ABSTRACT: To review the understanding of the pathogenesis of eosinophilic esophagitis (EoE) and the role of the immune system in the disease process.Peer-reviewed articles on EoE from PubMed searching for "Eosinophilic Esophagitis and fibrosis" in the period of 1995 to 2013.Studies on the clinical and immunologic features, pathogenesis, and management of EoE.Recent work has revealed that thymic stromal lymphopoietin and basophil have an increased role in the pathogenesis of disease. Additional understanding on the role of fibrosis in EoE is emerging.The incidence of EoE is increasing like most atopic disease. Similar to other allergic diseases, EoE is treated with topical steroids and/or allergen avoidance.
Project description:Eosinophilic esophagitis (EoE) is a food allergy-associated inflammatory disease characterized by esophageal eosinophilia. Current management strategies for EoE are nonspecific, and thus there is a need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis has been unclear. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE, but was dependent on TSLP and basophils, as targeting TSLP or basophils during the sensitization phase limited disease. Notably, therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. In human subjects with EoE, we observed elevated TSLP expression and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses in patients with EoE. Together, these data suggest that the TSLP-basophil axis contributes to the pathogenesis of EoE and could be therapeutically targeted to treat this disease.
Project description:PURPOSE OF REVIEW:Eosinophilic Esophagitis (EoE) is an emerging chronic atopic disease. Recent advances in understanding its genetic and molecular biology pathogenesis may lead to a better management of the disease RECENT FINDINGS:EoE is an atopic disease. Most of the patients affected by EoE have other atopic diseases such as allergic rhinitis, asthma, IgE-mediated food allergies and/or atopic dermatitis. The local inflammation is a T helper type 2 (Th2) flogosis, which most likely is driven by a mixed IgE and n-IgE-mediated reaction to food and/or environmental allergens. Epidemiological studies show that EoE is an atopic disease with a strong genetic component. Genetic studies have shown that EoE is associated with single nucleotide polymorphism on genes, which are released by the epithelium and important in atopic inflammation such as thymic stromal lymphopoietin located (TSLP) close to the Th2 cytokine cluster [interleukin (IL)-4, IL-5, IL-13] on chromosome 5q22, Calpain 14, EMSY, and Eotaxin3. When the EoE diagnosis is made, it is imperative to control the local eosinophilic inflammation not only to give symptomatic relief to the patient, but also to prevent complications such as esophageal stricture and food impaction. SUMMARY:EoE is treated like many other atopic diseases with a combination of topical steroids and/or food antigen avoidance. The new understanding of EoE may lead to more specific and definitive treatments of EoE.
Project description:Eosinophilic esophagitis (EoE) is increasingly diagnosed as a disorder throughout the world. It is characterized by eosinophils in the esophagus due to food allergies. Molecular analysis of esophageal biopsies and mouse models have indicated a clear role for the T helper 2 pathway, in particular interleukins 5 and 13, in this disease. Current treatment options for EoE involve avoidance of the allergens or using anti-inflammatory medications such as topical corticosteroids. In the past year, genomic research has led to the identification of single nucleotide polymorphisms in the gene encoding thymic stromal lymphopoietin (TSLP), and subsequently in the gene encoding its receptor, as disease susceptibility markers for EoE. Identification of this molecule and its receptor suggest the potential for new treatment options in the future.
Project description:Eosinophilic esophagitis (EoE) is a recently recognized inflammatory disease of the esophagus with clinical symptoms derived from esophageal dysfunction. The etiology of EoE is now being elucidated, and food hypersensitivity is emerging as the central cornerstone of disease pathogenesis. Herein, we present a thorough picture of the current clinical, pathologic, and molecular understanding of the disease with a focus on disease mechanisms.
Project description:Eosinophilic esophagitis (EoE) is an allergy-mediated disease culminating in severe eosinophilic inflammation and dysfunction of the esophagus. This chronic disorder of the esophagus causes significant morbidity, poor quality of life, and complications involving fibrosis and esophageal remodeling. Overlapping features between EoE and gastroesophageal reflux disease (GERD) pose great challenges to differentiating the two conditions, although the two disorders are not mutually exclusive. Recent findings suggest that the confounding condition proton pump inhibitor - responsive esophageal eosinophilia (PPI-REE) is likely a subset of EoE. Since PPIs have therapeutic properties that can benefit EoE, PPIs should be considered as a therapeutic option for EoE rather than a diagnostic screen to differentiate GERD, PPI-REE, and EoE. Other current treatments include dietary therapy, corticosteroids, and dilation. Immunomodulators and biologic agents might have therapeutic value, and larger trials are needed to assess efficacy and safety. Understanding the pathophysiology of EoE is critical to the development of novel therapeutics.
Project description:Eosinophilic esophagitis (EoE) is a recently recognized upper gastrointestinal allergic disorder characterized by esophageal dysfunction (e.g., dysphagia) and esophageal eosinophilia of ?15 eosinophils/high-power field in patients who have persistent esophagitis even on proton pump inhibitor (PPI) therapy. The histologic method is the gold standard of EoE diagnosis. However, EoE clinical symptoms do not always correlate with histology, and the histologic method has sensitivity and specificity issues due to the patchiness of EoE and the subjective nature of the method. The "EoE transcriptome" was initially discovered in 2006, which led to the invention of the EoE diagnostic panel (EDP). In addition to providing a definitive EoE diagnosis with high accuracy, the EDP has been useful in elucidating several key elements about the disease including the efficacy of specific drugs such as swallowed glucocorticoids and anti-IL-13 humanized antibody therapy, the relationship between EoE and PPI-responsive esophageal eosinophilia, and predicting the disease course and responsiveness to therapy. The EDP's long-term potential arises from its plasticity to incorporate new genes and uncover novel disease pathogenesis. We expect that the EDP will be increasingly helpful for personalized medicine approaches and improved diagnostics and disease monitoring.
