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Potential for Improving Therapy and Defining New Research Targets in Eosinophilic Oesophagitis Based on Understanding of Immunopathogenesis

Murch, Simon H.*; Allen, Katrina; Chong, Sonny; Dias, Jorge Amil§; Papadopoulou, Alexandra||on Behalf of the Eosinophilic Oesophagitis Working Group of ESPGHAN

Journal of Pediatric Gastroenterology and Nutrition: October 2013 - Volume 57 - Issue 4 - p 529–534
doi: 10.1097/MPG.0b013e3182a212ab
Consensus Statement

Objectives: This review considers the potential for therapeutic advances in the management of eosinophilic oesophagitis (EoE) based on recently increased understanding of the pathophysiology of the disorder.

Methods: This is a review of publications characterising mucosal changes and leucocyte recruitment patterns in human and experimental EoE.

Results: EoE, although diagnosed by epithelial infiltration of eosinophils, is actually a transmural inflammation in which eosinophil recruitment occurs via the deeper layers. Penetration of eosinophils into the epithelium is variable, explaining the need for multiple biopsies to diagnose what may be a clearly visible disorder. Fibrosis and neuromuscular dysfunction both occur within the subepithelial tissues. Recent murine studies have identified that T-cell recruitment underpins antigen-specific oesophageal eosinophil recruitment. Involvement of innate immunity is also suggested by the role of invariant natural killer T cells in experimental EoE.

Conclusions: Looking beyond present therapeutic options with a view to future studies, we identify T cells as candidates for “upstream therapy” if antigen specificity or homing markers are determined. Evidence of aeroallergen sensitisation suggests the possibility of lymphocyte priming within nasal-associated lymphoid tissue or Waldeyer ring, with the potential for topical therapy. We consider acquired neuromuscular dysfunction as a therapeutic target in acute symptomatic deterioration or bolus obstruction. We assess possible similarities with therapeutic stratagems for chronic asthma, recognising at the same time the anatomic specificity of the oesophagus and the difficulty in delivering effective topical medication to subepithelial tissues in this location compared with the airway.

*Division of Metabolic and Vascular Health, Warwick Medical School, Coventry, UK

Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia

Department of Paediatrics, St Mary's Hospital for Children, Carshalton, UK

§Department of Paediatrics, Hospital St João, Porto, Portugal

||Department of Paediatrics, Athens Children's Hospital, Athens, Greece.

Address correspondence and reprint requests to Professor Simon H. Murch, Division of Metabolic and Vascular Health, Warwick Medical School, Clinical Sciences Building, Clifford Bridge Road, Coventry CV2 2DX, UK (e-mail:

Received 18 June, 2013

Accepted 19 June, 2013

Additional members of the ESPGHAN Eosinophilic Esophagitis Working Group (in alphabetical order): H. Antunes (Portugal), M.K.H. Auth (UK), C. Dupont (France), R. Garcia-Puig (Spain), C. Gutiérrez Junquera (Spain), M. Fotoulaki (Greece), M. Furman (UK), C.M.F. Kneepkens (Netherlands), A. Kostovski (FYROM), R. Orel (Slovenia), C. Spray (UK), A. Staiano (Italy), M. Thomson (UK), V. Urbonas (Lithuania), Y. Vandenplas (Belgium), and N. Zevit (Israel).

The authors report no conflicts of interest.

Eosinophilic oesophagitis (EoE) is a recently recognised condition that results in symptoms of eosinophilic dysfunction that include but are not restricted to symptoms of reflux, with gastroesophaeal reflux disease (GORD) being the main differential diagnosis; however, EoE has been shown to be distinctly different from GORD in terms of both mechanisms of disease and genetic predispositions. In addition, EoE is distinct from GORD in that untreated EoE can result in severe esophageal fibrosis and difficult-to-treat stricture disease, providing evidence that unlike GORD, EoE has a higher propensity for transmural disease.

