EVIDENCE OF SUBEPITHELIAL INVOLVEMENT IN EOE
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.
RECRUITMENT OF OESOPHAGEAL EOSINOPHILS—THE PRIMARY ROLE OF T LYMPHOCYTES
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.
IMPORTANCE OF LYMPHOCYTE HOMING PATTERNS
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).
PATTERN OF EOSINOPHIL RECRUITMENT
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).
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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Keywords:© 2013 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
eosinophilic oesophagitis; pathogenesis; T cell; therapy