Reduced Paneth cell α-defensins in ileal Crohn's disease

Jan Wehkamp, Nita H. Salzman, Edith Porter, Sabine Nuding, Michael Weichenthal, Robert E. Petras, Bo Shen, Elke Schaeffeler, Matthias Schwab, Rose Linzmeier, Ryan W. Feathers, Hiutung Chu, Heriberto Lima, Klaus Fellermann, Tomas Ganz, Eduard F. Stange, Charles L Bevins

Research output: Contribution to journalArticle

723 Scopus citations

Abstract

The pathogenesis of Crohn's disease (CD), an idiopathic inflammatory bowel disease, is attributed, in part, to intestinal bacteria that may initiate and perpetuate mucosal inflammation in genetically susceptible individuals. Paneth cells (PC) are the major source of antimicrobial peptides in the small intestine, including human α-defensins HD5 and HD6. We tested the hypothesis that reduced expression of PC α-defensins compromises mucosal host defenses and predisposes patients to CD of the ileum. We report that patients with CD of the ileum have reduced antibacterial activity in their intestinal mucosal extracts. These specimens also showed decreased expression of PC α-defensins, whereas the expression of eight other PC products either remained unchanged or increased when compared with controls. The specific decrease of α-defensins was independent of the degree of inflammation in the specimens and was not observed in either CD of the colon, ulcerative colitis, or pouchitis. The functional consequence of α-defensin expression levels was examined by using a transgenic mouse model, where we found changes in HD5 expression levels, comparable to those observed in CD, had a pronounced impact on the luminal microbiota. Thus, the specific deficiency of PC defensins that characterizes ileal CD may compromise innate immune defenses of the ileal mucosa and initiate and/or perpetuate this disease.

Original languageEnglish (US)
Pages (from-to)18129-18134
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number50
DOIs
StatePublished - Dec 13 2005

Keywords

  • Bacteria
  • Inflammatory bowel disease
  • Innate immunity
  • Intestine

ASJC Scopus subject areas

  • Genetics
  • General

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