Triggers of food allergen absorption and anaphylaxis - PROJECT SUMMARY The rising prevalence of food allergies underscores the urgent need to unravel the pathogenesis of this disease and to develop effective therapies. Currently, our knowledge of the biological rules that govern which individuals respond to food allergens is incomplete. While food-specific IgE is necessary for symptomatic food allergy, it is not sufficient; some individuals with food specific IgE exhibit no allergic reaction upon eating foods they are sensitized to. This suggests that additional factors beyond IgE contribute to anaphylaxis risk. Our lab has demonstrated that, unlike C3H/HeJ and BALB/c mice, C57BL/6 mice exhibit minimal allergen absorption across the gut and are resistant to developing an anaphylactic response following oral challenge (termed “oral anaphylaxis”). Our forward genetic screen of oral anaphylaxis-susceptible and resistant mice identified allelic variants in the gene Dipeptidase 1 (Dpep1), which encodes an enzyme in the cysteinyl leukotriene synthesis pathway, as a key predictor of anaphylactic response. Further, we found that blocking leukotriene synthesis entirely with the drug zileuton significantly reduced gut permeability and protected sensitized, oral anaphylaxis- susceptible C3H/HeJ and BALB/c mice from anaphylaxis following allergen challenge. My proposal therefore investigates this novel role for cysteinyl leukotrienes as mediators of food allergen uptake across the gut barrier. My central hypothesis is that intestinal mast cell production of the cysteinyl leukotrienes LTC4 and LTD4 and their signaling via the cysteinyl leukotriene receptor 2 mediate gut absorption of food allergens and dysregulation of this pathway can result in enhanced risk of anaphylaxis after food sensitization. In my first aim, I will identify the specific cysteinyl leukotriene(s), cysteinyl leukotriene receptor(s), and cellular producers of cysteinyl leukotrienes relevant to absorption of allergens in the gut. To accomplish this, I will assess the effects of exogenous cysteinyl leukotriene administration, cysteinyl leukotriene receptor knockouts, and mast cell depletion on gut permeability and susceptibility to oral anaphylaxis. In my second aim, I will determine whether aspirin, a known clinical cofactor of anaphylaxis, enhances gut permeability and susceptibility to anaphylactic response by increasing cysteinyl leukotriene levels. To do so, I will evaluate the effects of aspirin treatment on cysteinyl leukotriene levels in the small intestine and intestinal absorption of food allergens in sensitized mice. Next, I will test whether cysteinyl leukotriene receptor knockout mice or pretreatment with leukotriene synthesis inhibitors decrease aspirin-mediated gut permeability. If successful, this project will define a previously undescribed mechanism of cysteinyl leukotriene-mediated allergen absorption in the gut. It also has the potential to elucidate the mechanism underlying the role of aspirin as a cofactor of anaphylaxis. These findings would offer novel therapeutic targets to prevent anaphylaxis in patients with food allergy.
