Perturbations to Homeostasis in Experimental Models Revealed Innate Pathways Driving Food Allergy

While type 2 immunity has been conventionally viewed as beneficial against helminths, venoms, and poisons, and harmful in allergy, contemporary research has uncovered its critical role in the maintenance of homeostasis. The initiation of a type 2 immune response involves an intricate crosstalk between structural and immune cells. Structural cells react to physical and chemical tissue perturbations by secreting alarmins, which signal the innate immune system to restore homeostasis. This pathway acts autonomously in the context of sterile injury and in the presence of foreign antigen initiates an adaptive Th2 response that is beneficial in the context of venoms, toxins, and helminths, but not food allergens. The investigation of the triggers and mechanisms underlying food allergic sensitization in humans is elusive because sensitization is a silent process. Therefore, the central construct driving food allergy modeling is based on introducing perturbations of tissue homeostasis along with an allergen which will result in an immunological and clinical phenotype that is consistent with that observed in humans. The collective evidence from multiple models has revealed the pre-eminent role of innate cells and molecules in the elicitation of allergic sensitization. We posit that, with the expanding use of technologies capable of producing formidable datasets, models of food allergy will continue to have an indispensable role to delineate mechanisms and establish causal relationships.