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 R, 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
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.
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Gastroenterology. 2017 May;152(6):1345-1357.e7. doi: 10.1053/j.gastro.2017.01.016. Epub 2017 Jan 26.
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.
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.
关于2型免疫反应在溃疡性结肠炎（UC）发病机制中的作用存在争议，来自未经治疗患者的数据较少。我们调查了与肠道黏膜2型免疫反应相关的基因在未经治疗的儿童UC患者中与克罗恩病（CD）相关性结肠炎患者或无炎症性肠病（IBD）患者相比是否上调，以及表达水平是否与临床结局相关。
我们使用实时逆转录定量聚合酶链反应阵列分析了138例未经治疗的患有IBD且有直肠宏观病变的儿童患者以及49例无IBD儿童（对照）的直肠黏膜样本中的信使核糖核酸（mRNA）表达模式，这些患者参与了2008年至2012年的一项多中心前瞻性观察研究。结果在对来自辛辛那提儿童医院医学中心的34例患有IBD且有直肠宏观病变的儿童患者和17例对照的独立队列的直肠RNA进行的实时逆转录定量聚合酶链反应分析中得到验证。
与仅患有结肠CD的患者相比，我们检测到UC患者黏膜样本中与2型免疫反应相关的mRNA（白细胞介素[IL]5基因、IL13和IL13RA2）以及与17型免疫反应相关的mRNA（IL17A和IL23）有显著增加。在回归模型中，IL5和IL17A mRNA表达增加可将UC患者与仅患有结肠CD的患者区分开来（P = 0.001；受试者操作特征曲线下面积为0.72）。我们在UC患者的直肠组织中确定了一种基因表达模式，其特征是检测到IL13 mRNA，该模式可预测6个月后对治疗的临床反应（优势比[OR]，6.469；95%置信区间[CI]，1.553 - 26.94）、12个月后的临床反应（OR，6.125；95% CI，1.330 - 28.22）以及12个月后的缓解情况（OR，5.333；95% CI，1.132 - 25.12）。
在对未经治疗的患有IBD的儿童患者的直肠组织进行的分析中，我们观察到UC早期过程中2型免疫反应的激活。基于介导2型和17型免疫反应的基因黏膜表达增加，我们能够将UC患者与仅患有结肠CD的患者区分开来。在诊断时介导2型免疫反应的基因表达增加与儿童UC患者的治疗反应和缓解相关。
