Epithelial origin of eosinophilic esophagitis

Abstract

Eosinophilic esophagitis (EoE) is a chronic, allergen-driven inflammatory disease of the esophagus characterized predominantly by eosinophilic inflammation, leading to esophageal dysfunction. Converging data have placed the esophageal epithelium at the center of disease pathogenesis. In particular, the main EoE disease susceptibility loci at 2p23 and 5p22 encode for gene products that are produced by the esophageal epithelium: the intracellular protease calpain 14 and thymic stromal lymphopoietin, respectively. Furthermore, genetic and functional data establish a primary role for impaired epithelial barrier function in disease susceptibility and pathoetiology. Additionally, the EoE transcriptome, a set of genes dysregulated in the esophagi of patients with EoE, is enriched in genes that encode for proteins involved in esophageal epithelial cell differentiation. This transcriptome has a high proportion of esophagus-specific epithelial genes that are notable for the unexpected enrichment in genes encoding for proteases and protease inhibitors, as well as in IL-1 family genes, demonstrating a previously unappreciated role for innate immunity responses in the esophagus under homeostatic conditions. Among these pathways, basal production of the serine protease inhibitor, Kazal-type 7 (SPINK7) has been demonstrated to be part of the normal differentiation program of esophageal epithelium. Profound lost expression of SPINK7 occurs in patients with EoE and is sufficient for unleashing increased proteolytic activity (including urokinase plasminogen activator), impaired barrier function, and production of large quantities of proinflammatory and proallergic cytokines, including thymic stromal lymphopoietin. Collectively, we put forth a model in which the esophagus is normally equipped as an anti-inflammatory sensing organ and that defects in this pathway, mediated by epithelial protease/protease inhibitor imbalances, unleash inflammatory responses resulting in disorders, such as EoE.

Keywords: Eosinophilic esophagitis; Kazal type; eosinophilic oesophagitis; epithelial barrier; epithelial differentiation; esophageal epithelium; protease inhibitors; proteases; serine protease inhibitors.

FIG 1.

Basic organization of human esophageal epithelium. Nonkeratinized, stratified squamous epithelium (E) and the underlying lamina propria (LP) are shown. Invaginations of the epithelial layer form characteristic papillae (P). The epithelium is divided into the basal zone, which contains the IBL and PBL, several layers of dividing TACs, and the suprabasal zones of nondividing more differentiated cells. Prototypic markers of each cell layer of the epithelium are shown. Notably, IBL cells express IL-33 in patients with active EoE and form colonies when grown in vitro. Part of the figure was extracted from Travers et al with copyright permission.

FIG 2.

Functional enrichment analysis of the esophageal transcriptome. The top 10 overrepresented gene ontology terms for molecular functions and biological processes for the esophagus-specific genes obtained from the Human Protein Atlas are shown. Genes associated with enriched pathways are shown in Table I. Enrichment analysis was performed with ToppFun (https://toppgene.cchmc.org/enrichment.jsp).

FIG 3.

Genetic associations in patients with EoE and those with FA. Genetic risk loci for EoE and FA were identified by using GWASs^,,– and candidate-gene studies.^,, Genes associated with individual and common risk loci are shown. *Genes with damaging rare mutations identified in WES. #Genes identified by using a candidate-gene approach (STAT6 for patients with FA and FLG for patients with EoE).

FIG 4.

Summary of proteases and protease inhibitors with putative roles in EoE pathogenesis grouped according to their origins. Esophageal enriched protease and protease inhibitors were identified by using proteomic analysis. Proteases and protease inhibitors with altered expression in patients with EoE were identified by using RNA sequencing. Genes in italics indicate genes with altered mRNA expression in patients with EoE, and genes not in italics indicate altered protein expression in patients with EoE. The inner green circle represents esophageal specific genes that are dysregulated in EoE. Classification of the genes in the inner green circle are indicated in the rectangular boxes.

FIG 5.

A schematic illustration of the potential role of the balance between proteases and protease inhibitors in the esophagus. Downregulation of protease inhibitors unleashes uncontrolled proteolytic activity. Proteolytic activation can lead to innate immune response by PAR2 or Toll-like receptor 4 activation, which in turn promote type 2 immunity. In addition, increased proteolytic activity can result in degradation of junctional proteins and an impaired epithelial barrier. As a result, antigen-presenting cells show increased access to external antigens and promote type 2 immunity.