ILCs in food allergy and oral tolerance development
IgE-mediated food allergy is the most common type of food
allergy, and affecting up to 10% of infants in western
populations.85, 86 It is characterized by specific IgE
(sIgE) production and IgE interaction with different immune cells (Th2
cells, mast cells and basophils).86, 87 The intestinal
mucosa is capable of secreting alarmins which can activate
ILC2s.88 In an experimental food allergy model, it was
found that deficiency of IL33 receptor (ST2) prevented the development
of food allergy.10 In another study, TSLP and
basophils were both found to be important in allergic cutaneous
sensitization while IL-33 was found to be necessary for the induction of
IgE-dependent anaphylaxis.89 The release of IL-33
following skin injury has been shown to induce IgE-mediated mast cell
degranulation and anaphylaxis; blocking ST2 prior to oral challenge
reduced the severity of reaction without affecting the Th2 response to
the allergen.6 Another important alarmin, IL-25, has
also been shown to increase following food
challenges.7 The authors also demonstrated that mice
deficient in IL-25 were more resistant to the symptoms of food allergy.
Following allergic sensitization, IL-25 and IL-2 derived from
CD4+ Th2 cells stimulate ILC2s resulting in the
production of large amounts of IL-13 and amplifying the IgE-mediated
response in this experimental model. In addition, ILC2s with defective
IL-13 production had a reduced ability to develop allergic inflammation,
resulting in resistance to food allergy.7 In a murine
model of food allergy, IgE‐stimulated mast cells induced IL‐13
production from ILC2s in an IL‐4Rα−dependent manner; in addition, ILC2s
amplified systemic anaphylaxis by increasing target tissue sensitivity
to mast cell mediators.90 These findings support a key
role of ILC2s in food allergy in an IL-13-dependent manner.
Tregs regulate the functions of ILC2s and suppress their type 2 cytokine
production. Reciprocally, ILC2s secrete IL-4 which downregulates Treg
functions and increases mast cell activation.10 In the
steady state, these networks function to facilitate tolerance; however,
genetic and environmental factors, such as microbiota dysregulation, may
stimulate alarmin production from the intestinal epithelial cells
resulting in ILC2 activation.88 Of note, medium-chain
triglycerides in peanut have been shown to increase alarmin production,
thus promoting allergic sensitization and
anaphylaxis.91 Inducible T regulatory cells (iTregs)
are inhibited by the effect of IL-4,10 and after
re-exposure to food allergens, activated mast cells can stimulate IL-33
production and ILC2 activation. This forms a positive feedback loop on
mast cell activation and a negative feedback loop on iTregs, promoting
the persistence of food allergy.92, 93
Commensal bacteria also have indirect effects on host immune responses
towards food antigens. Some Clostridia strains induce the
accumulation of Tregs in the colon.94, 95Clostridia also trıgger ILC3s to produce IL-22, strengthening the
epithelial barrier. In mice, Clostridia containing microbiota
suppressed food allergic responses.96 In response to
the microbial signals, macrophages secrete IL-1β which mediates GM-CSF
release from ILC3s. GM-CSF induces IL-10 and retinoic acid production by
DCs and macrophages and subsequently promotes the induction of Tregs.
Any interference with this crosstalk can result in loss of oral
tolerance to food allergens.97
Eosinophilic esophagitis (EoE) is a chronic disease
characterized by gastroesophageal reflux disease, and dysphagia leading
to food impactions and strictures. Pathologically, esophageal remodeling
consists of epithelial hyperplasia with barrier dysfunction,
subepithelial fibrosis, and smooth muscle
dysmotility.98 Although the role of IgE in the
pathophysiology of EoE is unclear, affected individuals usually have
elevated levels total IgE and IgE sensitization to foods and
aeroallergens.99 In children with EoE, sensitization
to both food and environmental allergens may be observed in 75%
of patients.100 Elimination of food allergens, or
elemental diets can reduce disease symptoms in 70–99% of patients,
however relapse is very common after re-introduction of food
allergens.101 This suggests that chronic food antigen
hypersensitivity is an essential feature of EoE. In addition, many
patients with EoE have a history of IgE-mediated food
allergy,100, 102 and there may be progression from
IgE-mediated food allergy to the later development of EoE towards the
same food.103EoE has been reported as an adverse event
in up to 10% of patients undergoing oral immunotherapy (OIT) for
IgE-mediated food allergy , although fortunately in this context
symptoms tend to resolve after discontinuation of the triggering
allergen (presumably on the basis that the development of symptoms in
the context of OIT is less chronic in natüre).104, 105Furthermore, OIT is known to stimulate the production of
IgG4, which may indicate its in the pathogenesis of
EoE.106, 107 Historically, EoE was proposed to ocur
through an IgE-mediated mechanism, however targeted dietary elimination
and the use of IgE-blocking strategies have failed to support this
notion. Measures of IgE sensitisation are not helpful in identifying the
responsible food allergen in clinical practice.108-111This, while EoE is associated with IgE sensitization, it is not
considered to be an IgE-mediated disease.
