Genetic dissection of eosinophilic esophagitis provides insight into disease pathogenesis and treatment strategies

Abstract

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus that is compounded by both genetic predisposition and aberrant responses to environmental antigens, particularly those that are food derived. Data have indicated a unique transcriptional response in vivo that defines EoE and that appears to be partially attributable to the T(H)2 cytokine IL-13. Moreover, a number of genetic risk variants in proinflammatory and epithelial cell genes associate with EoE susceptibility, demonstrating novel heritable mechanisms that contribute to disease risk. Here we discuss recent advances in our understanding of the intrinsic (genetic) and extrinsic (environmental) components that illustrate the complex nature of EoE.

Figure 1. The molecular pathogenesis of EoE

An allergic insult by either food antigens or aeroallergens initiates the transition of the esophagus from a normal (NL) to EoE phenotype through the production of TSLP by the esophageal epithelium. TSLP-activated DCs induce a robust Th2 response and enhanced IL-13, which in turn mediates marked dysregulation of gene expression (the EoE transcriptome). Enhanced eotaxin-3 (CCL26) secretion by the esophageal epithelium promotes eosinophil migration from the blood into the tissue. Eosinophil- and mast cell-derived TGF-β, along with IL-13, act on fibroblasts within the lamina propria to secrete periostin (POSTN) and stimulate the fibrotic response. Loss of FLG expression, partially due to IL-13 and/or genetic variants, may further enhance or even predispose EoE patients to antigen exposure and exacerbate Th2 inflammation.

Figure 2. Genetic risk variants in EoE

EoE risk variants near TSLP and in the TSLP receptor (TSLPR) gene (CRLF2) highlight a potential role for the TSLP pathway in EoE. SNPs in other key genes such as CCL26, TGFB1 and FLG can affect multiple aspects of EoE pathogenesis, including eosinophil chemotaxis, fibrosis and smooth muscle dysfunction, and decreased esophageal barrier function, respectively.