In this article, we review the known pathogenesis of EoE, with not only the viewpoint of assistance of optimisation of presently available therapies but also with the hope of raising the profile of research targets that may lead to therapeutic advances. We identify an important discordance between diagnostic methods based on epithelial eosinophilia and pathogenetic evidence that the epithelium is not the primary site of eosinophil recruitment, but that subepithelial pathology may determine long-term outcome. We also review the evidence that the primary cause of this disorder may reside, not in eosinophils but in T cells and other lymphocyte populations, and that knowledge of the recruitment pathways of these cells may provide more effective long-term therapy than the focus on eosinophils alone.

Based on these considerations, we suggest a pathogenesis-based logical augmentation of present therapeutic stratagems (Table 1). These do not supplant the recommendations for therapy of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition Working Group to be made in a separate publication, but instead suggest a framework for potential future studies for cases in which the present therapy is ineffective. In addition, we review possible future therapeutic stratagems using defined molecular targets (Table 2).





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The recognisable lesion of EoE includes architectural changes of furrowing and ridging that are clearly based on events occurring in the deeper layers beneath the epithelium. The characteristic dysmotility attests to the involvement of the oesophageal neural plexus and the deep muscular layers. Endoscopic ultrasound or computed tomography scan has confirmed that substantial thickening of the entire oesophageal wall occurs in approximately 50% of cases (1,2), whereas longitudinal muscle dysfunction with abnormal peristalsis has been identified on both ultrasound and manometry (3–5). Functional luminal imaging studies have shown evidence of reduced oesophageal distensibility (6), whereas wall compliance studies using pressure tomography have shown a pattern of pan-oesophageal pressurisation (7). The development of fibrosis in chronic or severe disease also occurs in subepithelial tissues, and has been found to be associated with increased serum and tissue transforming growth factor (TGF)-β1 and vascular cell adhesion molecule-1 (8).

It is, however, notable that penetration of eosinophils into the epithelial compartment is patchy, even in disease that exhibits widespread classic endoscopic features, to the extent that multiple biopsies are needed to ensure that sufficient evidence for disease confirmation is obtained. In a study examining transmural sections throughout the entire oesophagus, resected from a patient with EoE who died of adenocarcinoma, eosinophil deposition was patchy and potentially diagnostic biopsies would have been obtained in a minority of sites (8). Within this person's oesophagus, 4 epithelial biopsies would have been required for 95% confident diagnosis in areas of high eosinophil infiltration, rising to 12 biopsies in areas of average density and 31 biopsies in those areas of low eosinophil density (9). By contrast, eosinophils were found in some areas to be densely aggregated within the deeper layers, whereas epithelial density was low (9). These and other data demonstrate that epithelial biopsy can be an inefficient method for secure diagnosis of EoE, and that false-negative findings may occur in those cases with less-efficient eosinophil recruitment to the epithelial layer from the deeper tissues.

These findings also raise the question whether therapies applied topically may penetrate sufficiently deeply to inhibit subepithelial pathology, even if recruitment of eosinophils into the epithelium may be reduced. The anatomy of the oesophagus, with thick layers of squamous epithelial cells overlying the basement membrane, may make penetration of topically applied therapies less efficacious than in the lung in asthma, although many aspects of the mucosal pathology are notably similar. Although the squamous epithelium of the oesophagus shares features with the skin, where topical medications may be effective, it is less accessible to uniform application of medication in appropriate vehicles for maximal penetration, and adherence of topical medications may be reduced by peristalsis and swallowed foods.

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The pathogenesis of EoE is, to a great extent, antigen specific. Improvement of mucosal inflammation and symptoms can often be achieved by exclusion of dietary antigens. Initial studies in both humans and mice have confirmed the presence of T cells within the mucosa (10,11). The requirement for T-cell responses to initiate EoE has been confirmed in RAG (recombination activating gene)-1–deficient mice, who lack all of the T cells and are completely protected from allergen-induced EoE (12). This fundamental finding both highlights the primacy of T-cell responses in EoE and identifies T cells as an important therapeutic target (Fig. 1).



