Eosinophilic esophagitis: Immune mechanisms and therapeutic targets

Abstract

Eosinophilic esophagitis (EoE) is an emerging chronic inflammatory disease of the oesophagus and is clinically characterized by upper gastrointestinal (GI) symptoms including dysphagia and esophageal food impaction. Histopathologic manifestations, which include intraepithelial eosinophilic inflammation and alterations of the esophageal squamous epithelium, such as basal zone hyperplasia (BZH) and dilated intercellular spaces (DIS), are thought to contribute to esophageal dysfunction and disease symptoms. Corroborative clinical and discovery science-based studies have established that EoE is characterized by an underlying allergic inflammatory response, in part, related to the IL-13/CCL26/eosinophil axis driving dysregulation of several key epithelial barrier and proliferative regulatory genes including kallikrein (KLK) serine proteases, calpain 14 (CAPN14) and anoctamin 1 (ANO1). The contribution of these inflammatory and proliferative processes to the clinical and histological manifestations of disease are not fully elucidated. Herein, we discuss the immune molecules and cells that are thought to underlie the clinical and pathologic manifestations of EoE and the emerging therapeutics targeting these processes for the treatment of EoE.

Keywords: biologics; cytokines; eosinophilic esophagitis; eosinophils; mast cell.

FIGURE 1

Pathophysiology and clinical management of eosinophilic esophagitis (EoE). EoE is a chronic inflammatory disease of the oesophagus driven by food allergen exposure which triggers esophageal eosinophilia and esophageal epithelial remodelling. Esophageal epithelial derived cytokines TSLP and IL‐33 stimulate antigen presenting cells (APCs) presentation of food antigens to CD4⁺ T helper type 2 (TH2) cells and secretion of the cytokines IL‐4, IL‐5 and IL‐13. IL‐4 is responsible for driving mast‐cell (MC) and vascular endothelial adhesion responses, IL‐5 is responsible for eosinophil maturation, activation and survival, and IL‐13 is responsible for inducing pro‐inflammatory and pro‐adhesion pathways and inducing expression of pro‐proliferation, pro‐inflammatory, and barrier regulatory genes within the esophageal epithelial compartment which contribute to the “EoE Transcriptome.” Current standards to manage EoE symptoms include proton‐pump inhibitor (PPI) therapy, food elimination diet, and ingested topical corticosteroids. Several therapeutics and biologics, including monoclonal antibodies and small molecule inhibitors are under investigation which target various aspects of EoE pathophysiology. Created with BioRender.com