Investigating the role of IgE independent mast cell responses in allergic sensitization

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7. Project Summary/Abstract Allergy is a disorder of the immune system that occurs following sensitization to an allergen. Allergic sensitization results in immunological memory against an allergen that enables the body to quickly respond to subsequent allergen challenges. In the allergic response, mast cell activation causes several allergic symptoms via degranulation of pre-formed inflammatory mediators. This process can occur through immunoglobulin E (IgE)-dependent or -independent pathways. IgE-dependent mast cell activation is classically appreciated for its role in the allergic response after allergic memory has developed; however, the physiological relevance of IgE-independent mast cell responses is less understood. The MAS-related G protein-coupled receptor B2 (MRGPRB2) is a mast cell-specific receptor that induces mast cell activation upon binding small cationic molecules such as compound 48/80. While MRGPRB2 has been implicated in pseudo- allergic drug reactions, the immunological consequences of MRGPRB2-mediated mast cell activation are incompletely characterized. The objective of this proposal is to study the role of IgE-independent mast cell responses in the context of allergic sensitization. Based on preliminary data that compound 48/80 induces allergic memory in a mouse model of allergic airway inflammation, we hypothesize that allergic sensitization requires MRGPRB2-mediated mast cell activation. To test this hypothesis, two aims will be investigated. The first aim will examine the dependence of 48/80-mediated allergic sensitization on mast cells and on MRGPRB2 using mice that are deficient in mast cells or MRGPRB2. The second aim will investigate the downstream effect and dependence of 48/80-mediated allergic sensitization on dendritic cells using CD11c-deficient, mast cell-deficient, and MRGPRB2-deficient mice. Together, these studies will provide insight into mast cell function and may identify a previously uncharacterized role of mast cells in allergic inflammation. Alongside this research, the applicant will complete a program of advanced coursework, clinical electives, and scientific skill building under the close mentorship of her advisor. The research and training detailed in this application will prepare her to pursue a clinically relevant basic science career as an independent physician-scientist.