Eosinophilic EsophagitisPathophysiology of Eosinophilic Esophagitis
Section snippets
Genetic Etiology
The prevalence of EoE is approximately 1 in 2000 and has a known male predominance, with a male-to-female ratio approaching 3:1.4, 5 EoE has a strong hereditability pattern, with familial associations having relative risk ratios as high as 64-fold amongst brothers.6 Proband concordance in monozygotic twins is 58%, substantiating a genetic etiology.7 Several different studies, including candidate-gene identification and genome-wide association studies have identified multiple genes that are
Allergic Milieu Predisposes to Eosinophilic Inflammation
Multiple lines of evidence support an allergic etiology as an underlying mechanism for EoE. First, patients with EoE have a high incidence of concurrent atopic disease (Figure 3).5 Recent evidence shows that EoE is correlated with higher rates of asthma and airway hyperresponsiveness.17 Sensitization to cutaneous, ingested, and/or inhaled allergens is likely necessary in the development of EoE, and in some patients, seasonal allergens may play a role.18, 19, 20 Second, the success of dietary
Microbial Imbalance may Contribute to Esophagitis
Similar to patterns in other atopic diseases, an emerging body of evidence suggests a role for intestinal dysbiosis in the pathogenesis of EoE. Host commensal populations may be skewed toward a Th2 profile by early life events such as Caesarian section delivery and antibiotic exposure during infancy, which appear to increase the risk of EoE in both children and adults.54, 55, 56, 57 Of note, similar risk factors have been identified in other atopic conditions and inflammatory bowel disease.58
Eosinophil Transmigration and Activation
The esophageal epithelium is composed of non-keratinized, stratified squamous epithelium that is bathed by a layer of mucus and covers the rete pegs with its vascular elements. Though the normal gastrointestinal tract contains eosinophils in varying density in times of good health, the normal esophageal mucosa does not contain any eosinophils. Thus, identifying eosinophils and their progenitor cells in the esophageal mucosa indicates a pathogenic role for these cells in an inflammatory response.
Barrier Dysfunction Contributes to Esophageal Inflammation
The basal layer of esophageal tissues from patients with EoE becomes hyperplastic, and its integrity as a barrier structure is impaired, as evidenced by dilated intercellular spaces and spongiosis.12 Using impedance monitoring, van Rhijn et al79 demonstrated a significantly decreased esophageal barrier during active EoE compared with inactive EoE in adult subjects. Ussing chamber analyses identified similar findings with mucosal biopsies.12 Ultrastructural studies show not only increased
Esophageal Fibrosis and Strictures are a Chronic Feature of EoE
Emerging clinical evidence supports that the likely outcome of unbridled eosinophilia is esophageal fibrosis and stricture formation. Esophageal remodeling is defined by histologic parameters in the epithelium, including basal zone hyperplasia, dilated intercellular spaces, rete peg elongation, and desquamation, and by subepithelial lamina propria features such as increased vascularization and fibrosis.5, 85, 86, 87 The confounding aspect of this pathogenic process is why remodeling sometimes
Association With Other Conditions Provides Insight into Pathogenetic Mechanisms
Notably, EoE has known associations with several genetic conditions (Table 3), particularly connective tissue disorders with hypermobility syndromes, such as Loeys-Dietz syndrome and Ehlers-Danlos syndrome, hypermobility type.112 A common denominator between these 2 conditions is the increased production and/or signaling of TGF-β, which is thought to lead to increased contractility of smooth muscle, tissue remodeling, and Th2 responses.45, 86, 113 Another condition associated with increased
Conclusion
The recent formation of the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR, https://www.rarediseasesnetwork.org/cms/cegir), which is part of the Rare Diseases Clinical Research Network (RDCRN) of the National Institutes of Health, will undoubtedly lead to better understanding and treatment of EoE and related rare eosinophil-associated gastrointestinal diseases. CEGIR is focused on defining the natural history of eosinophilic gastrointestinal disorders, developing disease
Acknowledgments
The authors thank Shawna Hottinger for editorial assistance.
References (121)
Histopathologic features of eosinophilic esophagitis
Gastroenterol Clin North Am
(2014)- et al.
Epigenetic regulation of the IL-13-induced human eotaxin-3 gene by CREB-binding protein-mediated histone 3 acetylation
J Biol Chem
(2011) - et al.
IL-13 involvement in eosinophilic esophagitis: transcriptome analysis and reversibility with glucocorticoids
J Allergy Clin Immunol
(2007) - et al.
Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis
Mucosal Immunol
(2014) - et al.
Profound loss of esophageal tissue differentiation in patients with eosinophilic esophagitis
J Allergy Clin Immunol
(2017) - et al.
Calpain-14 and its association with eosinophilic esophagitis
J Allergy Clin Immunol
(2017) - et al.
Epicutaneous antigen exposure primes for experimental eosinophilic esophagitis in mice
Gastroenterology
(2005) - et al.
Clinical, endoscopic, and histologic findings distinguish eosinophilic esophagitis from gastroesophageal reflux disease
Clin Gastroenterol Hepatol
(2009) - et al.
Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis
Gastroenterology
(2014) - et al.
