Children with EoE often have other preexisting allergic diseases, and, presumptively, young children with EoE likely will develop other allergic disease s with age. The pathophysiological understanding of the allergic disease family has grown exponentially in the past decade, which is equally true of EoE [ 2 ].
In this paper we will contrast and compare the known pathophysiology and clinical circumstances of each of the allergic diseases and EoE and suggest that EoE has disadvantages to patients greater than or equal to its allergy family members. An excellent consensus paper with recommendations for treating children and adults with EoE has been recently published [ 3 ].
By every indicator IgE-mediated food allergy has increased in the past decade. In almost all cases, symptoms of IgE-mediated food allergy are readily defined and generally temporally approximate to the food ingested, but not persistent or chronic. The diagnosis is relatively straightforward, using a clinical history supported by appropriate allergy skin tests or specific IgE blood tests.
As long as the inciting food is avoided, symptoms are totally gone, and daily therapy is not indicated. With the exception of peanuts and tree nuts, food allergy generally resolves itself by late adolescence. The exact reason for the clinical presence of an allergy to a specific food s is still unknown, considering many children allergic to a specific food s have concomitant specific food serum IgE levels or positive skin tests to tolerated foods. In EoE an associated food allergy has been shown to have both pathophysiological and clinical relevance.
In contrast to IgE-mediated food allergy where the avoidance of the allergenic food s is almost always clinically beneficial, even an elemental diet does not induce remission in all subjects with EoE. And compared to conventional IgE-mediated food allergy, deciding on the food protein avoidance regimen in EoE involves both standard skin testing and in some cases allergy patch testing [ 4 ].
Despite the information gained using these techniques skin testing and patch testing in some situations complete food protein avoidance is necessary for effective control of symptoms [ 5 ].
And finally, in contrast to food allergy, current evidence does not support the eventual tolerance of allergic food s and the total resolution of EoE [ 6 ]. Although morbidity with EoE is relatively high, mortality, as compared to food allergy, has not been reported. In particular, abnormal filaggrin protein s an epidermal component has been linked to severe AD phenotypes [ 7 ], with a resultant loss of epidermal integrity, thus allowing interaction between the external environment and the heightened immune response.
Recent research has suggested a diminished filaggrin protein in EoE, resulting in decreased esophageal barrier function [ 8 ]. Atopy is a common finding in pediatric atopic dermatitis and EoE, although nonatopic forms of AD and EoE are not uncommon.
IgE-mediated sensitization to food protein s is commonly enhanced in both disease conditions, and the elimination of sensitized foods has been a cornerstone of therapy in EoE and a frequent discussion point in AD. Multiple studies investigating food avoidance as an effective therapy for AD have not been convincing, despite the fact that IgE-mediated food sensitization is common in AD. The clinical relevance of avoiding IgE-mediated sensitized foods in AD patients is limited.
Preceding the use of patch testing in EoE for foods was a movement to isolate clinically relevant food allergies in AD using a delayed 48—72 hours food response [ 9 ]. Although in limited use currently, these strategies suggest a more complex immune response to food protein than through a Type 1 immune reaction in both EoE and AD.
Also, food protein exposure in AD has several pathways to sensitization, including contact, airborne, and even transplacental or via breast milk, while in EoE food protein exposure may be through a systemic route with esophageal transmural migration, or possibly by direct contact during food ingestion.
Environmental allergen sensitization is common to both AD and EoE, but studies do not exist that compare rates of environmental sensitization in children with a single disease state EoE or AD , or each disease at different ages.
It is generally held that young AD patients eventually develop environmental allergen sensitization and often second or third allergic diagnoses, but similar studies showing the development of other allergic diseases have not been done with early onset EoE.
Conventional allergy immunotherapy, often issued in allergic rhinitis and allergic asthma, is not commonly utilized for AD and has not been reported for EoE. The prognosis of AD in children is considered good, with many children having resolution of active disease by adolescence.
The current longitudinal data for pediatric-onset EoE from a single center was not optimistic for improvement [ 6 ], strongly suggesting a persistent course, possibly into adulthood. Allergic rhinitis is a relatively straightforward and common allergic disease which usually starts in childhood.
The exposure and sensitization to an airborne allergen is then recentered to an intranasal allergy response on re-exposure. Although not commonly emphasized, the late phase allergic is largely responsible for chronicity of symptoms.