A paradigm has been established, based upon triggering by dietary antigens and response to dietary exclusions in both humans and animal models, in which homing is thought to occur from the gastrointestinal tract of antigen-specific T cells; these in turn establish an interleukin (IL)-5–dominated milieu favouring recruitment and activation of eosinophils (Fig. 2) (10). This may occur locally without systemic eosinophilia, although oesophageal eosinophilia could also occur in systemic hypereosinophilic disorders.



More important, in addition to ingested dietary antigens, oesophageal recruitment of TH2 T cells and eosinophils may occur in response to inhaled aeroallergens (13,14). In mouse models, intranasal sensitisation is in fact more potent than intragastric in inducing oesophageal eosinophilia (13,15).

Recent murine evidence points to the paraoesophageal lymphoid follicles as the initial recruitment base for the T lymphocytes that drive eosinophil recruitment (15). The homing pathway of these driver lymphocytes appears distinct from classic intestinal responses, as evidenced by the role that inhaled aeroallergens may play in pathogenesis and by the absence of eosinophilia lower in the gastrointestinal tract (13–15).

Regardless of the site of their induction, such oesophageal recruitment of TH2 lymphocytes will promote eosinophil recruitment in an antigen-specific manner. The secretion patterns of oesophageal T cells implicated in EoE include TH2 cytokines such as IL-5 and IL-13, pivotal in the eosinophil response (16,17). IL-5 is a critical determinant of eosinophil generation from precursors within the bone marrow, which also upregulates peripheral eosinophil numbers and promotes local eosinophil maturation. Exposure to excess IL-5, whether produced by activated TH2-type T cells or following exogenous administration, increases eosinophil recruitment to the oesophagus (16). Targeted expression of IL-5 in oesophageal epithelium in mice induces a lesion with the hallmarks of EoE upon induction of a local hypersensitivity reaction (18). IL-5 has been shown to be increased in EoE mucosa in humans, together with another TH2 cytokine, IL-13, and with the chemokine eotaxin-3 (19,20). IL-13 also appears to be important in the recruitment of eosinophils and may contribute directly to the oesophageal remodelling (5).

On the contrary, recent data from mice suggest that other leucocyte types, which may not demonstrate such antigen specificity, may be involved. A murine study of nasopharyngeal sensitisation identified an additional cell type—invariant-chain natural killer T (iNKT) cells—to be important in the pathogenesis of EoE (15). iNKT cells, which respond to lipid dietary antigens such as milk-derived sphingomyelins, presented by the major histocompatibility complex molecule CD1d, have been shown to be able to induce TH2-polarised mucosal allergic reactions and to interact with B cells (21–24). The homing pathway for recruitment to the oesophagus of both these driver T cells and iNKT cells occurred via paraoesophageal lymph nodes (15). The additional involvement of innate immune cells such as iNKT cells suggests that lipid dietary or inhaled antigens may be involved in pathogenesis, and potentially that some responses may be antigen independent. This may have implications for allergen exclusion stratagems.

It should be noted that a recently discovered population of innate lymphoid cells, type 2 innate lymphoid (ILC2) cells, capable of producing TH2 cytokines in an antigen-independent response, have been identified in animals as potent producers of IL-5 and IL-13 in allergic diseases including asthma (25,26). Human ILC2 cells have recently been identified within allergic nasal polyps in allergic rhinitis (27), whereas interferon-γ–producing ILC1 cells have been characterised within the mucosal lesion in Crohn disease (28). Thus, although innate lymphoid cells have yet to be found within the EoE lesion in the context of similarities of underlying immune mechanisms, it may be expected that at least some forms of EoE may also express innate lymphoid cells. A clear implication, if this turns out to be so, is that this element of the mucosal lesion will be unlikely to respond to antigen exclusion, either ingested or inhaled. For patients identified to have a significant infiltration of innate lymphoid cells (known to produce as much IL-5 in murine asthma as do TH2 T cells (25)), then dietary exclusion alone will prove insufficient. When more is known about the recruitment and activation pathways of innate lymphoid cells, then more specific therapeutic stratagems may become available if they are confirmed to play a role in EoE as appears likely. Alternatively, the identification of innate immune cells may provide a biomarker to differentiate subphenotypes of disease that have a differential response to therapeutic intervention with some patients responding to dietary exclusion and others better commenced on steroid treatment.

