DENDRITIC CELLS IN ATOPIC AND VIRUS-INDUCED AIRWAY DISEASE

描述(申请人提供)：在现代世界，过敏性疾病的流行率正在增加，严重的呼吸道病毒感染极大地增加了哮喘和过敏性(特应性)疾病的风险。病毒和过敏性疾病诱导IgE的产生，尽管抗病毒IgE的功能尚未被提出。树突状细胞(DC)是启动获得性免疫反应的关键细胞。这项建议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所起的作用。副粘病毒感染可诱导肺树突状细胞高亲和力IgE受体(FceRI)的表达，进而诱导病毒特异性IgE的表达。这种IgE可以结合和交联FceRI，从而释放一种对Th2和Treg细胞的趋化物质。以这种方式招募的Th2细胞产生IL-13，导致粘液细胞化生。DC FceRI表达的缺失导致Th2和Treg向肺的募集减少，并未能发展为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了针对该非病毒抗原的IgE。这些数据提示一种假设，即IgE介导的肺树突状细胞表面FceRI的交联会导致T细胞的募集和分化，从而传递特应性并启动针对非病毒环境抗原的IgE产生。为了验证这一假说，提出了以下两个具体目标：目的1.确定树突状细胞FceRI交联物对树突状细胞和T细胞功能的影响。为此，将利用体外和体内方法来研究FceRI改变DC功能从而导致Th2依赖的特应性反应的机制。目的II.研究树突状细胞FceRI表达与免疫球蛋白E的相关性。为此，我们将研究IgE调节DC表面FceRI表达的能力，以及DC FceRI表达在产生抗非病毒抗原的IgE中的作用。与公共卫生相关。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之间联系的机制的重要知识。此外，这些研究为集中治疗调节树突状细胞功能以改善病毒后变态反应疾病以及哮喘和特应性疾病的初始发展提供了基础。

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.