Transcriptome analysis of proton pump inhibitor–responsive esophageal eosinophilia reveals proton pump inhibitor–reversible allergic inflammation - 06/01/15
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.
Conclusion |
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.
Le texte complet de cet article est disponible en PDF.Key words : Eosinophil, glucocorticosteroid, molecular signature, eotaxin, reflux
Abbreviations used : CCHMC, EDP, EoE, FFPE, GERD, hpf, PCA, PPI-REE
Plan
| Supported in part by NIH P30 DK078392; NIH grants R37 A1045898, R01 AI083450, R01 DK076893, U19 AI070235, R01 AI092135 (to S.S.A.), K23 DK090073 (to E.S.D.), and K24 DK100303 (to G.T.F.); DOD FA100044 (to S.A.); the University of Cincinnati Institutional CTSA (UL1 TR000077); Campaign Urging Research for Eosinophilic Diseases (CURED) Foundation; the Food Allergy Research and Education (FARE); and the Buckeye Foundation. |
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| Disclosure of potential conflict of interest: T. Wen is an inventor for patents submitted and owned by Cincinnati Children's Hospital Medical Center. E. S. Dellon has received consultancy fees from Aptalis, Novartis, Receptos, and Regeneron; has received research support from Meritage and Receptos; and has stock/stock options in Diagnovus. G. T. Furuta has received consultancy fees from Genetech; has received research support from the National Institutes of Health (NIH), Morphotek, and Nutricia; and is a cofounder of and has a patent with EnteroTrack. S. S. Aceves has received research support from the NIH/National Institute of Allergy and Infectious Diseases (NIAID) and TIGERS; is a board member for MAB-FARE and MAB-APFED; has a patent for and has received royalties for Oral Viscous Budesonide; has stock/stock options in Meritage Pharma; and has received travel support from the NIH/National Institute of Diabetes and Digestive and Kidney Diseases. M. E. Rothenberg has received research support from the NIH; has received consultancy fees from and has stock/stock options in Immune Pharmaceuticals, Receptos, and Celsus Therapeutics; is an inventor of patents submitted and owned by Cincinnati Children's Hospital Medical Center; and has royalties for reslizumab, a drug being developed by Teva Pharmaceuticals. F. J. Moawad declares no relevant conflicts of interest. |
Vol 135 - N° 1
P. 187 - janvier 2015 Retour au numéro
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