Asthma is a complex inflammatory disease thought to reflect a dysregulated immune state that is established by elevated levels of the cytokines IL-4 and IL-13 in lung tissues. Increased numbers of innate and adaptive IL-4/IL-13-expressing cells, including Th2 cells, eosinophils, basophils and mast cells are found in chronically affected lung, and elevated levels of IgE are believed to contribute to sensitivity to aeroallergens. Despite the discovery of microbial ligands for receptors that induce inflammatory T helper cells subsets, including Th1 cells and Th17 cells, few molecular markers are known which induce immune responses by the characteristic cell types involved in allergy and asthma. We have recently discovered that a common constituent associated with many allergens is capable of inducing influx of eosinophils and basophils into the lungs of mice. Further, instillation induced the accumulation of alternatively activated macrophages, which are increasingly being recognized as a critical element of allergic immunity. This project will explore the contributions by this constituent component of helminths, insects and fungal cell walls in provoking changes in dendritic cells that mediate differentiation of Th2 cells, recruitment of innate IL-4/IL-13-producing cells, induction of B cell responses leading to IgE and lgG1, and ultimately a mucosal and tissue response. Using mice with genes modified to report faithful expression of key components of Th2-associated immunity, three specific aims are proposed: 1. To assess the role of chitin as an adjuvant and as a component of a fungal extract of Aspergillus in inducing dendritic cell activation in vivo. 2. To assess the role of chitin as an adjuvant and as a component of a fungal extract of Aspergillus in inducing Th2 cells and IL-4-dependent antibody isotypes. 3. To assess the role of chitin in the induction of feedback mechanisms that limit the inflammatory process in the lungs. LAY SUMMARY: The prevalence of asthma remains extensive in the United States and other developed countries. Knowledge of precise environmental agents that contribute to asthma and that can be studied in model animal systems is incomplete. This proposal will use mice to study novel and relevant mechanisms.
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