Uncovering mechanisms of anaphylaxis heterogeneity using a murine food allergy model 2261

Abstract Description Anaphylaxis is a severe, potentially life-threatening allergic reaction. It remains unclear why some sensitized individuals with food allergen-specific IgE develop anaphylaxis upon oral exposure while others do not. We hypothesized that elements of the inflammatory response in the gastrointestinal tract differentiate extreme from mild responders. Using a murine food allergy model, we analyzed the magnitude of elements of the mucosal immune response in the jejunum, ileum, cecum, and colon by qPCR, looking for correlations with anaphylaxis severity. Experiments were conducted across seven cohorts of 5-10 mice each (14 cages and 4 animal facility rooms over 2 years). We observed significant heterogeneity in the anaphylactic response (hypothermia) within and between cohorts that was independent of allergen-specific IgE, IgG1, and IgG2a levels, Type 2 inflammation, and mast cell activation (all elevated). We conducted a multivariate statistical analysis on the dataset, comparing it to individual body temperature changes. The strongest positive correlation to anaphylaxis was high expression levels of the Type 2 response/mast cell activation combined with induction of the inflammatory mediators Cxcl1, Cxcl2, G-CSF, and IL-36γ in the jejunum and ileum (R = 0.924, N = 52, p-value = 1.93E-09). Thus, severity of anaphylaxis in this food allergy model is significantly associated with upregulation of gene expression linked to neutrophil recruitment and activation in the small intestine. Funding Sources M-Food Allergy Research Accelerator (M-FARA) Mary H. Weiser Food Allergy Center Herman-Dorothy Miller Award, Immunology Program Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)