Pathogenesis of Food Allergy

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

One of the major limitations in the field of food allergy is the lack of testing modalities that can accurately diagnose food allergy. We also have an incomplete understanding of the precise molecular determinants within allergens that drive allergic responses to foods. To address these unmet needs, in FY21 we worked with our colleagues at Johns Hopkins to develop AllerScan, a bacteriophage display-based allergic antibody profiling platform. Briefly, overlapping epitopes of all 1,847 proteins contained in the Allergome database were cloned into the T7 phage display system to generate the AllerScan library. Serum from patients was incubated with the phage library, and IgG- or IgE-bound phage were then immunoprecipitated and sequenced to determine the profile of allergen peptide epitopes recognized by antibodies in the patient's serum. We used this technology to measure the pattern of IgE and IgG reactivity to wheat allergens in a group of children with IgE-mediated wheat allergy, a group sensitized to wheat (i.e. had positive wheat-specific IgE testing but who were able to tolerate wheat in their diet), and a group who were nonallergic and nonsensitized. We found that the most dominant wheat epitopes recognized by IgE in patients with wheat allergy were derived from alpha, beta, gamma, and omega gliadin and both high and low molecular weight glutenin (HMW and LMW respectively). We further found that reactivity to Tri a37, a plant defense protein, was very effective at distinguishing subjects who were sensitized versus truly allergic to wheat. Anti-Tri a 37 IgG reactivity was the most prevalent (72%) reactivity in nonallergic and sensitized children, whereas IgG reactivity was low among children who were allergic to wheat. On the other hand, IgE reactivity to Tri a 37 was found in 28% of wheat allergic subjects and only 2% of non-allergic/sensitized individuals. IgG and IgE reactivity to Tri a 37 may therefore have clinical utility in distinguishing patients who are sensitized/nonallergic versus allergic to wheat. We additionally performed AllerScan on serum collected from wheat allergic children during the course of a randomized placebo-controlled wheat oral immunotherapy trial (OIT). We found that OIT led to a dramatic shift from IgE to IgG reactivity to wheat peptides but had little effect on serologic reactivity to other allergens. While the placebo arm showed little change in IgE or IgG responses to wheat peptides, nearly all subjects who received active wheat OIT showed an overall reduction in wheat IgE reactivity and a corresponding increase in IgG reactivity. Overall, our study confirmed numerous known properties of wheat allergens and also revealed a novel epitope in Tri a37 that could distinguish between wheat allergy and sensitization. Patients with atopic dermatitis are especially at risk of having false positive tests to foods because they often have very elevated total IgE levels. In FY21, we also reported a case of a child who had a history of persistent atopic dermatitis who had been placed on an overly restrictive diet due to false positive food-specific IgE testing. In this child, extensive food avoidance contributed to severe vitamin D deficiency, growth failure, and the development of IgE-mediated food allergy. This case underscores the need for primary care doctors to judiciously use IgE testing for foods in patients with atopic dermatitis and to recognize the high rate of false positive testing in this patient population. Another major goal of this project is to understand the basic immunologic pathways that contribute to the pathogenesis of food allergy and other allergic diseases. One approach we've taken to accomplish this goal is to identify rare single gene disorders that strongly predispose (or protect) against the development of allergic diseases. During FY21, we sought to evaluate the prevalence of allergic inflammation in a number of monogenic autoinflammatory disorders. In this study, we found that patients with Cryopyrin Associated Periodic Syndrome (CAPS) exhibited a high prevalence of doctor-diagnosed allergic conditions and this was frequently associated with a peripheral eosinophilia and increased frequency of circulating IL-5+ Th2 cells. In contrast, other autoinflammatory conditions were associated with a very low prevalence of allergic disease, including Familial Mediterranean Fever (FMF) and Chronic Atypical Neutrophilic Dermatosis, Lipodystrophy, and Elevated temperature (CANDLE). And finally, patients with Deficiency of Adenosine DeAminase 2 (DADA2) often carried physician-diagnoses of allergic disorders, but these patients showed no evidence of increased Th2 immunity as evidenced by normal frequencies of circulating Th2 cells and IgE levels. These findings suggest that certain autoinflammatory diseases may manifest clinical phenotypes that masquerade as allergic disorders, which may have important therapeutic implications.