title: Defective paneth cell-mediated host defense in pediatric ileal Crohn's disease.
abstract: OBJECTIVE
  Adult ileal Crohn's disease (CD) is characterized by a specific decrease in ileal Paneth cell alpha-defensins. In addition to NOD2, we previously identified a disturbance of the Wnt-signaling transcription factor TCF-4 as a major mechanism for this deficiency. The aim of this study was to evaluate human alpha-defensin-5 (HD-5) and TCF-4 in an independent cohort of pediatric CD patients.
  
  
  METHODS
  Expression levels of HD-5 and TCF-4 mRNA were quantified by real-time PCR in biopsies from newly diagnosed untreated pediatric CD patients (<18 years, n=36) and age-matched symptomatic non-inflammatory bowel disease controls with a histologically normal gut (n=29). To assess the influence of current inflammation, mucosal interleukin-8 (IL-8) and fecal calprotectin levels were determined.
  
  
  RESULTS
  Small intestinal HD-5 and TCF-4 mRNA were significantly reduced in pediatric ileal CD (L1+L3) (P=0.022 and P=0.0005, respectively) and were significantly correlated (r=0.499; P=0.0001). In ileal but not colonic CD, TCF-4 was also reduced in the colon (P=0.005). Importantly, both HD-5 and TCF-4 were independent of inflammation, as measured by IL-8 expression or fecal calprotectin. In contrast to the small intestine, colonic Paneth cell HD-5 mRNA was significantly elevated in colonic CD (L2) (P=0.026) and was correlated with fecal calprotectin levels (r=0.481; P=0.020).
  
  
  CONCLUSIONS
  In this study, we describe a specific decrease in HD-5 and TCF-4 mRNA expression levels in children with ileal CD. In the small intestine, this decrease was independent of current inflammation, whereas inflammation seems to induce Paneth cell metaplasia in the colon. Our data extend the hypothesis of an important role of antimicrobial host defense in pediatric CD patients.
authors.affiliation: Department of Pediatrics, Akershus University Hospital and Oslo University Hospital, Oslo, Norway.
authors.forename: Gøri
authors.initials: G
authors.lastname: Perminow
authors.forename: Julia
authors.initials: J
authors.lastname: Beisner
authors.forename: Maureen
authors.initials: M
authors.lastname: Koslowski
authors.forename: Lars Gustav
authors.initials: LG
authors.lastname: Lyckander
authors.forename: Eduard
authors.initials: E
authors.lastname: Stange
authors.forename: Morten H
authors.initials: MH
authors.lastname: Vatn
authors.forename: Jan
authors.initials: J
authors.lastname: Wehkamp
mesh_terms: D000293:Adolescent; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003424:Crohn Disease / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D007079:Ileitis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007111:Immunity, Cellular; D007223:Infant; D008297:Male; D019879:Paneth Cells / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D023084:alpha-Defensins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C500225:DEFA5 protein, human; D012333:RNA, Messenger; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D023084:alpha-Defensins