title: Reduced Paneth cell alpha-defensins in ileal Crohn's disease.
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 alpha-defensins HD5 and HD6. We tested the hypothesis that reduced expression of PC alpha-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 alpha-defensins, whereas the expression of eight other PC products either remained unchanged or increased when compared with controls. The specific decrease of alpha-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 alpha-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.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of California, Davis, 95616, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Wehkamp
authors.forename: Nita H
authors.initials: NH
authors.lastname: Salzman
authors.forename: Edith
authors.initials: E
authors.lastname: Porter
authors.forename: Sabine
authors.initials: S
authors.lastname: Nuding
authors.forename: Michael
authors.initials: M
authors.lastname: Weichenthal
authors.forename: Robert E
authors.initials: RE
authors.lastname: Petras
authors.forename: Bo
authors.initials: B
authors.lastname: Shen
authors.forename: Elke
authors.initials: E
authors.lastname: Schaeffeler
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Rose
authors.initials: R
authors.lastname: Linzmeier
authors.forename: Ryan W
authors.initials: RW
authors.lastname: Feathers
authors.forename: Hiutung
authors.initials: H
authors.lastname: Chu
authors.forename: Heriberto
authors.initials: H
authors.lastname: Lima
authors.forename: Klaus
authors.initials: K
authors.lastname: Fellermann
authors.forename: Tomas
authors.initials: T
authors.lastname: Ganz
authors.forename: Eduard F
authors.initials: EF
authors.lastname: Stange
authors.forename: Charles L
authors.initials: CL
authors.lastname: Bevins
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003424:Crohn Disease / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D006801:Humans; D007079:Ileitis / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D007082:Ileum / Q000382:microbiology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009820:Ohio; D019879:Paneth Cells / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023084:alpha-Defensins / Q000378:metabolism*
chemical_list: D023084:alpha-Defensins