Background A key question in the allergy field is to understand how tissue specific disease is manifested. Eosinophilic esophagitis (EoE) is an emerging tissue specific allergic disease whose pathogenesis remains unclear. Objective Herein, we tested the hypothesis that a defect in tissue specific esophageal genes is an integral part of EoE pathogenesis. Methods We interrogated the pattern of expression of esophagus-specific signature genes derived from the Human Protein Atlas in the EoE transcriptome and in EPC2 esophageal epithelial cells. Western blot and immunofluorescence were used for evaluating expression of esophageal proteins in control and active EoE biopsies. Whole-exome sequencing (WES) was performed to identify mutations in esophagus-specific genes. Results We found that ~39% of the esophagus-specific transcripts were altered in EoE, with ~90% being downregulated. The majority of transcriptional changes observed in esophagus-specific genes were reproduced in vitro in esophageal epithelial cells differentiated in the presence of IL-13. Functional enrichment analysis revealed keratinization and differentiation as the most affected biological processes, and identified IL-1 cytokines and serine peptidase inhibitors (SERPINs) as the most dysregulated esophagus-specific protein families in EoE. Accordingly, EoE biopsies evidenced a profound loss of tissue differentiation, decreased expression of keratin 4 and cornulin and elevated expression of keratin 5 and 14. Whole-exome sequencing of 33 unrelated EoE cases revealed 39 rare mutations in 18 esophagus-specific differentially expressed genes. Conclusions A tissue-centered analysis has revealed a profound loss of esophageal tissue differentiation (identity) as an integral and specific part of the pathophysiology of EoE, and implicated protease- and IL-1–related activities as putative central pathways in disease pathogenesis.

The authors unravel the molecular action principle of nafamostat and camostat, two potential COVID-19 drugs targeting the human protein TMPRSS2.

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.