Profound Loss of Esophageal Tissue Differentiation in Eosinophilic Esophagitis

Publication date: Available online 17 January 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): M. Rochman, J. Travers, C.E. Miracle, M.C. Bedard, T. Wen, N.P. Azouz, J.M. Caldwell, K. Kc, J.D. Sherrill, B.P. Davis, J.K. Rymer, K.M. Kaufman, M.E. Rothenberg
BackgroundA 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.ObjectiveHerein, we tested the hypothesis that a defect in tissue specific esophageal genes is an integral part of EoE pathogenesis.MethodsWe 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.ResultsWe 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.ConclusionsA tissue-centered analysis has revealed a profound loss of esophageal tissue differentiation 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.

Teaser

There is a profound impairment of esophageal tissue differentiation including a loss of tissue identity genes in eosinophilic esophagitis, providing potential value for predictive medicine, diagnostics and treatment of this emerging disease.


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