Cutaneous factors and environmental exposures in the development
of FA
Early AD is implicated in the subsequent development of allergic
diseases, including FA, asthma, allergic rhinitis and is termed the
“atopic march”.2-4 In
the “outside-in” hypothesis, skin barrier defect allows penetration of
allergens and microbes leading to atopic sensitization whereas, in the
“inside-out” paradigm, a polarized immune response leads to a
defective skin barrier (Figure
4).25
Experimental models and clinical observations in humans support the
concept of epicutaneous food allergen
sensitization.20,26The epidermis plays a key role in preventing allergens, irritants and
microbes from penetrating the skin and eliciting the host immune
response. These events are facilitated by skin barrier dysfunction in
AD, promoting the penetration of food allergens from topical application
or the environment. Lack et
al.23 first reported
that peanut allergy was associated with the topical application of skin
creams containing peanut protein. Subsequently, Fox et
al.24 reported
increased FA in households that ate peanuts. In addition, Brough et
al.27 found house dust
dose-dependent peanut sensitization in patients with FLG mutations, and
the impact of developing allergy was greater in children with
AD28 and in children
with egg allergy.29These observations supported a role for the “outside-in” process of
food sensitization where exposure to environmental peanut in an
individual with skin barrier dysfunction leads to enhanced FA.
The “inside-out” process implicates the immune response in making the
skin barrier more susceptible to skin epithelial dysfunction,
development of AD, and allergen entry. The current understanding of
’AD’s pathogenesis is centered on the robust activation of Type 2 (IL-4,
IL-13, IL-31) and Type 22 (IL-22) cytokine axes in both skin and
serum.25,30-34Model systems showed that type 2 cytokine activation inhibits
keratinocyte terminal differentiation products (i.e., filaggrin,
loricrin), tight junctions (i.e., claudins), and lipid
products.35-38 Recent
findings show that Th2 cytokines decrease antimicrobial peptides,
causing AD skin to be more prone to colonization of infectious
organisms, such as S. aureus . Thus, IL-4 and IL-13 play a
hallmark role in the Th2 immune response in AD, contributing to both
immune activation and skin barrier dysfunction. IL-31, another Th2
cytokine, has been shown to interact synergistically with IL-4, driving
pruritus and contributing to the inflammatory and barrier defects of
AD.39-44 The Th22 axis
also plays a role in suppressing the epidermal barrier and the
lichenification and increase of S100As in chronic AD
lesions.45,46Additional proinflammatory axes, including Th17, are preferentially
upregulated in certain AD populations, such as Asians and children,
revealing the heterogeneous nature of AD across its
subtypes.47-51Recently, minimally invasive studies of the skin using tape strips,
performed in infants, children and adults with moderate-to-severe AD,
show robust upregulation of type 2 and 22 T-cell immune cytokines in
both lesional and non-lesional AD
skin.52-54 The
upregulation of immune markers in involved and uninvolved skin showed
high correlations with disease severity scores and the functional
barrier measure trans-epidermal-water-loss
(TEWL).55-57
Allergic disease development is associated with a Th2 cell-mediated
inflammatory
response58,59described above. Allergic disease is preceded by the formation of
specific IgE (sIgE) antibodies against environmental and food allergens,
also known as the sensitization phase. In epicutaneous sensitization,
specific resident dendritic cell (DC) subsets residing in the
skin60 sample antigens
and present to naïve CD4+ T cells in draining lymph
nodes This promotes differentiation into allergen-specific
CD4+ T cells favouring B cell isotype class switching
to sIgE cells further driving the production of IgE memory B
cells61. Through the
maturation and production of plasma cells, large amounts of sIgE
antibodies are produced. The sensitization phase drives the production
of a large memory pool of allergen-specific B cells and Th2 cells.
The sensitization phase is followed by the effector phase, which is
triggered by subsequent exposure to previously sensitized allergens.