Pollen and eosinophilic esophagitis
J Allergy Clin Immunol
(2003)
Intravenous anti-IL-13 mAb QAX576 for the treatment of eosinophilic esophagitis
J Allergy Clin Immunol
Food allergy testing in eosinophilic esophagitis: what the gastroenterologist needs to know
Clin Gastroenterol Hepatol
IgE antibody detection and component analysis in patients with eosinophilic esophagitis
J Allergy Clin Immunol Pract
Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE
Gastroenterology
Food-specific IgG4 is associated with eosinophilic esophagitis
J Allergy Clin Immunol
Hematopoietic prostaglandin D synthase defines a proeosinophilic pathogenic effector human T(H)2 cell subpopulation with enhanced function
J Allergy Clin Immunol
Hematopoietic prostaglandin D synthase: linking pathogenic effector CD4(+) T(H)2 cells to proeosinophilic inflammation in patients with gastrointestinal allergic disorders
J Allergy Clin Immunol
Induction of interleukin-9-producing mucosal mast cells promotes susceptibility to IgE-mediated experimental food allergy
Immunity
Oral immunotherapy-induced gastrointestinal symptoms and peripheral blood eosinophil responses
J Allergy Clin Immunol
Relation between eosinophilic esophagitis and oral immunotherapy for food allergy: a systematic review with meta-analysis
Ann Allergy Asthma Immunol
The prevalence of eosinophilic esophagitis in pediatric patients with IgE-mediated food allergy
J Allergy Clin Immunol Pract
Eosinophilic esophagitis during peanut oral immunotherapy with omalizumab
J Allergy Clin Immunol Pract
Prenatal, intrapartum, and postnatal factors are associated with pediatric eosinophilic esophagitis
J Allergy Clinical Immunol
The esophageal microbiome in eosinophilic esophagitis
Gastroenterology
Inverse association of esophageal eosinophilia with Helicobacter pylori based on analysis of a US pathology database
Gastroenterology
Periostin facilitates eosinophil tissue infiltration in allergic lung and esophageal responses
Mucosal Immunol
Proton pump inhibitors partially restore mucosal integrity in patients with proton pump inhibitor-responsive esophageal eosinophilia but not eosinophilic esophagitis
Clin Gastroenterol Hepatol
Filaggrin in atopic dermatitis
J Allergy Clin Immunol
Severe dermatitis, multiple allergies, and metabolic wasting syndrome caused by a novel mutation in the N-terminal plakin domain of desmoplakin
J Allergy Clin Immunol
Esophageal remodeling in pediatric eosinophilic esophagitis
J Allergy Clin Immunol
Esophageal epithelial cells acquire functional characteristics of activated myofibroblasts after undergoing an epithelial to mesenchymal transition
Exp Cell Res
The esophageal biopsy “pull” sign: a highly specific and treatment-responsive endoscopic finding in eosinophilic esophagitis (with video)
Gastrointest Endosc
Esophagogastric junction distensibility assessed with an endoscopic functional luminal imaging probe (EndoFLIP)
Gastrointest Endosc
Esophageal remodeling develops as a consequence of tissue specific IL-5-induced eosinophilia
Gastroenterology
ACG clinical guideline: evidenced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE)
Am J Gastroenterol
Proton pump inhibitor-responsive oesophageal eosinophilia: an entity challenging current diagnostic criteria for eosinophilic oesophagitis
Gut
Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults
United European Gastroenterol J
The 2010-2015 prevalence of eosinophilic esophagitis in the USA: a population-based study
Dig Dis Sci
Eosinophilic esophagitis: updated consensus recommendations for children and adults
J Allergy Clin Immunol
Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis
J Allergy Clin Immunol
Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease
Nat Genet
Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis
J Clin Invest
TSLP enhances the function of helper type 2 cells
Eur J Immunol
The effects of thymic stromal lymphopoietin and IL-3 on human eosinophil-basophil lineage commitment: relevance to atopic sensitization
Immun Inflamm Dis
Increased prevalence of airway reactivity in children with eosinophilic esophagitis
Pediatr Pulmonol
Seasonal variation in detection of oesophageal eosinophilia and eosinophilic oesophagitis
Aliment Pharmacol Ther
Significance of para-esophageal lymph nodes in food or aeroallergen-induced iNKT cell-mediated experimental eosinophilic esophagitis
Am J Physiol Gastrointest Liver Physiol
Indoor insect allergens are potent inducers of experimental eosinophilic esophagitis in mice
J Leukoc Biol
Smad3-deficient mice have reduced esophageal fibrosis and angiogenesis in a model of egg-induced eosinophilic esophagitis
J Pediatr Gastroenterol Nutr
A pathological function for eotaxin and eosinophils in eosinophilic gastrointestinal inflammation
Nat Immunol
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Conflicts of interest Unrelated to this manuscript, S.S.A. is a co-inventor with a UCSD patent on viscous budesonide, consults for regeneron, and has funding from Ferring Research Institute and the NIAID. M.E.R. is a consultant for Pulm One, Spoon Guru, Celgene, Shire, Astra Zeneca, GlaxoSmithKline, Allakos, Adare, Regeneron and Novartis and has an equity interest in the first three listed and Immune Pharmaceuticals, and royalties from reslizumab (Teva Pharmaceuticals). M.E.R. is an inventor of patents, owned by Cincinnati Children’s. The other authors disclose no conflicts.
Funding This work was supported in part by NIH U19 AI070235, NIH R01 AI124355, R37 R37 A1045898, NIH K24DK100303, the Campaign Urging Research for Eosinophilic Disease (CURED) Foundation, the Buckeye Foundation, and the Sunshine Charitable Foundation and its supporters, Denise A. Bunning and David G. Bunning. The study is also funded by U54 AI117804, which is part of the Rare Disease Clinical Research Network (RDCRN), an initiative of the Office of Rare Disease Research (ORDR), NCATS, and is funded through collaboration between NCATS, NIAID and NIDDK, as well as the patient advocacy groups American Partnership for Eosinophilic Disorders (APFED), CURED and the Eosinophilic Family Coalition (EFC), which have collectively resulted in the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR).