DENDRITIC CELLS IN ATOPIC AND VIRUS-INDUCED AIRWAY DISEASE

描述（由申请人提供）：在现代化的世界中，过敏性疾病的患病率正在增加，严重的呼吸道病毒感染使哮喘和过敏性（特应性）疾病的风险大大增加。病毒性和过敏性疾病诱导IgE的产生，尽管目前还没有提出抗病毒IgE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。本研究的主要目的是了解肺实质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上表达IgE高亲和力受体（FceRI），其次是病毒特异性IgE。这种IgE可以结合并交联FceRI，导致Th2和Treg细胞释放一种化学引诱剂。以这种方式募集的Th2细胞产生IL-13，导致粘膜细胞化生。DC FceRI表达的缺失导致Th2和Treg向肺的募集减少，并且不能发生病毒后粘膜细胞化生。最后，在病毒感染期间暴露于非病毒抗原诱导IgE对抗该非病毒抗原。这些数据表明，IgE介导的肺DC上的FceRI交联导致T细胞的募集和分化，这些T细胞赋予特应性并启动针对非病毒环境抗原的IgE产生。为了验证这一假设，提出了以下两个具体目标：目的1 .定义树突状细胞FceRI交联对树突状细胞和T细胞功能的影响。在这个目标中，体外和体内的方法将被用来研究FceRI改变DC功能从而导致Th2依赖性特应性反应的机制。目的二世。表征树突状细胞FceRI表达与IgE之间的相互依赖性。为此，我们将研究IgE调节DC上FceRI表达的能力，以及DC上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将呼吸道病毒感染与过敏性疾病和哮喘联系起来的机制的重要知识。此外，这些研究为通过调节树突状细胞功能来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.