Subepithelial thickening and remodeling are apparently present, but do not usually receive the same consideration as do the same processes in the lower airway. Food allergens only extremely rarely are involved in allergic rhinitis, although a corollary process, pollen-food allergy syndrome, may occasionally coexist.
Progressive tissue damage may result from this increased inflammatory cell recruitment facilitated by angiogenic products. It also induces fibroblast activation and differentiation into myofibroblasts, with consequent over-production of extracellular matrix ECM , predisposing to subepithelial fibrosis with consequent features of strictures and food impactions However, being a T-regulatory molecule, it is involved in the regulation of normal immune systems and is vital in repair Major basic protein levels correlate with basal cell hyperplasia 46 and has been associated with loss of barrier function in the esophageal epithelium MBP has consequently been proposed as a player in subepithelial fibrosis in EoE It appears to function by up-regulating the expression of fibroblast growth factor FGF -9, a molecule involved in epithelial homeostasis and proliferative response to injury While initially being uncharacterized in the esophagus, FGF-9 has now been found in biopsy specimens of patients with EoE 55 , hence the interest in its up-regulation by MBP.
Another function of this molecule is smooth muscle contraction through its action on muscarinic M 2 receptors, which may contribute to the dysphagia experienced by many patients with EoE A molecule with similar function to MBP, MMP-9 can be generated by structural and inflammatory cells and has the ability to secrete and activate latent matrix-bound growth factors MMP-9 can thus degrade proteoglycans thereby enhancing airway fibrosis and smooth muscle proliferation Although current research implicate MBP and MMP-9 in cell proliferation and tissue fibrosis, it must be highlighted that these molecules may have an organ-specific function, in which case their effect on bronchial remodeling may not be able to be generalized to esophageal remodeling.
Mast cells contain several preformed mediators including histamine, cytokines, serine proteases tryptase, chymase , and proteoglycans that are stored in cytoplasmic granules They have a central role in innate immunity especially in allergic diseases, being the predominating cells in IgE-mediated responses. Attwood and colleagues 3 first discovered the presence of mast cells in the EoE inflammatory infiltrate. Due to the suggested immunoallergenic nature of EoE, the study of the involvement of mast cells in this disease has recently increased The role of mast cells in EoE has been supported by both human and animal studies.
Several studies have identified increased mast-cell numbers in patients with EoE 46 , 60 , Further, epithelial mast-cell infiltration was noted to precede eosinophil accumulation in a guinea pig model of EoE Mast-cell numbers were also significantly increased after intranasal exposure to cockroach and dust mite allergen in a murine model of EoE Importantly, studies on humans with EoE have found a correlation between mast-cell counts and characteristic features of EoE including intraepithelial eosinophil numbers, basal zone hyperplasia, and eotaxin-3 level 30 , The immunoregulatory function of mast cells has been increasingly recognized in EoE Through its action on H2 and H4 receptors, mast-cell-derived histamine has been shown to modulate immune responses by acting on dendritic cells and T-lymphocytes It may act to maintain a favorable environment for allergic immune responses by recruiting T-lymphocytes, enhancing the proliferation of eosinophils in the bone marrow and inducing B-cell class switching to IgE production Additionally, mast-cell-derived proteoglycans such as heparin are known to potentiate eotaxin-induced eosinophil recruitment in vivo 67 , highlighting a key combinatory role amongst eosinophils and mast cells in EoE pathogenesis.
Mast cells may also have an effector function through specific enzymes. Mast-cell-specific genes encoding for proteins including chymase, tryptase, and carboxypeptidase A3 are significantly unregulated in EoE These proteins are known to increase mucus secretion and smooth muscle contraction in the bronchi of asthmatics Additionally, mast cells have been found in the muscle layers of the esophagus and may cause contraction of muscularis mucosae through histamine-activated acetylcholine resulting in trachealization of the esophagus, as observed endoscopically in patients with EoE Despite evidence supporting mast-cell involvement in EoE, there is currently no evidence supporting therapies targeting mast cells in EoE.
Lucendo et al. In the same study however, there was a significant reduction in IgE positive cells. However, 1-month treatment of EoE in a pediatric cohort, with the mast-cell stabilizer sodium cromoglycate mg q. Overall, this suggests that although the involvement of mast cells is clear, its role in the pathogenesis of EoE is not yet fully characterized. Inferentially, the majority of EoE cases may be associated with an IgE-mediated type 1 hypersensitivity reaction.
