title: Profound loss of esophageal tissue differentiation in patients with eosinophilic esophagitis.
abstract: 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 with an unclear pathogenesis.
  
  
  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 blotting and immunofluorescence were used for evaluating expression of esophageal proteins in biopsy specimens from control subjects and patients with active EoE. Whole-exome sequencing was performed to identify mutations in esophagus-specific genes.
  
  
  RESULTS
  We found that approximately 39% of the esophagus-specific transcripts were altered in patients with EoE, with approximately 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 as the most dysregulated esophagus-specific protein families in patients with EoE. Accordingly, biopsy specimens from patients with EoE evidenced a profound loss of tissue differentiation, decreased expression of keratin 4 (KRT4) and cornulin (CRNN), and increased expression of KRT5 and KRT14. Whole-exome sequencing of 33 unrelated patients with EoE 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.
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Mark
authors.initials: M
authors.lastname: Rochman
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jared
authors.initials: J
authors.lastname: Travers
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Cora E
authors.initials: CE
authors.lastname: Miracle
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Bedard
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Ting
authors.initials: T
authors.lastname: Wen
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Nurit P
authors.initials: NP
authors.lastname: Azouz
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Caldwell
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Kiran
authors.initials: K
authors.lastname: Kc
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Sherrill
authors.affiliation: Department of Internal Medicine, Division of Immunology, University of Iowa Hospitals and Clinics, Iowa City, Iowa.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Davis
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Rymer
authors.affiliation: Center for Autoimmune Genomics and Etiology, Department of Pediatrics, Division of Rheumatology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, and the Cincinnati VA Medical Center, Research Department, Cincinnati, Ohio.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kaufman
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Aronow
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: Marc.Rothenberg@cchmc.org.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
mesh_terms: D000293:Adolescent; D002454:Cell Differentiation / Q000187:drug effects; D002648:Child; D057765:Eosinophilic Esophagitis / Q000235:genetics*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004947:Esophagus / Q000378:metabolism*; D005260:Female; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology; D008297:Male; D009154:Mutation; D059467:Transcriptome
chemical_list: D018793:Interleukin-13
keywords: Eosinophilic esophagitis; IL-1 cytokines; IL-13; differentiation; mutations; protease activity; whole-exome sequencing