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The implication for therapy of EoE in humans is that there appears to be a substantial variability in the pattern of allergen exposure. For some persons, mucosal sensitisation to ingested antigens may have occurred within the intestine, leading to the well-characterised generation of TH2 T cells expressing α4β7 integrin, which home widely throughout the gut (29). Oesophageal recruitment would then follow as part of a broader pattern of homing, and it is likely that eosinophil or mast cell density may be increased more widely within the intestinal tract (Fig. 1).

Conversely, lymphocytes sensitised to aeroallergens express different homing markers and have different patterns of tissue distribution. Lymphocytes originating from nasal-associated lymphoid tissue (NALT), eustachian tube–associated lymphoid tissue, and bronchus-associated lymphoid tissue do not home to the intestine, but instead to salivary, bronchial, and mammary glands and the middle ear mucosa (29). The fact that oesophageal eosinophilia occurs without concomitant increased small or large bowel infiltration implicates NALT as a possible inductive site for at least some cases of EoE (Fig. 1). If NALT (or eustachian tube–associated lymphoid tissue) were to be identified as the primary source of EoE lymphocyte homing, this would offer an important potential advance in therapy, even using existing medicines because of the accessibility of these structures to topical therapy.

Homing to NALT is mediated by different addressins to gut-associated lymphoid tissue, in particular the peripheral node addressin, PNAd (30). NALT has been identified in a postmortem study as a distinctive structure, in addition to Waldeyer ring tissues (adenoids and tonsils), in approximately 40% of children younger than 2 years (31). Lymphocytes primed within NALT that home to the lung do not express α4β7 integrin but are CLA selectin and variably express αEβ7 integrin (30). These NALT-derived cells do not home to the gastrointestinal tract (29), and it is presently unknown whether the oesophageal lymphocytes driving eosinophil recruitment in EoE express similar lung homing markers or are distinct. This will be fundamentally important to ascertain. Should oesophageal T cells specific for dietary antigens express airway rather than gut homing markers, this would point to primary sensitisation within NALT or Waldeyer ring tissues, implicating GOR or incoordinate swallowing in sensitisation, unless priming occurs within tonsillar tissues during swallowing. It is thus notable that EoE occurs more commonly in children with cerebral palsy and in those who have undergone surgery for tracheo-oesophageal stricture, supporting a potential role for severe GOR in allowing dietary antigen exposure to NALT (32–34).

In mice, nasal application of antigen is clearly more potent than intragastric gavage in inducing oesophageal eosinophilia (15). These murine studies show that common environmental-inhaled antigens, including Aspergillus, house dust mite, and cockroach, are particularly potent inducers of oesophageal eosinophil recruitment (35). Identification of sensitisation to these antigens in a patient with EoE may thus be of clinical significance, and raises the question whether topical corticosteroid therapy targeted to NALT may be therapeutically effective.

In terms of interrupting lymphocyte recruitment in human EoE, one implication is that local corticosteroid application to nasopharyngeal and adenotonsillar lymphoid tissue may provide more effective “upstream therapy” than delivery to the surface oesophageal epithelium. One research priority would therefore be characterisation of homing marker expression on oesophageal T cells, to identify whether an inductive site can be determined and whether such local inhibition of T cell sensitisation may interrupt the drive to eosinophil recruitment.

For maximising effective antigen exclusion, it should also be recognised that the driving T-cell responses may not necessarily induce a detectable IgE-mediated response, meaning that non–IgE-mediated food allergies may drive a localised pathology without peripheral responses. In that case, skin prick tests and specific IgE testing may be negative even if a food is implicated, as seen in non–IgE-mediated food allergies (36). As with other non–IgE-mediated responses, both exclusion and challenge are required to identify the illiciting antigen(s).