There is increasing evidence for epithelial barrier dysfunction in EoE
followed by eosinophilic inflammation like AD. The expression of FLG,
zonula occludens (ZO)-3 and claudin-1 is decreased in EoE patients,
correlating with spongiosis,112 and mutations in FLG
are higher in patients with EoE.113 EoE pathogenesis
is determined by TSLP produced by epithelial cells and IL-5 and IL-13
produced by inflammatory cells, including ILC2s. IL-5 production leads
to esophageal eosinophilia and IL-13 induces EoE-specific epithelial
gene expression and remodeling like angiogenesis.114Eosinophil granulocyte-derived extracellular traps stimulate alarmin
(IL-33, TSLP) production in airway epithelial cells that enhances ILC2
activation and cytokine production.115 It remains
unknown as to whether eosinophil cells contribute to ILC2 activation in
patients with EoE. IL-33 gene expression has been implicated in
pediatric EoE development.12 Inhibition of the
esophageal Treg function by IL-33 may induce loss of antigen specific
tolerance and provide a mechanistic rationale for EoE
development.12 IL-33 and TSLP induce human ILC2s to
produce large amounts of Th2 cytokines. Recently it was shown that ILC2s
were significantly increased in tissues from patients with active EoE
versus inactive EoE and were also higher than ILC2s in controls.
Importantly, levels of ILC2s in biopsy specimens correlated with numbers
of eosinophils in esophagus tissue. This supports a role for ILC2s in
EoE pathogenesis.13 Mast cells and IL-9 have also been
implicated. ILC2s produce IL-9 and are located close to mast cells in
human lung, suggesting a crosstalk between these two cell
types.116, 117 Both IL-33 and TSLP activate ILC2s from
esophageal lymphoid tissue which provides a proof of concept for ILC2s
induction in EoE (Figure 4).13 Indeed, TSLP is highly
expressed in EoE tissue.98, 118
Atopic dermatitis (AD) is a relapsing chronic inflammatory skin
disease characterized by epithelial barrier dysfunction and type 2
inflammation.119 During the development of AD,
environmental allergens and genetic factors affect the skin barrier
function and trigger type 2 inflammation. This may lead to the failure
of the mechanisms of oral tolerance, resulting in the development of
food allergy. Infants with AD at 4 months of age are at increased risk
for allergy to hen’s egg.79 An important risk factor
for AD is the FLG gene mutation. FLG mutations cause skin barrier
disruption and decrease the level of E-cadherin which is an important
inhibitor of ILC2s through its receptor (Killer cell lectin-like
receptor subfamily G member 1 (KLRG1).51 In an
experimental model of AD with FLG mutations, skin inflammation was
associated with the expansion of IL-5-producing ILC2s. Additionally,
mice with FLG mutations showed increased frequency of ILC2s in the skin
in comparison to control subjects.27
Interaction of ILC2s with other cell types may also be important.
Although basophils in healthy human skin are rare, they are enriched in
the dermis of AD lesions and located in close proximity to ILC2. ILC2s
express IL-4 receptor α (IL-4Rα) and proliferate in an IL-4-dependent
manner. IL-4 is supplied by basophils during AD inflammation, which
suggests a relationship between these two cell types in AD
pathogenesis.120 Dermal ILC2s locate perivascularly
and are in close proximity to the skin resident mast cells. ILC2s
produce IL-9 and IL-13 and these cytokines may activate mast cells. On
the other hand, mast cells produce IL-25, Prostaglandin D2 (PGD2), and
Leukotriene C4 (LTC4) which can activate the ILC2s.121Both mast cells and ILC2s can be activated by TSLP which may potentiate
the function of both of these cell types.