Most adaptive immune responses are a mixture of both T H 1 and T H 2 however, as suggested by the cytokine expression profile, EoE is a predominantly T H 2-mediated condition Unfortunately, despite this knowledge of B cells in allergic reactions, their role in EoE is poorly understood. In Vicario and colleagues 71 study, evidence showed local B lymphocyte class switching to IgE expression Another study found no change in B-cell numbers in untreated or corticosteroid-treated EoE patients The possible discrepancy between the studies may be due to differences in patient demographics, and further such studies are required to substantiate the role of B cells in EoE.
IL-4 stimulates B-cell proliferation and maturation within plasma cells, regulates class switching of antibodies, and increases IgE production. Blanchard and colleagues 13 found no significant differences in the level of IL-4 between EoE patients and non-EoE controls, however IL-4 mRNA levels were significantly decreased in EoE patients following glucocorticoid therapy or elemental diets. Interestingly, there was no statistical difference in eotaxin-3 or IL mRNA levels between the two patient groups.
This may indicate a dysregulation of IL-4 and IL-5 in allergic EoE patients which possibly reflect their systemic allergic history rather than activity of the disease However, this difference in cytokine expression between allergic and non-allergic EoE patients may open avenues for further research such as investigating possible difference in severity and response to treatments between the two patient groups.
Interleukin-5 functions in the proliferation, differentiation, and survival of eosinophils, T H 0 cells, and mast cells Mishra et al.
In this model, IL-5 was shown to be essential in aeroallergen-induced eosinophil recruitment to the esophagus More recently, Blanchard et al. The same study confirmed the importance of eotaxin-3 in the ILdependent induction of esophageal eosinophilia as a fold decrease in eosinophil number was found in eotaxin-deficient mice when subjected to the same aeroallergen challenge IL-5 appears to function by enhancing eosinophil responsiveness to endogenous chemokines expressed by the esophagus such as eotaxin-3 discussed later Despite compelling evidence suggesting the importance of IL-5 in EoE, drugs targeting IL-5 have shown little clinical efficacy.
A randomized controlled trial evaluating the anti-IL-5 antibody mepolizumab showed little clinical improvement, despite the decreased tissue eosinophilia compared to placebo controls This questions current understanding of the mechanism by which IL-5 contributes to EoE, or that perhaps esophageal damage may prevail through other mechanisms, aside from that of ILrecruited eosinophils.
Concordantly, reslizumab, another anti-IL-5 antibody reduced eosinophil counts in esophagi of children and adolescents, but symptom improvements were observed in all treatment groups and were not associated with changes in eosinophil number in the esophagus Interleukin, similar in structure and function to IL-4, may have a role in propagating the inflammatory response toward a T H 2 mechanism, and has also been implicated in tissue fibrosis Interestingly, ILinduced lung eosinophilia consequently induced esophageal eosinophilia as well 75 , suggesting a possible intimate connection between respiratory and esophageal epithelia, or simply the systemic allergic reaction in both cases.
Studies on bronchial remodeling in asthma, have shown that IL is essential for tissue fibrosis and airway mucous production Similar findings were seen in EoE, when Blanchard and colleagues 60 found a fold increase in IL mRNA in biopsies of pediatric patients with esophageal fibrosis, compared to non-EoE controls. IL is also known to stimulate eotaxin-3 production by epithelial cells, which in turn stimulates eosinophil recruitment Additionally, IL may stimulate fibroblasts to overexpress periostin and down-regulate filaggrin.
Periostin is an ECM molecule that promotes eotaxin-induced eosinophil recruitment and regulates eosinophil adhesion Filaggrin is a structural barrier protein in skin keratinocytes; down-regulation of this protein has been implicated in the impairment of esophageal barrier function and development of atopic dermatitis Filaggrin is a member of the epithelial differentiation cluster EDC , and together with involucrin another EDC member , prevents the proteolytic destruction of keratin during differentiation of epidermal cells 77 , This forms an important barrier function in cornified epithelial cells, although its function in esophageal epithelial cells is less clear.
