Mechanisms of atopic disease development in the lung

Medical College Of Wisconsin, Milwaukee WI

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Abstract

? DESCRIPTION (provided by applicant): Asthma and atopic diseases are major health burdens in the westernized world. The mechanism(s) responsible for the development and exacerbation of these diseases are not well understood. Respiratory viral infections have been implicated in development and exacerbation of atopic disease. We have utilized a mouse model of paramyxoviral infection where infection with Sendai virus (SeV) leads to a long-lasting post-viral atopic disease with airway hyperreactivity and mucous cell metaplasia. This pro-atopic paradigm depends upon recruitment of CD49d expressing neutrophils (PMN), which, through an unknown mechanism, drive expression of the high-affinity receptor for IgE on lung dendritic cells. Anti-SeV IgE is made which crosslinks this receptor, ultimately leading to recruitment of IL13 producing Th2 cells. Whether modulation of the PMN subsets can impact disease is not known, nor is it clear what role IgE plays during the antiviral immune response. We hypothesize that specific components of the pulmonary immune response to viruses (i.e., CD49d+ PMN and IgE) drive development of atopic disease, and can be modulated to reduce the atopic disease risk. To test this hypothesis we propose these specific aims: 1) Determine if manipulation of CD49d expressing PMN can prevent post-viral atopic disease. 2) Determine the mechanism through which CD49d expressing PMN induce cDC FceRI. 3) Determine the functional relevance of IgE during the antiviral immune response. Upon completion of this project, we will have determined how CD49d+ PMN differ from CD49d- PMN, whether modulation of their recruitment affects the development of post-viral atopic disease, and whether similar cells exist in humans. The mechanism through which CD49d+ PMN drive dendritic cell expression of FceRI will be known, and we will have determined the functional relevance of IgE in the antiviral immune response. Together, these studies will help us refine and focus potential therapeutic interventions in the future to prevent the development and exacerbation of post-viral atopic disease.