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