title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rosen
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Karns
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jefferson E
authors.initials: JE
authors.lastname: Vallance
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Ramona
authors.initials: R
authors.lastname: Bezold
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Amanda
authors.initials: A
authors.lastname: Waddell
authors.affiliation: 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.
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Collins
authors.affiliation: 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.
authors.forename: Yael
authors.initials: Y
authors.lastname: Haberman
authors.affiliation: 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.
authors.forename: Phillip
authors.initials: P
authors.lastname: Minar
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Baldassano
authors.affiliation: Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, Connecticut.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Hyams
authors.affiliation: Digestive Diseases and Nutrition Center, Women and Children's Hospital of Buffalo, Buffalo, New York.
authors.forename: Susan S
authors.initials: SS
authors.lastname: Baker
authors.affiliation: Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine, Houston, Texas.
authors.forename: Richard
authors.initials: R
authors.lastname: Kellermayer
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Noe
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Griffiths
authors.affiliation: Goryeb Children's Hospital/Atlantic Health, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Joel R
authors.initials: JR
authors.lastname: Rosh
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology and Nutrition, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Wallace V
authors.initials: WV
authors.lastname: Crandall
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of California San Francisco, San Francisco, California.
authors.forename: Melvin B
authors.initials: MB
authors.lastname: Heyman
authors.affiliation: Department of Pediatrics and Children's Hospital of Eastern Ontario Inflammatory Bowel Disease Centre, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
authors.forename: David R
authors.initials: DR
authors.lastname: Mack
authors.affiliation: Division of Pediatric Gastroenterology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Kappelman
authors.affiliation: Division of Pediatric Gastroenterology and Nutrition, Cohen Children's Medical Center of New York, New Hyde Park, New York.
authors.forename: James
authors.initials: J
authors.lastname: Markowitz
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Dedrick E
authors.initials: DE
authors.lastname: Moulton
authors.affiliation: Division of Pediatric Gastroenterology, Nutrition and Liver Diseases, Hasbro Children's Hospital, Providence, Rhode Island.
authors.forename: Neal S
authors.initials: NS
authors.lastname: Leleiko
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Walters
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University, Atlanta, Georgia.
authors.forename: Subra
authors.initials: S
authors.lastname: Kugathasan
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
authors.affiliation: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Hogan
authors.affiliation: 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.
authors.forename: Lee A
authors.initials: LA
authors.lastname: Denson
mesh_terms: D000293:Adolescent; D019540:Area Under Curve; D016022:Case-Control Studies; D002648:Child; D003093:Colitis, Ulcerative / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D003106:Colon / Q000473:pathology; D003424:Crohn Disease / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D018928:Immunity, Mucosal / Q000235:genetics*; D018793:Interleukin-13 / Q000235:genetics; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000235:genetics; D020381:Interleukin-17 / Q000235:genetics; D053759:Interleukin-23 / Q000235:genetics; D015848:Interleukin-5 / Q000235:genetics; D007378:Interleukins / Q000235:genetics*; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism; D008297:Male; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D012333:RNA, Messenger / Q000032:analysis; D012372:ROC Curve; D012007:Rectum; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: C508717:IL17A protein, human; D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D020381:Interleukin-17; D053759:Interleukin-23; D015848:Interleukin-5; D007378:Interleukins; D012333:RNA, Messenger
keywords: AUROC; Gene Expression Profile; Immune Regulation; Prognostic Factor