title: Transcriptome analysis of proton pump inhibitor-responsive esophageal eosinophilia reveals proton pump inhibitor-reversible allergic inflammation.
abstract: BACKGROUND
  Esophageal eosinophilia can be proton pump inhibitor (PPI) resistant or responsive, representing 2 entities known as eosinophilic esophagitis (EoE) and PPI-responsive esophageal eosinophilia (PPI-REE), respectively. Although they present with similar clinical features, EoE is accepted to be an antigen-driven, TH2-associated allergic disorder, whereas the cause of PPI-REE remains a mystery.
  
  
  OBJECTIVE
  In this study, our aim was to investigate the pathogenesis of PPI-REE by using a recently described EoE diagnostic panel (EDP) composed of a set of 94 esophageal transcripts and to determine whether PPI therapy reverses any esophageal transcriptional abnormalities.
  
  
  METHODS
  We evaluated the EDP signature in biopsy samples obtained from adult and pediatric patients with PPI-REE from 4 institutions and compared the pre- and post-PPI therapy expression profiles of these subjects with those of patients with active EoE.
  
  
  RESULTS
  The EDP differentiated patients with EoE from control subjects with 100% accuracy among the 4 clinical sites. Bioinformatics analysis revealed largely overlapping transcriptomes between patients with PPI-REE and those with EoE, including the genes for eosinophil chemotaxis (eotaxin 3, CCL26), barrier molecules (desmoglein 1, DSG1), tissue remodeling (periostin, POSTN), and mast cells (carboxypeptidase A, CPA3). PPI monotherapy alone almost completely reversed the allergic inflammatory transcriptome of patients with PPI-REE. Furthermore, we identified a set of candidate genes to differentiate patients with EoE from those with PPI-REE before treatment.
  
  
  CONCLUSIONS
  These findings provide definitive evidence that PPI-REE is a disease entity with significant molecular overlap with EoE, suggesting that many patients with PPI-REE represent a continuum of the same pathogenic allergic mechanisms that underlie EoE and thus might constitute a subphenotype of patients with EoE. The ability of PPI therapy to nearly entirely reverse gene expression associated with PPI-REE, particularly that associated with classic features of allergic inflammation, provides new insight into potential disease etiology and management strategies for patients with significant esophageal eosinophilia.
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Ting
authors.initials: T
authors.lastname: Wen
authors.affiliation: Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC.
authors.forename: Evan S
authors.initials: ES
authors.lastname: Dellon
authors.affiliation: Gastroenterology Service, Department of Medicine, Walter Reed National Military Medical Center, Bethesda, Md.
authors.forename: Fouad J
authors.initials: FJ
authors.lastname: Moawad
authors.affiliation: Department of Pediatrics, Children's Hospital Colorado, Digestive Health Institute, Gastrointestinal Eosinophilic Diseases Program, University of Colorado School of Medicine, Aurora, Colo.
authors.forename: Glenn T
authors.initials: GT
authors.lastname: Furuta
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics and Medicine, University of California, Rady Children's Hospital, San Diego, La Jolla, Calif.
authors.forename: Seema S
authors.initials: SS
authors.lastname: Aceves
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address: Rothenberg@cchmc.org.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology; D004802:Eosinophilia / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D004947:Esophagus / Q000276:immunology; D005260:Female; D005764:Gastroesophageal Reflux / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D054328:Proton Pump Inhibitors / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D054328:Proton Pump Inhibitors
keywords: Eosinophil; eotaxin; glucocorticosteroid; molecular signature; reflux