The Pathogenesis of Eosinophilic Esophagitis Beyo

Authors: Evan S Dellon

Publish Date: 2013/04/27

Volume: 58, Issue: 6, Pages: 1445-1448

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Abstract

Over the past two decades eosinophilic esophagitis EoE has undergone a remarkable transformation What used to be a rare casereportable condition about which little was known is now widely recognized as an important cause of upper GI morbidity and the subject of intense research activity The clinical syndrome has been defined treatment trials have been performed and guidelines for diagnosis and management have been published 1 In parallel with this has been a rapid increase in our understanding of the pathogenesis and genetic basis of EoE 2 3 4 5 While the consensus is that EoE is an allergic/immunemediated condition in which the eosinophil plays a central role recent data suggest that “noneosinophil cell types” play important and possibly crucial roles as well The allergic basis for the disease is based on several lines of evidence Patients with EoE have a high burden of concomitant atopic conditions 6 7 8 9 10 allergenfree elemental diets cause nearly universal improvement in symptoms and resolution of eosinophilia 11 12 and there is a seasonal variation in EoE possibly due to aeroallergens 10 13 14 15 16 Prompted by the review by Zhang and colleagues in this issue of Digestive Diseases and Sciences 17 this editorial summarizes the role of the eosinophil and several other cell types in the pathogenesis of EoE including lymphocytes mast cells fibroblasts and epithelial cells Recognizing and characterizing the role of the noneosinophil cell types is likely to be central to future advances in the diagnosis and treatment of EoEThe importance of the eosinophil in EoE is almost a tautology—after all it is classified as an allergic disease and called eosinophilic esophagitis Since the normal human esophagus is normally devoid of eosinophils their presence in the epithelium is abnormal 18 While not pathognomonic for EoE esophageal eosinophils are currently a requirement for the diagnosis of EoE 1 19 The understanding of why they are there and what they are doing however remains incomplete Eosinophils are multifunctional cells which when activated secrete a wide variety of inflammatory mediators cytokines chemokines neuromediators and cytotoxic granule proteins 20 Eosinophil activation and degranulation may mediate the pathogenesis of EoE 21 22 In particular eosinophils induce esophageal remodeling via a TGFβ pathway resulting in subepithelial fibrosis epithelialmesenchymal transition and smooth muscle dysfunction and increase the rate of epithelial proliferation in the esophagus 23 24 25 26 27 28 This provides a possible explanation for clinical features of EoE such as dysphagia esophageal rings strictures and dysmotility In animal models of EoE neither IL5 deficient nor eosinophil deficient mice develop the experimental phenotype of EoE 29 30 Nevertheless there is more to EoE than just eosinophilsIn this issue of Digestive Diseases and Sciences Zhang and colleagues 17 describe EoE as a disease process driven by Th2 lymphocytes Expression of Th2associated cytokines such as IL4 IL5 and IL13 are increased in EoE 31 32 33 34 Further the abundance of CD3+ and CD8+ T cells and to a lesser extent CD4+ cells is increased in EoE with pathobiological implications 35 Adaptive T cell immunity is critical for developing EoE in mouse models as illustrated in experiments where mice deficient in B cells develop EoE whereas mice deficient in B and T cells do not 36 B cells can generate local production of IgE in EoE via a classswitching mechanism although this response is not required for initiating the inflammatory cascade that leads to the disease 36 37The current model of EoE pathogenesis holds that antigens either food allergens or aeroallergens are presented to the esophagus and stimulate a Th2 response IL13 and IL5 produced by lymphocytes stimulate the esophageal epithelium to produce eotaxin3 a potent chemokine which then recruits and activates eosinophils 38 Eotaxin3 is associated strongly with the pathogenesis of EoE since it is the most upregulated gene and bears a diseaseassociated single nucleotide polymorphism SNP 3 IL13 is also essential This cytokine induces EoE in a mouse model and in human esophageal cell cultures IL13 induces an RNA transcript expression profile similar to that of humans with EoE 3 4 39 Another important factor is thymic stromal lymphopoietin TSLP A genomewide association study identified a SNP in the TSLP associated with EoE and TSLP expression was increased in EoE patients 5 TSLP is an IL7like cytokine involved in the initiation of allergic responses in atopic diseases likely through a dendritic cellmediated Th2 response 40 Although T cell costimulatory molecules are likely important in EoE pathogenesis this hypothesis has yet to be fully tested 17Mast cells have been implicated in the