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Although the diagnosis of the disorder is based upon the density of eosinophils lying within the surface mucosa, the initial recruitment of eosinophils to the oesophagus in both humans and mice is via vessels deeper within the oesophageal wall (11,13,16,37). The eotaxin group of chemokines, particularly eotaxins-1 and -3, are critically required for oesophageal eosinophil recruitment (19,35). Eotaxin-3 is the most upregulated single gene in EoE mucosa, although its exact localisation in human disease has not been delineated (19). Eotaxin-1 localises at the basal epithelial layer of the oesophagus and may function as a gatekeeper to the epithelium for newly recruited subepithelial eosinophils (11).

Penetration of eosinophils from the submucosa through the basal epithelial layer is variable, leading to the paradox, which is sometimes seen, that a macroscopically visible disorder may require numerous biopsies to identify a single histologically diagnostic biopsy. Interaction between endothelial or epithelial eotaxins and eosinophils is mediated by the chemokine receptor CCR3 on the eosinophil surface (38). Of likely importance in the oesophageal environment, particularly in the context of the expanded intercellular spaces characteristic of EoE (39), CCR3 interaction with eotaxin-expressing eosinophils is highly pH dependent in the physiological range. Thus, a change in pH from 7.6 to 7.0 induces a 10-fold decrease in CCR3 signalling (40). One implication is that acid reflux may inhibit recruitment to the surface of subepithelial T cells, whereas alkaline reflux (or acid-suppression therapy) may promote surface eosinophilia. For that reason, the prolonged use of proton pump inhibitors is not desirable once diagnosis has been established, unless symptom control is inadequate and the patient notices clinical benefit.

Eosinophils promote epithelial hyperproliferation, potentially through production of TGF-α (41) and also via triggering of the epithelial calcium-sensing receptor by secreted major basic protein (42). This induces epithelial production of fibroblast growth factor 9, which in turn stimulates bone morphogenic protein-4 to induce cell turnover (42). Thus, the histological finding of widespread basal cell hyperplasia and elongation of the rete pegs, even in the absence of epithelial eosinophilia, may be a diagnostic marker indicating eosinophil degranulation in the subepithelial compartment. Eosinophil secretion products also induce mislocalisation of the tumour suppressor protein p27Kip1, with potential implications in progression to dysplasia, as well as hyperproliferation (43). The potential implications of these interactions, in addition to focusing attention on basal cell hyperproliferation in the diagnosis of EoE in which epithelial eosinophilia is not prominent, include recognition that reduction of epithelial proliferation may be a histological marker of successful therapy because epithelial eosinophil density is such a poor guide to actual disease progress.

Inhibition of activation of recruited eosinophils may be attempted by a variety of therapies, including corticosteroids, leukotriene antagonists, and monoclonals against IL-5 and IgE, so far with variable results (44). Recognition that ion channels play an obligatory role in eosinophil activation has led to identification of sulphonyl ureas such as gliburide as potent inhibitors of eosinophil activation, with notable synergy with corticosteroids (45).

In addition to infiltration of eosinophils, specific staining confirms substantial increase of oesophageal mast cell density (46), whereas microarray analysis confirms a distinct mast cell–associated transcriptome and involvement of the mast cell transcription factor c-kit in disease pathogenesis (47). The products of activated mast cells may synergise with eosinophil-derived mediators to influence dysmotility, potentially triggered acutely via IgE, and may also contribute to tissue remodelling via TGF-β production (48). It is thus possible that mast cell–specific therapy, when available, may be helpful in reducing the progression to fibrosis in EoE. Recent evidence suggests that targeting mast cell activation by inhibiting the PIP3 activation pathway may be substantially more effective than present therapies in allergic disease (49). Use of a chimeric toxin binding to FcεR1 and delivering a lipid PIP3 phosphatase allowed selective adhesion to mast cells and effectively blocked antigen-induced degranulation in vivo (50). In addition, basophil recruitment and activation may be mediated by epithelial expression of thymic stromal lymphopoietin, known to be increased within the mucosa in EoE (51).

