Efficacy of IgE in Mediating Allergic Reactions in Vivo

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DESCRIPTION (provided by applicant): The central element in allergic diseases such as asthma, rhinitis and eczema, is the presence of IgE antibody. While there is general acceptance of the central role for IgE in these diseases, there remains only a poor understanding of the quantitative requirements for IgE in the expression of these diseases. This application focuses on obtaining better quantitative insights on several aspects of the problem. In project by Bochner, two underlying hypotheses are examined, 1) that it is the ratio of antigen-specific IgE to total IgE that is a critical determinant of an in vivo response to allergen challenge and 2) that mast cells are a central determinant in early tissue localized reactions like those in the nose while basophils are involved in food reactions where antigen exposure is likely to occur in the blood. Project 2 offers an extended hypothesis for critical parameters, that not only is the specific to total IgE ratio important, but cellular sensitivity (the quantitative assessment of a cell's ability to respond to antigen) also defines the response. Other aims in project by Macglashan address issues of FceRI expression, how the beta subunit of this receptor is controlled and its influence on overall expression of FceRI and how other early signaling molecule expression is regulated by IgE antibody. A common theme in these studies as well as a theme that binds the various projects together is that the regulation is quantitatively different in vivo than in vitro and we will be assessing these differences and how they influence our understanding of disease expression. In one respect, project by Shroeder re-examines quantitative aspects of basophil and mast cell responses. While staying with the theme of IgE centrality, Project 3 examines the FceRI-bearing antigen-presenting cells and the interaction of FceRI and innate immune receptors. Aims in this project will examine how changes in IgE antibody alter expression of FceRI on dendritic cells and whether this results in changes in the expression and profile of cytokines elaborated by these cells. Changes in the expression and function of innate receptors on dendritic cells and basophils will also be a focus of this project. Finally, this project will examine the influence of IgE on the systemic effects of large local reactions by examining various parameters of basophil and dendritic cell function following in vivo manipulation of IgE and experimental antigen exposure. All projects will modulate IgE levels in vivo to make quantitative determinations of the effects these changes have on various outcomes associated with allergic diseases. Beyond the required administrative core (A), there are two scientific Cores. The Subject Characterization and Recruitment Core provides the comprehensive subject recruitment and characterization that is required for all three projects. The Diagnostics Core provides the comprehensive diagnostic and laboratory assays needed for all three projects.