Intestinal epithelial immunological responses and food allergen sampling

Project SummaryFood allergy is rapidly increasing in prevalence and is the most common cause of anaphylaxis. While significantprogress has been made in our understanding of the underlying immunologic pathways involved in dendritic cell(DC) presentation of food allergens, the development of the CD4+ Th2 repertoire, and the IgE-MC?dependenteffector processes, there has been little attention to the processes underlying the passage of food allergensacross the GI epithelium and presentation of these allergens to the immune compartment.We have recently reported 1) that goblet cells (GCs) in the small intestine (SI) of nave mice can act as a conduitand permit the passage of food allergens across the intestinal epithelial (IE) layer and presentation to the SIlamina propria immune compartment (termed Goblet cell antigen passages; GAPs)13; 2) that food allergic miceutilize a different IE transport mechanism involving SI villus and crypt GCs, enteroendocrine cells, and Panethcells that passage food allergens across the intestinal epithelial layer (termed secretory epithelial antigenpassages; SAPs)24 and 3) a critical role for IE cell-derived pro-Type 2 cytokines such as TSLP, IL-25 and IL-33in the development of food-induced anaphylaxis in mice14.In a series of preliminary studies, we interconnect these observations demonstrating that induction of SAPs anduptake of food allergens in murine intestinal epithelial cells leads to expression of the pro-allergic cytokine, IL-33 and employing a human intestinal organoid (HIO) transplant model system demonstrate that the molecularprocesses, GAPs and SAPs are conserved in humans.The current gap in knowledge is the specificity of food allergen uptake by secretory intestinal epithelial celllineages; the potential existence of environmental trigger programming of IEs which leads to modified antigenpassage patterning (GAPs vs SAPs); and the relationship between food allergen uptake by SAPs and expressionof pro-Type 2 cytokines in human tissue. We hypothesize that SAPs are a mechanism by which food allergensare channeled across the intestinal epithelium, promote the production of pro-Type 2 cytokines and whosecomposition and function are modulated by environmental triggers.In Aim I we will define the SI secretory cell lineages involved in food allergen passages and the impact ofenvironmental triggers on food allergen passage patterning and Aim II, define the transcriptional inflammatorysignature of human intestinal epithelial cells following food allergen uptake. With respect to the expectedoutcomes, the studies proposed in Aim I are expected to identify the involvement of distinct SI epithelial-specificfood allergen transport processes and how they are influenced by environmental triggers, and those in Aim IIare expected to reveal a link between pro-Th2 cytokine production and food allergen uptake by SI intestinalepithelial cells and define the pro-allergic transcriptional inflammatory signature of antigen passages.Collectively, these studies will illuminate new IE-restricted processes by which food allergens are sampled bythe human SI compartment; link food allergen uptake with pro-Type 2 cytokine production and identify divergentpathways of SI IEs food allergen uptake that are influenced by FA status.