A recent study on the effect of IL on genes involved in epithelial differentiation concluded that IL plays a large role in the up-regulation of genes such as Ki67 and down-regulation of EDC genes such as filaggrin and involucrin, which cumulatively contribute to the eotaxin-mediated recruitment of eosinophils to the esophageal epithelium.
Not only does this open an avenue for further research on possible therapeutic strategies targeting IL in EoE, but also suggests the importance of IL in the pathogenesis of EoE. Recently, Zhu et al. Additionally, the level of esophageal eosinophilia in patients both treated and untreated EoE correlated significantly with the IL transcript.
Interestingly however, these mice were not protected from airway inflammation, suggesting that IL many have an organ-specific mechanistic induction of esophageal eosinophilia in mice. The three eotaxins are chemokines with selective eosinophil-chemoattractant activity and act on CCR-3 receptors Blanchard and colleagues 30 found an increase in eotaxin-3 levels in esophageal biopsies of patients with EoE.
In the same study, these levels correlated with esophageal eosinophil numbers. Interestingly, eotaxin-1 and eotaxin-2 levels did not correlate.
Battacharya and colleagues 81 however showed contradicting findings with increased eotaxin-1, -2, and -3 levels in EoE, but also no correlation between eotaxin-3 levels and tissue eosinophilia. A recent genome-wide expression analysis identified eotaxin-3 as the single most up-regulated gene in EoE Furthermore, a single nucleotide polymorphism in the untranslated region of the eotaxin-3 gene is associated with EoE Interestingly, this expression profile is not associated with GERD, a disease triggered by acid reflux, also associated with esophageal eosinophilia Blanchard et al.
Additionally, IL-5 and IL have shown to increase eotaxin-3 release by esophageal epithelial cells 81 suggesting the combined contributions of these molecules in esophageal eosinophilia. Eotaxin-3 has been increasingly recognized as a more accurate biomarker for the diagnosis of EoE. The same study concluded that increased numbers of cells staining for MBP and eotaxin-3 was more predictive of EoE than eosinophil counts alone.
This suggests possible flaws in current diagnostic criteria, and highlights the importance of eotaxin-3 in EoE. Combining this evidence, the importance of eotaxin-3 in esophageal eosinophilia is widely accepted. It is proposed that IL, produced by T H 2 inflammatory cells under allergic contexts stimulates the production of eotaxin-3 by epithelial cells.
IL-5 and eotaxin-3 may act synergistically to induce esophageal eosinophil infiltration, allowing eosinophilic inflammation to ensue. However, the reason for which this inflammatory process is restricted to the esophagus remains elusive.
Regardless, this localized function of eotaxin-3 in EoE may be important in minimizing side-effects, if it were to be considered a future therapeutic target.
The esophagus is composed of stratified squamous epithelium, protected by a variety of organ-specific molecules such as mucous and antibodies. Additionally, the epithelium is a potent reservoir of cytokines and lipid mediators, which normally functions to cleanse the epithelial surface Swallowed steroids act locally on the esophagus and are minimally absorbed through the gastrointestinal tract. Although steroids for EoE are generally safe and effective, they do not lead to a long-term cure because the disease tends to come back as long as patients continue to eat foods that trigger the underlying allergic response.
Patients may also opt to identify their food trigger and eliminate it from the diet, and this represents a more definitive treatment approach. Unfortunately, currently available allergy testing does not accurately predict the foods that cause EoE. Trigger foods generally need to be identified using a process of food elimination and reintroduction.
Wheat and dairy are the two most common triggers for EoE, and patients will often start by eliminating these two foods for about eight weeks. At that point, their symptoms are reassessed, and they also undergo a repeat endoscopy with biopsies to determine if the eosinophils have disappeared in response to the dietary changes.
Several medication therapies are on the horizon. These include better formulations of steroids and biologic medications that reduce the activity of eosinophils.
If you are having trouble swallowing or have experienced episodes of food getting stuck in the esophagus, particularly if you have other allergic conditions, discuss your symptoms with your doctor. Unrecognized or untreated EoE can lead to permanent damage to your esophagus. For more information or to learn about strategies for living with EoE, visit the American Partnership for Eosinophilic Disorders.
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Nat Genet — Keywords: eosinophilic esophagitis, reflux, EoE diagnostic panel, transcriptome, eosinophils, T helper type 2, histology, molecular profiling.
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