Local B cell memory in airway hypersensitivity.

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Project Summary/Abstract Allergic asthma is a chronic inflammatory disease of the airway that currently has no cure. Production of immunoglobulin E (IgE) to inhaled allergens drives inflammation and the allergic response seen in allergic asthma. Over half of patients exhibit allergen-specific IgE at the respiratory mucosa but not systemically in circulation, illustrating the importance of local production of IgE. However, the mechanisms that promote and maintain local pathogenic IgE responses are not understood. Using a mouse model of airway hypersensitivity, we have identified a population of memory B cells that localize to the lungs after repeated exposures to inhaled allergens. These lung-localized memory B cells exhibit specificity for allergens, persist after the resolution of inflammation, expand upon re-challenge with increase of local allergen-specific IgE. We hypothesize that tissue- resident memory B cells are the major source of local responses in asthmatic lungs, responsible for maintaining long-term hypersensitivity in the airway. In this proposal, we will elucidate the cellular environment that maintains lung residency of memory B cells in asthmatic lungs and investigate their functions in airway hypersensitivity. Specifically, in Aim 1, using in vivo depletion of circulating cells and parabiosis experiments we will verify the tissue-residency of memory B cells in asthmatic lungs. We will identify the potential niches of lung-localized memory B cells and examine the cellular environment responsible for their maintenance in the lungs using cutting-edge imaging technologies. In Aim 2, we will inhibit recruitment of circulating B cells during re-challenge and perform adoptive cell transfer of tissue-resident memory B cells to delineate the function of tissue-resident memory B cells in airway hypersensitivity. In summary, we aim to shed light on the fundamental biology of memory B cells in the respiratory tract and reveal their functions in airway hypersensitivity. This study may reveal a crucial cell population that can be targeted to treat or prevent the progression of allergic asthma in humans. This fellowship will provide the crucial support for the applicant to pursue a career as an independent investigator in immunology.