Project description:Eosinophilic esophagitis (EoE) is a relatively new condition described as an allergic-mediated disease of the esophagus. Clinically, it is characterized by dysphagia, food impaction, and reflux-like symptoms. Multiple genome-wide association studies (GWAS) have been conducted to identify genetic loci associated with EoE. The integration of numerous studies investigating the genetic polymorphisms in EoE and the Mendelian diseases associated with EoE are discussed to provide insights into the genetic risk of EoE, notably focusing on CCL26 and CAPN14. We focus on the genetic loci investigated thus far, and their classification according to whether the function near the loci is known. The pathophysiology of EoE is described by separately presenting the known function of each cell and molecule, with the major contributors being eosinophils, Th2 cells, thymic stromal lymphopoietin (TSLP), transforming growth factor (TGF)-?1, and interleukin (IL)-13. This review aims to provide detailed descriptions of the genetics and the comprehensive pathophysiology of EoE.
Project description:Eosinophilic esophagitis (EoE) is a chronic inflammatory condition characterized by symptoms of esophageal dysfunction and eosinophilic infiltration of the esophageal mucosa. The diagnosis requires esophageal biopsies demonstrating at least 15 eosinophils per high-powered field following a course of high-dose proton pump inhibitors. Management of EoE consists of the three Ds: drugs, dietary therapy, and esophageal dilation. In this review, we discuss the epidemiology, pathogenesis, diagnosis, and treatment of EoE to include the role of emerging therapies.
Project description:Background/Aims:The epidemiology and pathogenesis of eosinophilic esophagitis (EoE) remain unclear in Asian countries. We investigated clinicopathological characteristics and diagnostic trends of EoE, and evaluated 3 tissue biomarkers for correlation with disease activity and treatment response in Korean patients with EoE. Methods:We retrospectively reviewed 25 271 esophageal biopsies performed during upper endoscopies between 2006 and 2017. We diagnosed EoE based on ≥ 15 eosinophils/high-power field (HPF) and, symptoms of esophageal dysfunction. We performed immunohistochemical analysis for tryptase, eosinophilic derived neurotoxin (EDN), and eotaxin-3. Results:We diagnosed EoE in 72 patients (53 men and 19 women; mean age, 46.2 years) with presenting symptoms of, dysphagia (15.3%), epigastric pain (31.9%), and heartburn (30.6%). The diagnostic rate of EoE considerably increased between 2006 and 2017, from 0.29 diagnoses to 7.99 diagnoses per 1000 esophageal biopsies ( P < 0.001). The mean peak eosinophil count (PEC) was 56.0 (± 77.8)/HPF. Whereas the EDN (rho = 0.667, P < 0.001) and eotaxin-3 levels (rho = 0.465, P < 0.001) correlated with PEC, tryptase and PEC were weakly correlated (rho = 0.291, P = 0.013). EDN (rho = 0.279, P = 0.017), and tryptase (rho = 0.279, P = 0.033) correlated with the inflammatory score of Eosinophilic Esophagitis Endoscopic Reference Score. Immunohistochemical analysis and changes in tryptase, EDN, and eotaxin-3 levels were associated with histologic and endoscopic improvements. Conclusions:EoE incidence considerably increased during the 12-year period, regardless of endoscopic esophageal biopsy rate. Tryptase, EDN, and eotaxin-3 levels in esophageal biopsy specimens could be promising biomarkers for disease activity, symptom, and endoscopic response in Korea.
Project description:<h4>Objective</h4>The microbiome has been implicated in the pathogenesis of a number of allergic and inflammatory diseases. The mucosa affected by eosinophilic esophagitis (EoE) is composed of a stratified squamous epithelia and contains intraepithelial eosinophils. To date, no studies have identified the esophageal microbiome in patients with EoE or the impact of treatment on these organisms. The aim of this study was to identify the esophageal microbiome in EoE and determine whether treatments change this profile. We hypothesized that clinically relevant alterations in bacterial populations are present in different forms of esophagitis.<h4>Design</h4>In this prospective study, secretions from the esophageal mucosa were collected from children and adults with EoE, Gastroesophageal Reflux Disease (GERD) and normal mucosa using the Esophageal String Test (EST). Bacterial load was determined using quantitative PCR. Bacterial communities, determined by 16S rRNA gene amplification and 454 pyrosequencing, were compared between health and disease.<h4>Results</h4>Samples from a total of 70 children and adult subjects were examined. Bacterial load was increased in both EoE and GERD relative to normal subjects. In subjects with EoE, load was increased regardless of treatment status or degree of mucosal eosinophilia compared with normal. Haemophilus was significantly increased in untreated EoE subjects as compared with normal subjects. Streptococcus was decreased in GERD subjects on proton pump inhibition as compared with normal subjects.<h4>Conclusions</h4>Diseases associated with mucosal eosinophilia are characterized by a different microbiome from that found in the normal mucosa. Microbiota may contribute to esophageal inflammation in EoE and GERD.