Pathogenesis of Food Allergy

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Children with food allergy often live with persistent fear of life-threatening allergic reactions. Even minimal exposure to food allergens can trigger severe reactions, and currently we have no reliable biomarkers that can predict reaction severity. Consequently, the greatest public health impact of food allergy arguably lies in its negative effect on quality of life (FAQOL). In FY25, we investigated the key factors that influence FAQOL in children with food allergy and examined how this varies across ages. Our study included 125 individuals with food allergy who had a median age of 9 years (range, 2-27 years). Sixty-three percent of the participants were male. The participants completed age-specific validated questionnaires that assessed their psychosocial functioning across several domains including allergen avoidance and risk of accidental exposures, social and dietary limitations, and the emotional impact of having food allergy. We found that age was the strongest predictor of FAQOL, with greater impairment in psychosocial functioning as age increased. Poor FAQOL was also observed in children who strictly avoided all products that carried a “may contain” or other precautionary labels, who reacted to trace allergen exposures, or who experienced more severe allergic reactions as assessed by their need to use epinephrine and/or who required treatment in the emergency department. Notably, FAQOL improved with greater time elapsed since their last severe allergic reaction. We further found that FAQOL of children who were avoiding more than 2 foods was worse than those only avoiding 1-2 foods. Allergies to milk, egg, soy, sesame, and wheat were particularly associated with poor FAQOL. Interestingly, in young children (2-7 years old), the number of foods they avoided was most strongly associated with their FAQOL, while the total number of allergic reactions they had experienced in their lifetime was the factor most associated with FAQOL in teens and young adults. Neither of these factors had a strong influence on FAQOL in the 8–12-year-old age group. Overall, our results underscore the importance of age-specific strategies to improve FAQOL in children with food allergy. In FY25, we investigated the role of intestinal barrier dysfunction in the pathogenesis of food allergy. A defect in the integrity of the intestinal epithelial barrier has been hypothesized to allow food allergens to reach immune cells residing beneath the epithelial layer, triggering a break in tolerance and the development of food allergy. Many prior studies have shown that eczema is a potent risk factor for the subsequent development of food allergy. While eczema is known to cause a breach in the integrity of the skin epithelial barrier, whether eczema predisposes to food allergy by also altering intestinal permeability is not known. To address this question, we collaborated with investigators at King’s College and the Immune Tolerance Network to analyze serum from infants enrolled in the Learning Early About Peanut Allergy (LEAP) study. The LEAP study enrolled infants 4-11 months of age at high risk for developing peanut allergy as a result of having eczema and/or egg allergy and randomized them to early peanut consumption versus peanut avoidance. To assess intestinal barrier function in infants enrolled in LEAP, we measured serum biomarkers of epithelial integrity and tight junction function including zonulin, soluble CD14 (sCD14), and intestinal fatty acid binding protein (I-FABP). Zonulin is a member of a family of proteins that regulates assembly of the tight junctions between intestinal epithelial cells and is thereby an important regulator of antigen trafficking. Soluble CD14 is a co-receptor for lipopolysaccharide and is released into the circulation following monocyte activation. Plasma concentrations of sCD14 can serve as a biomarker of bacterial translocation and systemic immune activation. I-FABP is a small cytosolic protein found in enterocytes of the small intestine where it functions in fatty acid transport. Basal levels of I-FABP in blood are thought to reflect the physiological turnover rate of enterocytes, whereas elevated levels indicate damage to intestinal epithelial cells due to release of I-FABP into the circulation. We measured the levels of zonulin, I-FABP, and sCD14 in 237 LEAP participants who had both food allergy and eczema and 76 atopic controls who only had eczema. We did not detect any significant differences in any of these 3 intestinal permeability markers (IPMs) at either the baseline (4-11 mo of age) or 5 years of age timepoints between these 2 groups, suggesting that serum IPM levels in infants with eczema do not distinguish those who will go on to develop food allergy from those who will not. IPM levels also did not correlate with eczema severity, suggesting impaired skin barrier function does not correlate with impaired intestinal barrier function. Our results further suggested that peanut consumption does not adversely impact intestinal permeability, even in infants sensitized to peanut. In FY25, we also collaborated with Xiaobin Wang and colleagues at Johns Hopkins University to study the effect of maternal exposure to per- and polyfluoroalkyl substances (PFAS) on infant vaccine responses. These responses were assessed using VARscan, a bacteriophage-based epitope-level antibody profiling platform that quantifies serum antibody reactivity to a wide range of viral peptides. PFAS are ubiquitous synthetic chemicals that persist in the environment, can be transferred from mothers to fetuses through the placenta, and may have immune suppressant effects. Our study included 748 mother-child pairs from the Boston Birth Cohort. We found that greater maternal PFAS levels were associated with reduced infant immune responses (lower IgG reactivity) to the measles vaccine. This effect was most pronounced in Black and pre-term children. One of the major limitations in the field of food allergy is the lack of testing modalities that can accurately diagnose food allergy. Patients with eczema are especially at risk of false positive tests to foods because they often have very elevated total IgE levels. In FY25, we have continued to recruit participants on our clinical trial (19-I-0053) to validate diagnostic IgE cut-offs for milk and peanut (and/or their components) that estimate a 50% likelihood of tolerance, a level where oral food challenges are generally offered in clinical practice, in patients with a history of eczema and elevated total IgE levels. We are also investigating novel diagnostic approaches in these children as well.