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

Michael J. Rosen, Rebekah Karns, Jefferson E. Vallance, Ramona Bezold, Amanda Waddell, Margaret H. Collins, Yael Haberman, Phillip Minar, Robert N. Baldassano, Jeffrey S. Hyams, Susan S. Baker, Richard Kellermayer, Joshua D. Noe, Anne M. Griffiths, Joel Rosh, Wallace V. Crandall, Melvin B. Heyman, David R. Mack, Michael D. Kappelman, James Markowitz & 7 others Dedrick E. Moulton, Neal S. Leleiko, Thomas D. Walters, Subra Kugathasan, Keith T. Wilson, Simon P. Hogan, Lee A. Denson

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1345-1357.e7
JournalGastroenterology
Volume152
Issue number6
DOIs
StatePublished - May 1 2017

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Ulcerative Colitis
Crohn Disease
Colon
Pediatrics
Genes
Inflammatory Bowel Diseases
Therapeutics
Rectal Diseases
Messenger RNA
Interleukin-13
Odds Ratio
Interleukin-5
Confidence Intervals
Reverse Transcription
Gene Expression
Polymerase Chain Reaction
Colitis
Intestinal Mucosa
ROC Curve
Observational Studies

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Rosen, Michael J. ; Karns, Rebekah ; Vallance, Jefferson E. ; Bezold, Ramona ; Waddell, Amanda ; Collins, Margaret H. ; Haberman, Yael ; Minar, Phillip ; Baldassano, Robert N. ; Hyams, Jeffrey S. ; Baker, Susan S. ; Kellermayer, Richard ; Noe, Joshua D. ; Griffiths, Anne M. ; Rosh, Joel ; Crandall, Wallace V. ; Heyman, Melvin B. ; Mack, David R. ; Kappelman, Michael D. ; Markowitz, James ; Moulton, Dedrick E. ; Leleiko, Neal S. ; Walters, Thomas D. ; Kugathasan, Subra ; Wilson, Keith T. ; Hogan, Simon P. ; Denson, Lee A. / 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. In: Gastroenterology. 2017 ; Vol. 152, No. 6. pp. 1345-1357.e7.
@article{f4d9a3ec00ee4837999a9236e13f9c45,
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 = "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.",
author = "Rosen, {Michael J.} and Rebekah Karns and Vallance, {Jefferson E.} and Ramona Bezold and Amanda Waddell and Collins, {Margaret H.} and Yael Haberman and Phillip Minar and Baldassano, {Robert N.} and Hyams, {Jeffrey S.} and Baker, {Susan S.} and Richard Kellermayer and Noe, {Joshua D.} and Griffiths, {Anne M.} and Joel Rosh and Crandall, {Wallace V.} and Heyman, {Melvin B.} and Mack, {David R.} and Kappelman, {Michael D.} and James Markowitz and Moulton, {Dedrick E.} and Leleiko, {Neal S.} and Walters, {Thomas D.} and Subra Kugathasan and Wilson, {Keith T.} and Hogan, {Simon P.} and Denson, {Lee A.}",
year = "2017",
month = "5",
day = "1",
doi = "10.1053/j.gastro.2017.01.016",
language = "English (US)",
volume = "152",
pages = "1345--1357.e7",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "6",

}

Rosen, MJ, Karns, R, Vallance, JE, Bezold, R, Waddell, A, Collins, MH, Haberman, Y, Minar, P, Baldassano, RN, Hyams, JS, Baker, SS, Kellermayer, R, Noe, JD, Griffiths, AM, Rosh, J, Crandall, WV, Heyman, MB, Mack, DR, Kappelman, MD, Markowitz, J, Moulton, DE, Leleiko, NS, Walters, TD, Kugathasan, S, Wilson, KT, Hogan, SP & Denson, LA 2017, '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', Gastroenterology, vol. 152, no. 6, pp. 1345-1357.e7. https://doi.org/10.1053/j.gastro.2017.01.016

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. / Rosen, Michael J.; Karns, Rebekah; Vallance, Jefferson E.; Bezold, Ramona; Waddell, Amanda; Collins, Margaret H.; Haberman, Yael; Minar, Phillip; Baldassano, Robert N.; Hyams, Jeffrey S.; Baker, Susan S.; Kellermayer, Richard; Noe, Joshua D.; Griffiths, Anne M.; Rosh, Joel; Crandall, Wallace V.; Heyman, Melvin B.; Mack, David R.; Kappelman, Michael D.; Markowitz, James; Moulton, Dedrick E.; Leleiko, Neal S.; Walters, Thomas D.; Kugathasan, Subra; Wilson, Keith T.; Hogan, Simon P.; Denson, Lee A.

In: Gastroenterology, Vol. 152, No. 6, 01.05.2017, p. 1345-1357.e7.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Rosen, Michael J.

AU - Karns, Rebekah

AU - Vallance, Jefferson E.

AU - Bezold, Ramona

AU - Waddell, Amanda

AU - Collins, Margaret H.

AU - Haberman, Yael

AU - Minar, Phillip

AU - Baldassano, Robert N.

AU - Hyams, Jeffrey S.

AU - Baker, Susan S.

AU - Kellermayer, Richard

AU - Noe, Joshua D.

AU - Griffiths, Anne M.

AU - Rosh, Joel

AU - Crandall, Wallace V.

AU - Heyman, Melvin B.

AU - Mack, David R.

AU - Kappelman, Michael D.

AU - Markowitz, James

AU - Moulton, Dedrick E.

AU - Leleiko, Neal S.

AU - Walters, Thomas D.

AU - Kugathasan, Subra

AU - Wilson, Keith T.

AU - Hogan, Simon P.

AU - Denson, Lee A.

PY - 2017/5/1

Y1 - 2017/5/1

N2 - 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.

AB - 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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DO - 10.1053/j.gastro.2017.01.016

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SP - 1345-1357.e7

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JF - Gastroenterology

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