Michael J Rosen1, Rebekah Karns2, Jefferson E Vallance2, Ramona Bezold2, Amanda Waddell2, Margaret H Collins3, Yael Haberman4, Phillip Minar5, Robert N Baldassano6, Jeffrey S Hyams7, Susan S Baker8, Richard Kellermayer9, Joshua D Noe10, Anne M Griffiths11, Joel R Rosh12, Wallace V Crandall13, Melvin B Heyman14, David R Mack15, Michael D Kappelman16, James Markowitz17, Dedrick E Moulton18, Neal S Leleiko19, Thomas D Walters11, Subra Kugathasan20, Keith T Wilson21, Simon P Hogan22, Lee A Denson5. 1. Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address: michael.rosen@cchmc.org. 2. Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 3. Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio. 4. Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Pediatric Gastroenterology Unit, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel. 5. Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio. 6. Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 7. Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, Connecticut. 8. Digestive Diseases and Nutrition Center, Women and Children's Hospital of Buffalo, Buffalo, New York. 9. Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine, Houston, Texas. 10. Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin. 11. Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Canada. 12. Goryeb Children's Hospital/Atlantic Health, Icahn School of Medicine at Mount Sinai, New York, New York. 13. Division of Pediatric Gastroenterology, Hepatology and Nutrition, Nationwide Children's Hospital, Columbus, Ohio. 14. Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of California San Francisco, San Francisco, California. 15. Department of Pediatrics and Children's Hospital of Eastern Ontario Inflammatory Bowel Disease Centre, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada. 16. Division of Pediatric Gastroenterology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 17. Division of Pediatric Gastroenterology and Nutrition, Cohen Children's Medical Center of New York, New Hyde Park, New York. 18. Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee. 19. Division of Pediatric Gastroenterology, Nutrition and Liver Diseases, Hasbro Children's Hospital, Providence, Rhode Island. 20. Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University, Atlanta, Georgia. 21. Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee. 22. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
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.
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.
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