pathogenesis of EoE The number of mast cells is increased in EoE compared to gastroesophageal reflux disease or healthy controls 31 33 41 42 43 44 45 In some cases the number of mast cells is actually higher than the number of eosinophils indeed quantifying levels of tryptase positive mast cells has diagnostic utility in EoE 44 Moreover mast cellassociated genes such as carboxypeptidase A3 tryptase and the histamine receptor are specifically upregulated in EoE and normalize after treatment with a topical corticosteroid 3 45Although the mechanisms underlying local esophageal mastocytosis have yet to be fully elucidated they in part are prompted by the Th2 response in EoE possibly via IL9 2 The importance of mast cells is such that one author even proposed renaming the disease mastocytic esophagitis 46 Furthermore mast cells may represent a future therapeutic target To date only a small number of patients with EoE have been treated with the mast cell stabilizer cromolyn Though they did not respond favorably lack of success may have been due to suboptimal dosing and issues related to formulation and route of administration rather than true lack of efficacy 47 A recent pilot study of a novel antagonist to the chemoattractant receptorhomologous molecule prostaglandin D2 receptor expressed on Th2 cells reported a modest but significant decrease in tissue eosinophilia compared to placebo in steroidrefractory EoE patients further implicating mast cells a major source of prostaglandin D2 in EoE pathogenesis 48Fibroblasts are also important in EoE leading to the collagen deposition and esophageal scarring responsible for many of the clinical manifestations of EoE 27 This process appears to be mediated by TGFβ which is produced by eosinophils and mast cells 24 28 A recently recognized mechanism for fibroblast differentiation and activation is the epithelialmesenchymal transition whereby epithelial cells transform to and acquire mesenchymaltype features 25 49 TFGβ also induces periostin production by fibroblasts 50 Periostin expression is highly upregulated in EoE increasing eosinophil adherence to fibronectin in the extracellular matrix Therefore periostin can perpetuate the cycle of eosinophilic inflammation in the esophagus 3 50Esophageal epithelial cells are another noneosinophil cell involved in the pathogenesis of EoE Normally the epithelial cells in the human esophagus are joined by a series of tight junctions adherens junctions and desmosomes which contain key proteins including claudin1 and 4 Ecadherin and desmoglein 51 Spongiosis or dilated intercellular spaces is present in EoE histologically indicative of a leaky barrier due to breakdown of junctional proteins 18 Defects in barrier function can facilitate penetration of luminal antigens into the tissue serving as the initial trigger for EoE In this respect some barrier proteins are differentially expressed in EoE 3 Additionally expression of filaggrin also known as the epidermal differentiation complex is decreased in patients with EoE and in an IL13 stimulated EoE simulating experimental system 52 Once antigens penetrate the epithelial barrier eosinophils and even esophageal epithelial cells can present antigen 53 54 Clearly the esophageal epithelium is more than a passive barrier for protection against noxious acid/peptic stimuli It is an immunologically active tissue involved in the multiple inflammatory pathways in EoEThere have been rapid developments in our understanding of the pathogenesis of EoE over the past decade with an increasing recognition that cell types beyond the eosinophil are likely critical to disease development Several genetic predispositions to EoE including SNPs in eotaxin3 and TSLP have been implicated The current model holds that food or environmental allergens contact a possibly leaky esophageal epithelium triggering a Th2mediated cytokine response where IL5 and IL13 stimulate the esophageal epithelium to produce eotaxin3 Eotaxin3 in turn recruits eosinophils to the esophageal epithelium where they are activated IL13 downregulates epidermal differentiation complex genes further impairing the esophageal epithelial barrier Th2 lymphocytes additionally produce IL9 which recruits mast cells into the esophagus Eosinophils and mast cells produce TGFβ which induces the epithelialmesenchymal transition and esophageal remodeling Since the eosinophil is still considered to be central to this process the disease should not yet be termed “mastocytic esophagitis” “Th2ocytic esophagitis” “fibroblastic esophagitis” or “barrieropenic esophagitis” Yet the recognition of the importance of noneosinophil cell types in EoE is an important step forward The presence of these cells may help to define EoE clinical subphenotypes explain persistent symptoms in some patients who have resolution of esophageal eosinophilia after treatment and open areas where novel or combination therapies can be explored

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