Mucosal Expression of Type 2 and Type 17 Immune Response Genes Distinguishes Ulcerative Colitis From Colon-Only Crohn's Disease in Treatment-Naive Pediatric Patients

• Type of Material: Article
• Authors: Michael J. Rosen, Cincinnati Children’s Hospital Medical Center; Rebekah Karns, Cincinnati Children’s Hospital Medical Center; Jefferson E. Vallance, Cincinnati Children’s Hospital Medical Center; Ramona Bezold, Cincinnati Children’s Hospital Medical Center; Amanda Waddell, Cincinnati Children’s Hospital Medical Center; Margaret H. Collins, Cincinnati Children’s Hospital Medical Center; Yael Haberman, Cincinnati Children’s Hospital Medical Center; Phillip Minar, Cincinnati Children’s Hospital Medical Center; Robert N. Baldassano, Children's Hospital of Philadelphia; Jeffrey S. Hyams, Connecticut Children’s Medical Center; Susan S. Baker, Women and Children’s Hospital of Buffalo; Richard Kellermayer, Baylor University; Joshua D. Noe, Medical College of Wisconsin; Anne M. Griffiths, The Hospital for Sick Children; Joel R. Rosh, Goryeb Children’s Hospital; Wallace V. Crandall, Nationwide Children’s Hospital; Melvin B. Heyman, University of California San Francisco; David R. Mack, Children’s Hospital of Eastern Ontario; Michael D. Kappelman, University of North Carolina Chapel Hill; James Markowitz, Cohen Children’s Medical Center of New York; Dedrick E. Moulton, Vanderbilt University; Neal S. Leleiko, Hasbro Children’s Hospital; Thomas D. Walters, The Hospital for Sick Children; Subra Kugathasan, Emory University; Keith T. Wilson, Vanderbilt University; Simon P. Hogan, University of Cincinnati; Lee A. Denson, University of Cincinnati
• Language: English
• Date: 2017-05-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 AGA Institute
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1053/j.gastro.2017.01.016
• Title of Journal or Parent Work: Gastroenterology
• ISSN: 0016-5085
• Volume: 152
• Issue: 6
• Start Page: 1345
• End Page: 1357.e7
• Grant/Funding Information: Research reported in this publication was supported primarily by the National Institute Of Diabetes And Digestive And Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) under award number K23DK094832 (MJR).; This project was also supported in part by the NIH Clinical and Translational Science Award (CTSA) 1UL1TR001425-01 (REDCap Database), NIDDK P30DK078392 (Gene and Protein Expression Core) of the Digestive Disease Research Core Center in Cincinnati, NIH P30ES006096 of the University of Cincinnati College of Medicine Center for Environmental Genetics (Genomics, Epigenomics and Sequencing Core), NIH R01DK090119 and Crohn’s & Colitis Foundation of America Senior Research Award (SPH), NIH K23DK105229 (PM), and the Gutsy Kids Fund including philanthropic donation from the Karen and Brock Wagner Family (RK).; Biospecimens were obtained from the RISK Stratification Study, funded by the Crohn’s & Colitis Foundation of America.
• Keywords: EUROKIDS REGISTRY; AUROC; Life Sciences & Biomedicine; INTESTINAL-MUCOSA; PROFILES; Gene Expression Profile; TH2 CYTOKINE; INFLAMMATORY-BOWEL-DISEASE; Science & Technology; INTERLEUKIN-13; HYMENOLEPIS-DIMINUTA; OXAZOLONE COLITIS; Prognostic Factor; NK-T-CELLS; PHASE IIA; Gastroenterology & Hepatology; Immune Regulation
• Research Categories: Biology, Genetics; Health Sciences, Nutrition; Health Sciences, Immunology

Abstract

Background & Aims There is controversy regarding the role of the type 2 immune response in the pathogenesis of ulcerative colitis (UC)—few data are available from treatment-naive patients. We investigated whether genes associated with a type 2 immune response in the intestinal mucosa are up-regulated in treatment-naive pediatric patients with UC compared with patients with Crohn's disease (CD)-associated colitis or without inflammatory bowel disease (IBD), and whether expression levels are associated with clinical outcomes. Methods We used a real-time reverse-transcription quantitative polymerase chain reaction array to analyze messenger RNA (mRNA) expression patterns in rectal mucosal samples from 138 treatment-naive pediatric patients with IBD and macroscopic rectal disease, as well as those from 49 children without IBD (controls), enrolled in a multicenter prospective observational study from 2008 to 2012. Results were validated in real-time reverse-transcription quantitative polymerase chain reaction analyses of rectal RNA from an independent cohort of 34 pediatric patients with IBD and macroscopic rectal disease and 17 controls from Cincinnati Children's Hospital Medical Center. Results We measured significant increases in mRNAs associated with a type 2 immune response (interleukin [IL]5 gene, IL13, and IL13RA2) and a type 17 immune response (IL17A and IL23) in mucosal samples from patients with UC compared with patients with colon-only CD. In a regression model, increased expression of IL5 and IL17A mRNAs distinguished patients with UC from patients with colon-only CD (P =.001; area under the receiver operating characteristic curve, 0.72). We identified a gene expression pattern in rectal tissues of patients with UC, characterized by detection of IL13 mRNA, that predicted clinical response to therapy after 6 months (odds ratio [OR] , 6.469; 95% confidence interval [CI], 1.553–26.94), clinical response after 12 months (OR, 6.125; 95% CI, 1.330–28.22), and remission after 12 months (OR, 5.333; 95% CI, 1.132–25.12). Conclusions In an analysis of rectal tissues from treatment-naive pediatric patients with IBD, we observed activation of a type 2 immune response during the early course of UC. We were able to distinguish patients with UC from those with colon-only CD based on increased mucosal expression of genes that mediate type 2 and type 17 immune responses. Increased expression at diagnosis of genes that mediate a type 2 immune response is associated with response to therapy and remission in pediatric patients with UC.