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 language | English (US) |
|---|---|
| Pages (from-to) | 18129-18134 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 102 |
| Issue number | 50 |
| DOIs | |
| State | Published - Dec 13 2005 |
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Keywords
- Bacteria
- Inflammatory bowel disease
- Innate immunity
- Intestine
ASJC Scopus subject areas
- Genetics
- General
Cite this
Reduced Paneth cell α-defensins in ileal Crohn's disease. / Wehkamp, Jan; Salzman, Nita H.; Porter, Edith; Nuding, Sabine; Weichenthal, Michael; Petras, Robert E.; Shen, Bo; Schaeffeler, Elke; Schwab, Matthias; Linzmeier, Rose; Feathers, Ryan W.; Chu, Hiutung; Lima, Heriberto; Fellermann, Klaus; Ganz, Tomas; Stange, Eduard F.; Bevins, Charles L.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 50, 13.12.2005, p. 18129-18134.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Reduced Paneth cell α-defensins in ileal Crohn's disease
AU - Wehkamp, Jan
AU - Salzman, Nita H.
AU - Porter, Edith
AU - Nuding, Sabine
AU - Weichenthal, Michael
AU - Petras, Robert E.
AU - Shen, Bo
AU - Schaeffeler, Elke
AU - Schwab, Matthias
AU - Linzmeier, Rose
AU - Feathers, Ryan W.
AU - Chu, Hiutung
AU - Lima, Heriberto
AU - Fellermann, Klaus
AU - Ganz, Tomas
AU - Stange, Eduard F.
AU - Bevins, Charles L
PY - 2005/12/13
Y1 - 2005/12/13
N2 - 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.
AB - 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.
KW - Bacteria
KW - Inflammatory bowel disease
KW - Innate immunity
KW - Intestine
UR - http://www.scopus.com/inward/record.url?scp=29144483937&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=29144483937&partnerID=8YFLogxK
U2 - 10.1073/pnas.0505256102
DO - 10.1073/pnas.0505256102
M3 - Article
C2 - 16330776
AN - SCOPUS:29144483937
VL - 102
SP - 18129
EP - 18134
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 50
ER -