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.