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.
. 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.
|Tam, Jonathan S; Jackson, William T; Hunter, Desire et al. (2013) Rhinovirus specific IgE can be detected in human sera. J Allergy Clin Immunol 132:1241-3|
|Vasudev, Monica; Cheung, Dorothy S; Pincsak, Hannah et al. (2012) Expression of high-affinity IgE receptor on human peripheral blood dendritic cells in children. PLoS One 7:e32556|
|Salti, Suzan M; Hammelev, Erin M; Grewal, Jenny L et al. (2011) Granzyme B regulates antiviral CD8+ T cell responses. J Immunol 187:6301-9|
|Khan, Sadia Hayat; Grayson, Mitchell H (2010) Cross-linking IgE augments human conventional dendritic cell production of CC chemokine ligand 28. J Allergy Clin Immunol 125:265-7|
|Cheung, Dorothy S; Ehlenbach, Sarah J; Kitchens, Robert T et al. (2010) Cutting edge: CD49d+ neutrophils induce FcepsilonRI expression on lung dendritic cells in a mouse model of postviral asthma. J Immunol 185:4983-7|
|Cheung, Dorothy S; Ehlenbach, Sarah J; Kitchens, Tom et al. (2010) Development of atopy by severe paramyxoviral infection in a mouse model. Ann Allergy Asthma Immunol 105:437-443.e1|