Pathogenesis of Food Allergy

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

Management of food allergy involves strict elimination of allergens, many of which supply nutrients essential for bone development. However, little is known about which children with food allergy would benefit most from monitoring of bone mineral density (BMD). In FY23, we performed a cross-sectional study that included 95 children with IgE-mediated food allergy. We found that participant age negatively correlated with BMD, perhaps because of longer duration of food avoidance. The BMD of white children and those allergic to 2 foods was lower than non-white children and those with a single allergy, respectively. As expected, cows milk allergy was associated with lower BMD. Total fat and protein intake positively correlated with BMD while carbohydrate intake was negatively associated, suggesting that dietary intake of macronutrients may be a modifiable factor contributing to BMD in children with food allergy. Additionally, BMI z-scores showed a positive relationship with bone density, indicating that low BMI may be an important risk factor for low bone mass in children with food allergy. BMD z-scores in food allergic children with asthma or EoE were not statistically different than those without these conditions although children with food allergy and atopic dermatitis or allergic rhinitis tended to have lower BMD at certain sites including the hip. Interestingly, vitamin supplements, calcium and vitamin D intake, as well as calcium and vitamin D blood levels were not significantly associated with BMD. However, median BMD values were often lower in the no supplement groups, especially calcium. In summary, we found that children with IgE-mediated food allergy were more likely to have reduced BMD than age-, race-, height-, and sex-matched controls. Food allergic children who are older (>11 years), white, have multiple food allergies, cows milk allergy, and low BMI may warrant more careful evaluation of bone health. T helper (Th9) cells are known to promote allergic inflammation but have been difficult to study due to their heterogeneity and instability. In work led by Dr. Daniella Schwartz in my group, we demonstrated that Th9 cells possess a unique transcriptome and epigenome that distinguishes these cells from Th2 and other Th subsets. In FY23, we demonstrated that the plasticity and instability of the Th9 lineage lies in dynamic chromatin accessibility that allows for innate-like IL-9 production. In resting mouse and human Th9 cells, STAT-dependent cytokines including IL-2 and IL-4 were able to induce IL-9 expression without T cell receptor (TCR) restimulation. This bystander activation occurred at the level of transcription and was the result of dynamic chromatin remodeling at the IL9 locus. During Th9 differentiation, the IL9 locus opens, allowing TCR-independent STAT5/STAT6-dependent bystander activation. However, once the TCR crosslinking stimulus is removed, reduced accessibility of STAT5-binding cis- regulatory elements leads to Th9 lineage instability. Experiments in mice revealed that in vivo-generated Th9 cells undergo STAT-dependent bystander activation to promote airway inflammation in the absence of acute MHC-II/antigen-TCR interactions. Moreover, blocking Th9 activation with JAK-STAT inhibitors could attenuate IL-9 mediated allergic airway inflammation and prevent Th9 expansion in patients with allergic disease. Pathogenic effector T helper type 2 (peTh2) cells have been reported to play a role in the pathogenesis of both IgE-mediated food allergy and eosinophilic gastrointestinal disease (EGID), although the clinical features and presentation of these disorders are different. While some patients with EGID also have IgE-mediated food allergy, others report that specific food(s) trigger their EGID symptoms and tissue eosinophilia but do not cause IgE-mediated reactions. To better understand the role of peTh2 cells in food allergy and EGID pathogenesis, we collaborated with Dr. Fei Li Kuang and colleagues to examine peTh2 cell frequency and phenotype in the following patient groups: 1)IgE-mediated food allergy only, 2) EGID with IgE-mediated food allergy and food triggers, 3) EGID with food triggers but no IgE-mediated food allergy, and 4) EGID without any known food allergy or food triggers. We found that peTh2 cells were elevated in all patient groups compared to healthy volunteers, but the profile of cytokines produced by peTh2 cytokine profiles were different. peTh2 cells from EGID patients produced elevated Th2 cytokines (IL-5 and IL-13), whereas IgE-mediated food allergy patients had peTh2 cells with increased expression of IL-17A. Thus, this study suggests that peTh2 cells may have different roles in the pathogenesis of IgE-mediated food allergy and EGID, which will be investigated in future studies. 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 atopic dermatitis are especially at risk of having false positive tests to foods because they often have very elevated total IgE levels. In FY23, 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 atopic dermatitis and elevated total IgE levels. In FY23, we additionally established collaborations with advocacy groups and organizations including the Asthma and Allergy Foundation of America to enhance enrollment of a more diverse population of patients for this study.