Finally, there is murine evidence of an oesophageal remodelling pathway independent of eosinophils but dependent on pulmonary production of IL-13, identifying this among the candidates for future specific immunotherapy (52,53).

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Subepithelial and Neural Involvement in EoE

Recognition of this recruitment sequence via the deeper oesophageal wall is important for understanding the potential limitations of present treatment regimens and may provide insight for development of future strategies.

One possible implication of this deep eosinophil recruitment and subepithelial pathology is that topical corticosteroids may be less effective than in asthma because of the much greater thickness of the epithelial layer. Systemic oral corticosteroids may prove necessary in some cases with severe subepithelial pathology in periods of exacerbation. For persons with a consistent pattern of seasonal exacerbation, timed administration of topical or oral corticosteroids may prevent an otherwise inevitable relapse.

Finally, it is possible that sudden symptomatic exacerbation, such as acute dysphagia or bolus impaction during meals, is most likely to be caused by smooth muscle spasm (5). There has been surprisingly little attention paid to this aspect of symptomatology. Further analogy with asthma would suggest the potential use of β-adrenergic agonists in treating acute symptomatic exacerbations, of swallowed topical agents such as salbutamol to provide symptomatic relief, and of β-adrenergic inhalers to resolve episodes of acute dysphagia. In acute bolus impaction, however, it is also possible that systemic administration of agents such as aminophylline may provide a safer alternative to endoscopic removal or emergency dilatation procedures.

