The link between skin barrier disruption and response to food allergens in the GIT
Food allergy frequently develops in infancy,74 so establishing oral tolerance though exposure to food allergens early in life may be protective against food allergy. The LEAP study showed that the introduction of peanut into the infant diet before 12 months of age decreased the risk of peanut allergy by 81% at age 5 years in children at high risk of developing peanut allergy due to egg allergy or severe eczema.75 Although the GIT mucosa is continuously exposed to allergens and commensal microorganisms, the immune system usually mounts a tolerant response to these antigens. Induced regulatory T cells (iTregs) and Tr1 lymphocytes play an important role in this immune tolerance. Tolerogenic CD103+ dendritic cells present the luminal antigens and induce FOXP3+ Tregs in a Transforming growth factor-β (TGF-β) and retinoic acid dependent pathway.76, 77 In children who “outgrow” and become tolerant to cows milk protein, the level of Tregs are higher than in those with persisting allergy to cow’s milk.78 Genetic and environmental factors shape the immune responses in the skin when an exposure to food allergens occurs. In two epidemiologic studies, AD and the filaggrin (FLG) gene mutation have been identified as potential risk factors for the development of food allergy.79, 80 In animal models, epicutaneous exposure to food allergens resulted in intestinal food allergy development in a Th2 dependent manner.54, 81 However, the mechanism by which allergic sensitization in the skin is able to disrupt oral tolerance and lead to the development of food allergy remains unclear. It has been proposed that the triggering effect of epicutaneous food allergen exposure stimulates TSLP, IL-33 and IL-25 production in skin keratinocytes; these alarmins induce the activation of ILC2s and dendritic DCs.45, 51, 54-56, 76, 77 The migration of DCs to the lymph nodes triggers the proliferation of Th2 effector and memory cells.82 Ingestion of the food in the context of pre-existing sensitization may cause migration of these Th2 cells into the GIT where they communicate with ILC2s, which, in turn produce IL-13. Intestinal epithelial cells also produce IL-33 and IL-25, further stimulating ILC2s. These processes then induce the development of food allergy.83, 84