Molecular, Genetic, and Cellular Bases for Treating Eosinophilic Esophagitis

Abstract

Eosinophilic esophagitis (EoE) was historically distinguished from gastroesophageal reflux disease on the basis of histology and lack of responsiveness to acid suppressive therapy, but it is now appreciated that esophageal eosinophilia can respond to proton pump inhibitors. Genetic and environmental factors contribute to risk for EoE—particularly early-life events. Disease pathogenesis involves activation of epithelial inflammatory pathways (production of eotaxin-3 [encoded by CCL26]), impaired barrier function (mediated by loss of desmoglein-1), increased production and/or activity of transforming growth factor-β, and induction of allergic inflammation by eosinophils and mast cells. Susceptibility has been associated with variants at 5q22 (TSLP) and 2p23 (CAPN14), indicating roles for allergic sensitization and esophageal specific protease pathways. We propose that EoE is a unique disease characterized by food hypersensitivity, strong hereditability influenced by early-life exposures and esophageal specific genetic risk variants, and allergic inflammation and that the disease is remitted by disrupting inflammatory and T-helper type 2 cytokine–mediated responses and through dietary elimination therapy.

Long-Term Loss of Response in Proton Pump Inhibitor-Responsive Esophageal Eosinophilia Is Uncommon and Influenced by CYP2C19 Genotype and Rhinoconjunctivitis

“…Our fi ndings show that both genetic (a CYP2C19 rapid metabolizer genotype) and environmental (rhinoconjunctivitis, likely refl ecting exposure to airborne allergens) factors were the most infl uential factors determining recurrence. Th is observation, the fi rst of its kind in PPI-REE, appears to mirror the interacting genetic and environmental factors that contribute to the pathogenesis of EoE ( 18 ). In this regard, it is tempting to speculate that responsiveness to PPI in PPI-REE might be modulated by the interaction of acid exposure (increased due to ineffi cacy of PPI in CYP2C19 r apid metabolizers) and esophageal aeroallergen exposure.…”

Mast Cells Distinguish Eosinophilic Esophagitis in Pediatric Patients

“…Concerning the pathogenesis of PPI-responsive eosinophilic esophagitis, it has been hypothesized that a peptic and allergic hypersensitivity component is present. This fact has been interpreted as an indicative that PPI-responsive eosinophilic esophagitis and EoE represent different stages of a single nosologic entity (22) . Eosinophils are not normally seen in healthy esophageal mucosa, but as an evidence of esophageal inflammation (7) .…”

“…Several studies have investigated the role of special staining to identify inflammatory mediators and eosinophil derived elements, aimed at increasing the predictive value of the differential diagnosis. Some reports have indicated that a higher count of mast cells in the esophageal mucosa may be a diagnostic marker for EoE and PPI-responsive eosinophilic esophagitis (1,4,10,18,19,22) . The aim of this study was to confirm that the presence of mast cells in the esophageal epithelium of children, identified by immunohistochemistry for tryptase, may be associated with EoE and/or PPI-responsive eosinophilic esophagitis and can be useful in the differential diagnosis with RE.…”

Eosinophilic esophagitis: New insights in pathogenesis and therapy

“…This disease is associated with a variety of mendelian genetic based disorders [41] . The most frequent associations of EoE are with hereditary collagen disorders such as Marfan and Ehlers-Danlos syndromes with an incidence of about 1% [42] .…”