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1. Fox VL, Nurko S, Teitelbaum J, et al. High-resolution EUS in children with eosinophilic “allergic” esophagitis. Gastrointest Endosc 2003; 57:30–36.
2. Kinoshita Y, Furuta K, Ishimaura N, et al. Clinical characteristics of Japanese patients with eosinophilic esophagitis and eosinophilic gastroenteritis. J Gastroenterol 2012; 48:333–339.
3. Nurko S, Rosen R, Furuta GT. Esophageal dysmotility in children with eosinophilic esophagitis: a study using prolonged esophageal manometry. Am J Gastroenterol 2009; 104:3050–3057.
4. Martín Martín L, Santander C, Lopez Martín MC, et al. Esophageal motor abnormalities in eosinophilic esophagitis identified by high-resolution manometry. J Gastroenterol Hepatol 2011; 26:1447–1450.
5. Korsapati H, Babaei A, Bhargava V, et al. Dysfunction of the longitudinal muscles of the oesophagus in eosinophilic oesophagitis. Gut 2009; 58:1056–1062.
6. Kwiatek MA, Hirano I, Kahrilas PJ, et al. Mechanical properties of the esophagus in eosinophilic esophagitis. Gastroenterology 2011; 140:82–90.
7. Roman S, Hirano I, Kwiatek MA, et al. Manometric features of eosinophilic esophagitis in esophageal pressure topography. Neurogastroenterol Motil 2011; 23:208–214.
8. Aceves SS, Newbury RO, Dohil R, et al. Esophageal remodelling in pediatric eosinophilic esophagitis. J Allergy Clin Immunol 2007; 119:206–212.
9. Saffari H, Peterson KA, Fang JC, et al. Patchy eosinophil distributions in an esophagectomy specimen from a patient with eosinophilic esophagitis: implications for endoscopic biopsy. J Allergy Clin Immunol 2012; 130:798–800.
10. Mulder DJ, Justinich CJ. Understanding eosinophilic esophagitis: the cellular and molecular mechanisms of an emerging disease. Mucosal Immunol 2011; 4:139–147.
11. Butt AM, Murch SH, Ng CL, et al. Upregulated eotaxin expression and T cell infiltration in the basal and papillary epithelium in cows’ milk associated reflux oesophagitis. Arch Dis Child 2002; 87:124–130.
12. Mishra A, Schlotman J, Wang M, et al. Critical role for adaptive T cell immunity in experimental eosinophilic esophagitis in mice. J Leukoc Biol 2007; 81:916–924.
13. Mishra A, Hogan SP, Brandt EB, et al. An etiological role for aeroallergens and eosinophils in experimental esophagitis. J Clin Invest 2001; 107:83–90.
14. Moawad FJ, Veerappan GR, Lake JM, et al. Correlation between eosinophilic oesophagitis and aeroallergens. Aliment Pharmacol Ther 2010; 31:509–515.
15. Rajavelu P, Rayapudi M, Moffitt M, et al. Significance of para-esophageal lymph nodes in food or aeroallergen-induced iNKT cell-mediated experimental eosinophilic esophagitis. Am J Physiol Gastrointest Liver Physiol 2012; 302:G645–G654.
16. Mishra A, Hogan SP, Brandt EB, et al. IL-5 promotes eosinophil trafficking to the esophagus. J Immunol 2002; 168:2464–2469.
17. Abonia JP, Rothenberg ME. Eosinophilic esophagitis: rapidly advancing insights. Annu Rev Med 2012; 63:421–434.
18. Masterson JC, McNamee EN, Hosford L, et al. Local hypersensitivity reaction in transgenic mice with squamous epithelial IL-5 overexpression provides a novel model of eosinophilic oesophagitis. Gut 2012; Nov 17 [Epub ahead of print].
19. Blanchard C, Wang N, Stringer KF, et al. Eotaxin-3 and a uniquely conservedgene-expression profile in eosinophilic esophagitis. J Clin Invest 2006; 116:536–547.
20. Blanchard C, Stucke EM, Rodriguez-Jimenez B, et al. A striking local esophageal cytokine expression profile in eosinophilic esophagitis. J Allergy Clin Immunol 2011; 127:208–217.
21. Spinozzi F, Porcelli SA. Recognition of lipids from pollens by CD1-restricted T cells. Immunol Allergy Clin North Am 2007; 27:79–92.
22. Meyer EH, DeKruyff RH, Umetsu DT. iNKT cells in allergic disease. Curr Top Microbiol Immunol 2007; 314:269–291.
23. Jyonouchi S, Abraham V, Orange JS, et al. Invariant natural killer T cells from children with versus without food allergy exhibit differential responsiveness to milk-derived sphingomyelin. J Allergy Clin Immunol 2011; 128:102–109.
24. Lehuen A, Fazilleau N. Innate iNKT cell help to B cells: fast but does not last. Nat Immunol 2011; 13:11–13.
25. Scanlon ST, McKenzie AN. Type 2 innate lymphoid cells: new players in asthma and allergy. Curr Opin Immunol 2012; 24:707–712.
26. Klein Wolterink RG, Kleinjan A, van Nimwegen M. et al Pulmonary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma. Eur J Immunol 2012; 42:1106–1116.
27. Mjösberg JM, Trifari S, Crellin NK, et al. Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat Immunol 2011; 12:1055–1062.
28. Bernink JH, Peters CP, Munneke M, et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat Immunol 2013; 14:221–229.
29. Brandtzaeg P, Farstad IN, Haraldsen G. Regional specialization in the mucosal immune system: primed cells do not always home along the same track. Immunol Today 1999; 20:267–277.
30. Ohmichi Y, Hirakawa J, Imai Y, et al. Essential role of peripheral node address in lymphocyte homing to nasal-associated lymphoid tissues and allergic immune responses. J Exp Med 2011; 208:1015–1025.
31. Debertin AS, Tschernig T, Tönjes H, et al. Nasal-associated lymphoid tissue (NALT): frequency and localization in young children. Clin Exp Immunol 2003; 134:503–507.
32. Miele E, Staiano A, Tozzi A, et al. Clinical response to amino acid-based formula in neurologically impaired children with refractory esophagitis. J Pediatr Gastroenterol Nutr 2002; 35:314–319.
33. Batres LA, Liacouras C, Schnaufer L, et al. Eosinophilic esophagitis associated with anastomotic strictures after esophageal atresia repair. J Pediatr Gastroenterol Nutr 2002; 35:224–226.
34. Oliveira C, Zamakhshary M, Marcon P, et al. Eosinophilic esophagitis andintermediate esophagitis after tracheoesophageal fistula repair: a case series. J Pediatr Surg 2008; 43:810–814.
35. Rayapudi M, Mavi P, Zhu X, et al. Indoor insect allergens are potent inducers of experimental eosinophilic esophagitis in mice. J Leukoc Biol 2010; 88:337–346.
36. Latcham F, Merino F, Winter C, et al. A consistent pattern of minor immunodeficiency and subtle enteropathy in children with multiple food allergy. J Pediatr 2003; 143:39–47.
37. Hogan SP, Mishra A, Brandt EB, et al. A pathological function for eotaxin and eosinophils in eosinophilic gastrointestinal inflammation. Nat Immunol 2001; 2:353–360.
38. Sallusto F, Lenig D, Mackay CR, et al. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J Exp Med 1998; 187:875–883.
39. Ravelli AM, Villanacci V, Ruzzenenti N, et al. Dilated intercellular spaces: a major morphological feature of esophagitis. J Pediatr Gastroenterol Nutr 2006; 42:510–515.
40. Dairaghi DJ, Oldham ER, Bacon KB, et al. Chemokine receptor CCR3 function is highly dependent on local pH and ionic strength. J Biol Chem 1997; 272:28206–28209.
41. Wong DT, Weller PF, Galli SJ, et al. Human eosinophils express transforming growth factor α. J Exp Med 1990; 172:673–681.
42. Mulder DJ, Pacheco I, Hurlbut DJ, et al. FGF9-induced proliferative response to eosinophilic inflammation in oesophagitis. Gut 2009; 58:166–173.
43. Nguyen KD, Blain SW, Gress F, et al. Inflammatory mediators of esophagitis alter p27 Kip1 expression in esophageal epithelial cells. J Pediatr Gastroenterol Nutr 2010; 51:556–562.
44. Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011; 128:3–20.
45. Bankers-Fulbright JL, Kephart GM, Loegering DA, et al. Sulfonylureas inhibit cytokine-induced eosinophil survival and activation. J Immunol 1998; 160:5546–5553.
46. Kirsch R, Bokhary R, Marcon MA, et al. Activated mucosal mast cells differentiate eosinophilic (allergic) esophagitis from gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2007; 44:20–26.
47. Abonia JP, Blanchard C, Butz BB, et al. Involvement of mast cells in eosinophilic esophagitis. J Allergy Clin Immunol 2010; 126:140–149.
48. Aceves SS, Chen D, Newbury RO, et al. Mast cells infiltrate the esophageal smooth muscle in patients with eosinophilic esophagitis, express TGF-β1, and increase esophageal smooth muscle contraction. J Allergy Clin Immunol 2010; 126:1198–1204.
49. Shenker BJ, Ali H, Boesze-Battaglia K. PIP3 regulation as promising targeted therapy of mast-cell-mediated diseases. Curr Pharm Des 2011; 17:3815–3822.
50. Shenker BJ, Boesze-Battaglia K, Zekavat A, et al. Inhibition of mast cell degranulation by a chimeric toxin containing a novelphosphatidylinositol-3,4,5-triphosphate phosphatase. Mol Immunol 2010; 48:203–210.
51. Siracusa MC, Saenz SA, Hill DA, et al. TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation. Nature 2011; 477:229–233.
52. Zuo L, Fulkerson PC, Finkelman FD, et al. IL-13 induces esophageal remodeling and gene expression by an eosinophil-independent, IL-13R α2-inhibited pathway. J Immunol 2010; 185:660–669.
53. Wechsler ME, Fulkerson PC, Bochner BS, et al. Novel targeted therapies for eosinophilic disorders. J Allergy Clin Immunol 2012; 130:563–571.

eosinophilic oesophagitis; pathogenesis; T cell; therapy

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