This causes cross-linking of sIgE bound to receptor FcεRI on sensitized
mast cells and basophils. Activation of these cells leads to the release
of inflammatory mediators triggering an allergic
reaction62. The immune
mechanisms linking the skin and gut have their origins in skin
injury-induced release of IL-33 from keratinocytes, leading to
intestinal mast cell hyperplasia and food-induced anaphylaxis in
mice.63 IL-33 blocking
antibodies have also been shown to prevent peanut allergy induced
anaphylaxis.64
Interestingly, skin sampling in patients with peanut allergy but not AD
reveals low filaggrin levels but increased long-chained lipid species,
which may protect the skin from dryness and
AD.65 Other risk
factors have been associated with peanut allergy, including filaggrin
mutations, severe infantile AD, environmental irritant exposures such as
detergents and S. aureus colonization on the
skin.66-68
Skin dysbiosis, often observed among individuals with AD, is often
characterized by reduced microbial diversity and the presence of one or
few dominant microbes. The loss of commensal microbes is likely due to
several factors including host genetics, local immune response,
environmental factors such as pH, temperature, humidity, hygiene
practice and exposure to antibiotics. It is estimated that 30% to 100%
of individuals with AD are colonized by S. aureus , a dominant
pathogen implicated in this disease (Figure 5a).69 S. aureusaffects the development of both innate and adaptive immune responses. It
can lead to uncontrolled inflammation by inducing lymphocyte and
macrophage activation. The increased presence of S. aureus in the
dermis directly correlates with a Th2 response evident by increased
expression of IL-4, IL-13, IL-31 and
TSLP.70 These Th2
cytokines in turn suppress the production of antimicrobial peptides
(AMPs) by the skin that inhibits S. aureusproliferation.71Therefore, it is not surprising that colonization by S. aureus is
associated with increased AD severity and treatment thereof has been
shown to decrease disease
severity.72,73
Malassezia spp., previously known as Pityrosporum, is a genus of
lipophilic yeast. Its role in AD’s pathogenesis was initially speculated
when some AD patients responded to topical and systemic antifungal
therapies.74-78 A large
population study showed more than 40% of children with seborrheic
dermatitis during early childhood will develop AD later on, suggesting
early sensitization of seborrheic skin may result in the onset of
AD.79 Most of the
Malassezia species lack fatty acid synthases genes, therefore relying on
exogenous fatty acid sources that are abundant at certain cutaneous
sites such as the head, neck and skin folds (Figure
5b).80 Although the
pathogenesis of Malassezia spp in AD is not entirely clear, yeast
is known to trigger a multitude of immune responses. It is estimated
that 80% of adults with AD have detectable Malassezia IgE
antibodies.81-83Malassezia spp. in the epidermis and dermis, can be recognized by
keratinocytes and Langerhans cells as well as dermal DCs. These antigen
presenting cells in turn activate downstream immunologic cascades that
lead to the release of proinflammatory cytokines such as TNF-alpha, IL6,
IL-8, IL-10, and IL-12p70. Induced expression of TLR2 and TLR4 on human
keratinocytes and DCs upon exposure to Malassezia spp. have been
observed, suggesting direct activation of innate immune
response.84,85In addition, the NLRP3 inflammasome in skin DCs can also be activated byMalassezia spp with subsequent release of Th2 cytokines (e.g.,
IL-1beta, IL-4, 5, 13,) likely directly contributing to AD
pathogenesis.86,87
Lamellar bilayer structural integrity is highly organized in normal
skin, seen under electron microscopy, but very abnormal in those with AD
and peanut allergy. The epidermis in AD with peanut allergy is
associated with high TEWL, high type 2 immune activation, S.
aureus colonization, reduced filaggrin breakdown products, and a
reduced proportion of long-chained lipid products. These observations
suggest that a defective skin barrier in patients with AD and peanut
allergy may predispose affected individuals to epicutaneous allergen
sensitization. The availability of minimally invasive skin tape sampling
techniques may play an important role in identifying infants with early
epidermal barrier dysfunction who may benefit from timely initiation of
novel therapies for skin barrier dysfunction, non-lesional immune
activation, and microbial dysbiosis. Using this technique epidermal
profiling of lipids, proteins, and transcriptome identifies differences
in the epidermis between patients with peanut allergy and AD versus AD
alone.65,88
Barrier protection is the cornerstone of AD management. Skin hydration
and prevention of TEWL are keys in maintaining skin barrier homeostasis.
Animal studies also suggest that changes in hydration and corneocyte
adhesion within stratum corneum affect the development and maturation of
epidermis.89 Although
there has been considerable controversy about whether early application
of skin emollients can prevent AD and
FA,20 these studies
have often not targeted high-risk infants with pre-existing evidence for
skin barrier dysfunction, or the ingredients of emollients has not been
optimized for infant skin barrier repair. The use of topical steroids to
prevent AD flares and control subclinical inflammation is being
evaluated as a potential strategy to prevent FA in
AD.20 Other novel
pathogenesis-based topical and systemic therapies targeting inflammation
of the skin have also been investigated for their roles in preventing
FA.90
Petrolatum, a non-physiologic mineral lipid, is often considered a gold
standard ointment-based emollient that can prevent TEWL effectively for
4-6 hours. Therefore, to maintain optimal skin hydration, ointment-based
emollients should be applied 3 to 4 times daily to provide complete
protection. However, ointment-based emollients can also exacerbate AD;
therefore, alternatives must be considered. Lipids including ceramide,
fatty acids and cholesterol are mixed in appropriate ratio within
stratum corneum to maintain its
integrity.91,92Atopic skin is known to be deficient in lipids especially ceramide and
hygroscopic amino acids that are the result of filaggrin breakdown
products.93,94Newer generations of emollients containing these lipids have been
developed in recent
years.95,96A recent study demonstrated a trilipid cream was more effective than a
paraffin-based emollient in reducing TEWL and sIgE
levels.20,97However, efficacy in AD or FA prevention is yet to be proven in a
randomized clinical
trial.98 While treating
AD patients with a barrier-based approach, a liver X receptor agonist
upregulated terminal differentiation and lipid products in the skin of
patients with AD, consistent with its mechanism of
action;99 however, it
was not associated with clinical benefit or suppression of immune
products (Th17/Th22/IL6). This suggests that although barrier-based
approaches may be valuable for disease prevention, the immune
abnormalities perpetuate the AD disease phenotypes and should be
targeted to resolve active AD.
The discovery of cytokine dysregulation in non-lesional skin from AD
patients suggest the role of systemic therapy especially for individuals
with severe disease. The increased understanding of AD’s immune
pathogenesis led to the development of immune-based treatments targeting
Th2 cytokines.100-105Downregulation of immune markers in the skin of patients treated with
such agents highly correlated with reductions in disease severity
scores, demonstrating clinical
improvement.33,106-111Furthermore, the Th2-targeting anti-IL-4R mAb dupilumab was shown to
induce significant changes in the microbiome of skin lesions, again
supporting the key role of the Th2 cytokines in inducing the disease
pathogenesis.112