Characterization of innate and IgE-mediated mast cell functions in honeybee venom allergy using Collaborative Cross mice

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PROJECT SUMMARY/ABSTRACT We will use Collaborative Cross (CC) mice to define how genetic traits influence innate and/or IgE-mediated responses of mast cells (MCs) to honeybee venom. In IgE-dependent allergic reactions, crosslinking of MC high affinity IgE receptors (i.e., FceRI) by the binding of bivalent or multivalent allergen to antigen-specific IgE activates MCs to secrete three major classes of products: 1) preformed mediators stored in cytoplasmic granules, 2) newly synthesized lipid-derived mediators, and 3) cytokines, chemokines and growth factors. These MC products are responsible for many of the signs and symptoms of allergic diseases. MC activation, with or without the involvement of IgE, is also thought to contribute to the inflammation, tissue damage, and even fatal shock induced by envenomation. Components of hymenoptera venoms (e.g., honeybee venom), pharmaceutical agents, and foods are the most common triggers for anaphylaxis in humans. Many people have been sensitized to hymenoptera venoms and some unfortunate individuals react after exposure to such insect stings with serious systemic reactions and even fatal anaphylaxis. However, recent experiments in mice and zebra fish demonstrate that MC-derived proteases can degrade animal venoms and diminish their toxicity. Also, IgE/FceRI-mediated MC activation can enhance the survival of mice challenged with honeybee venom or a snake venom, or with S. aureus bacteria. Yet the benefits of “allergic immune responses”, mediated by IgE/MC- dependent mechanisms, have not been widely recognized. While the exact mechanisms determining whether the outcomes of hymenoptera envenomation are detrimental or favorable have been elusive, we know that genetic factors can significantly influence the development, progression, and severity of allergy and anaphylaxis. We hypothesize that genetic traits, by modulating the strength and/or composition of MC responses to honeybee venom and/or the Th2-IgE-MC immune axis, can influence the outcomes of honeybee stings. In this project, we propose to use genetically diverse CC mice to identify genetic modifiers regulating MC functions in insect venom allergy. In Aim 1, we will screen a panel of CC mice for their susceptibility to the toxicity of honeybee venom, development and features of venom-specific type 2 immunity, and induction of MC activation with or without crosslinking of venom-specific IgE/FceRI. We will also perform quantitative trait locus (QTL) mapping of the venom-induced phenotypes in CC mice to identify distinct genetic loci and novel regulators associated with MC-dependent susceptibility vs. resistance to honeybee venom. In Aim 2, we will confirm, in mouse MCs, important regulators of MC functions that are identified by screening CC mice using QTL analysis to assess the involvement of these regulators in innate and/or IgE-mediated MC functions. We think that the identification of genetic modifiers that distinguish beneficial vs. harmful effects of innate and/or allergic immune responses to honeybee venom will improve the treatment of severe reactions to insect venom and probably other disorders in which IgE and MCs have a critical role. 1