本提案的主要目标是了解肺实质DC和IgE在呼吸道病毒诱导的特应性疾病发展中的作用。副粘病毒感染诱导肺DC上IgE的高亲和力受体（FceRI）的表达，随后是病毒特异性IgE。这种IgE可以结合并交联FceRI，导致Th 2和Treg细胞的化学引诱物的释放。以这种方式募集的Th 2细胞产生IL-13，其导致粘液细胞化生。DC FceRI表达的丧失导致Th 2和Treg向肺的募集减少，并且未能发展病毒后粘液细胞化生。最后，在病毒感染期间暴露于非病毒抗原诱导针对该非病毒抗原的IgE。这些数据表明了肺DC上IgE介导的FceRI交联导致T细胞的募集和分化的假设，所述T细胞赋予特应性并启动针对非病毒环境抗原的IgE产生。为了检验这一假设，提出了以下两个具体目标：定义树突细胞FceRI交联对树突细胞和T细胞功能的影响。在该目的中，将利用体外和体内方法来检查FceRI改变DC功能以导致Th 2依赖性特应性应答的发展的机制。Aim II.表征树突状细胞FceRI表达和IgE之间的相互依赖性。在该目的中，将研究IgE调节DC上FceRI表达的能力，以及DC FceRI表达产生针对非病毒抗原的IgE的作用。公共卫生相关性。这些研究的相关性在于，它们提供了有关呼吸道病毒感染与过敏性疾病和哮喘相关机制的重要知识。此外，这些研究为调节树突状细胞功能以改善病毒后过敏性疾病以及哮喘和特应性的初始发展提供了治疗浓度的基础。

DESCRIPTION (provided by applicant): The prevalence of allergic disease is increasing in the modernized world, with severe respiratory viral infections imparting a greatly increased risk for asthma and allergic (atopic) disease. Viral and allergic diseases induce production of IgE, although no known functional role has been proposed for antiviral IgE. Dendritic cells (DC) are the critical cells initiating the adaptive immune response. The primary goal of this proposal is to understand the role lung parenchyma DC and IgE play in the development of respiratory virus- induced atopic disease. Paramyxoviral infection induces expression of the high affinity receptor for IgE (FceRI) on lung DC, followed by viral specific IgE. This IgE can bind and crosslink FceRI leading to release of a chemoattractant for Th2 and Treg cells. The Th2 cells that are recruited in this manner produce IL-13, which leads to mucous cell metaplasia. Loss of DC FceRI expression led to reduced Th2 and Treg recruitment to the lung and a failure to develop post-viral mucous cell metaplasia. Finally, exposure to a non-viral antigen during the viral infection induced IgE against this non-viral antigen. These data suggest the hypothesis that IgE- mediated crosslinking of FceRI on lung DC leads to recruitment and differentiation of T cells that impart atopy and initiate IgE production against non-viral environmental antigens. To test this hypothesis the following two specific aims are proposed: Aim I. Define the effect of dendritic cell FceRI crosslinking on dendritic and T cell function. In this aim in vitro and in vivo approaches will be utilized to examine the mechanisms by which FceRI alters DC function to lead to the development of a Th2 dependent atopic response. Aim II. Characterize the interdependence between dendritic cell FceRI expression and IgE. In this aim the ability of IgE to modulate FceRI expression on DC will be studied, as will the role of DC FceRI expression to generate IgE against non-viral antigens. PUBLIC HEALTH RELEVANCE. The relevance of these studies is that they provide important knowledge on the mechanisms involved in linking respiratory viral infection to allergic disease and asthma. Further, these studies provide the basis for therapeutic concentration on modulating dendritic cell function to ameliorate post-viral allergic disease and the initial development of asthma and atopy.