Evidence for epicutaneous sensitization in FA pathogenesis
In support of the dual allergen exposure hypothesis, epicutaneous exposure to food allergens induces a potent pro-allergic Th2 immune response, leading to systemic food-allergic reactions, including anaphylaxis, on subsequent oral exposure in mice.8Murine models have consistently shown that epicutaneous sensitization through an impaired skin barrier primes the gut for subsequent allergic reactions more effectively than oral or intraperitoneal sensitization.8-10 IL-33 is released by mechanical skin injury and interacts with ST2 receptors on mast cells, resulting in expansion of intestinal mast cells, increased intestinal permeability, and anaphylaxis following oral exposure in mice.11, 12Furthermore, skin barrier disruption worsened symptoms of food allergy (FA) even after allergen exposure was removed, whereas topical steroid treatment could reduce allergic reactions in mice.13One of the mechanisms for epicutaneous sensitization is thought to occur through enhanced cutaneous antigen capture by activated Langerhans cells which penetrate tight junctions to a greater extent in AD lesional skin compared to healthy skin.14
Epidemiological studies have found a link between exposure to environmental food allergens through the skin, and the development of food sensitization and allergy. The Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort was the first to report that 90% of peanut-allergic children with AD had been exposed to peanut creams containing Arachis oil in the first six months of life.15 In children with peanut allergies, a dose-response relationship was observed between environmental peanut exposure and peanut allergy development.16 In children with FLG mutations, greater quantities of household peanut protein exposures significantly raised the risk of peanut sensitization.17
Cutaneous sensitization can also occur through high-dose, high frequency skin exposures even with an intact skin barrier. Fukutomi et al. reported that among Japanese women, contact exposure to hydrolysed wheat protein in facial soaps was significantly associated with an increased risk of wheat allergy.18 Boussault et al. noted that children with AD exhibited greater oat sensitization compared to unexposed children, which could be attributed to repeated application of oat-based cosmetics on their inflamed skin.19Preliminary evidence also suggests that clinically significant coconut allergy is more common in topical coconut emollient users.20
The use of multi-omic analyses have further enhanced our understanding of epicutaneous sensitization of food allergens. Earlier studies have shown that microbial dysbiosis, characterized by an overgrowth ofStaphylococcus aureus , is associated with skin barrier dysfunction as it degrades epidermal structural proteins and metabolizes lipids.21, 22 A temporal association was also evident, in which the increased S. aureus abundance was found to precede the onset of AD in birth cohort studies.23-25Furthermore, in a study that utilized minimally invasive skin tape stripping (STS), children with AD and FA were found to have increased transepidermal water loss (TEWL) that was associated with higher levels of S. aureus abundance, lower filaggrin breakdown fatty acid content and enhanced type 2 immune responses in their non-lesional skin, as compared to those without FA and nonatopic controls.26 Other evidence has also shown thatS. aureus colonization in humans prevented natural tolerance to cow’s milk, hen’s egg, and peanut, and disrupted oral tolerance induction to peanut.27 There is likely a complex multidirectional interplay among these various factors on the risk of AD and FA, which also depends on the genetic and environmental factors impacting a given individual. Overall, a growing body of evidence supports the hypothesis that the development of food sensitization and allergy is primarily caused by an inflamed skin barrier with perturbed skin microbiome.