Journal article
Profound loss of esophageal tissue differentiation in patients with eosinophilic esophagitis
Journal of allergy and clinical immunology, Vol.140(3), pp.738-749.e3
09/2017
DOI: 10.1016/j.jaci.2016.11.042
PMCID: PMC5513800
PMID: 28104354
Abstract
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.
Herein we tested the hypothesis that a defect in tissue-specific esophageal genes is an integral part of EoE pathogenesis.
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.
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.
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.
Details
- Title: Subtitle
- Profound loss of esophageal tissue differentiation in patients with eosinophilic esophagitis
- Creators
- Mark Rochman - Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OhioJared Travers - Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OhioCora E Miracle - Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OhioMary C Bedard - Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OhioTing Wen - Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OhioNurit P Azouz - Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OhioJulie M Caldwell - Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OhioKiran KC - Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OhioJoseph D Sherrill - Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OhioBenjamin P Davis - Department of Internal Medicine, Division of Immunology, University of Iowa Hospitals and Clinics, Iowa City, IowaJeffrey K Rymer - Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OhioKenneth M Kaufman - 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, OhioBruce J Aronow - Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OhioMarc E Rothenberg - Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
- Resource Type
- Journal article
- Publication Details
- Journal of allergy and clinical immunology, Vol.140(3), pp.738-749.e3
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.jaci.2016.11.042
- PMID
- 28104354
- PMCID
- PMC5513800
- ISSN
- 0091-6749
- eISSN
- 1097-6825
- Grant note
- Sunshine Charitable Foundation R37 AI045898; R01 AI124355; U19 AI070235; F30 DK109573; P30 DK078392 / National Institutes of Health (http://dx.doi.org/10.13039/100000002) Gene and Protein Expression Core Buckeye Foundation (http://dx.doi.org/10.13039/100008477)
- Language
- English
- Date published
- 09/2017
- Academic Unit
- Stead Family Department of Pediatrics; Immunology; Internal Medicine
- Record Identifier
- 9984093598402771
Metrics
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