Pathogenesis of Eosinophilic Esophagitis: A Comprehensive Review of the Genetic and Molecular Aspects

Abstract

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)-β1, and interleukin (IL)-13. This review aims to provide detailed descriptions of the genetics and the comprehensive pathophysiology of EoE.

Keywords: genetic susceptibility; pathophysiology; polymorphism.

Figure 1

Overview of EoE pathophysiology. Allergens stimulate the esophageal epithelium, inducing TSLP/IL-33, leading to stimulation of Th2 cells, NK cells, mast cells, basophils, and iLC2. Main receptors on each cell are indicated. NK cells, mast cells, basophils, iLC2, and Th2 cells induce IL-4 which induce Th2 differentiation. IL-4 and IL-13 induced by Th2 cells induce eotaxin-3 (CCL26), which stimulates eosinophils to secrete IL-5. IL-5, secreted by Th2 cells and mast cells, also stimulate eosinophils. Mast cells also induce TGF-β1 which stimulate eosinophils and fibroblasts, as outlined in the blue box. IL-13 induces impaired barrier function and tissue remodeling, as outlined in the orange box.