NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal α-defensin expression

J. Wehkamp, J. Harder, M. Weichenthal, M. Schwab, E. Schäffeler, M. Schlee, K. R. Herrlinger, A. Stallmach, F. Noack, P. Fritz, J. M. Schröder, Charles L Bevins, K. Fellermann, E. F. Stange

Research output: Contribution to journalArticle

613 Citations (Scopus)

Abstract

Background: Mutations in NOD2, a putative intracellular receptor for bacterial peptidoglycans, are associated with a subset of Crohn's disease but the molecular mechanism linking this protein with the disease pathogenesis remains unclear. Human α defensins (HD-5 and HD-6) are antibiotic effector molecules predominantly expressed in Paneth cells of the ileum. Paneth cells also express NOD2. To address the hypothesis that the function of NOD2 may affect expression of Paneth cell defensins, we compared their expression levels with respect to NOD2 mutations in Crohn's disease. Methods: Forty five Crohn's disease patients (24 with NOD2 mutations, 21 with wild-type NOD2) and 12 controls were studied. Real time reverse transcription-polymerase chain reaction was performed with mucosal mRNA for HD-5, HD-6, lysozyme, secretory phospholipase A2 (sPLA2), tumour necrosis factor α, interleukin 8, and human hypoxanthine phosphoribosyltransferase (housekeeping gene). Immunohistochemistry with anti-HD-5 and histological Paneth cell staining were performed in 10 patients with NOD2 mutations or wild-type genotypes. Results: Ileal expression of HD-5 and HD-6, but not sPLA2 or lysozyme, were diminished in affected ileum, and the decrease was significantly more pronounced in patients with NOD2 mutations. In the colon, HD-5, HD-6, and sPLA2 were increased during inflammation in wild-type but not in NOD2 mutated patients. In both the colon and ileum, proinflammatory cytokines and lysozyme were unaffected by NOD2 status. Immunohistochemistry identified Paneth cells as the sole source of HD-5. Conclusion: As alpha defensins are important in the mucosal antibacterial barrier, their diminished expression may explain, in part, the bacterial induced mucosal inflammation and ileal involvement of Crohn's disease, especially in the case of NOD2 mutations.

Original languageEnglish (US)
Pages (from-to)1658-1664
Number of pages7
JournalGut
Volume53
Issue number11
DOIs
StatePublished - Nov 2004

Fingerprint

Defensins
Paneth Cells
Crohn Disease
Secretory Phospholipase A2
Mutation
Muramidase
Ileum
Colon
alpha-Defensins
Immunohistochemistry
Inflammation
Hypoxanthine Phosphoribosyltransferase
Essential Genes
Interleukin-8
Reverse Transcription
Genotype
Staining and Labeling
Cytokines
Anti-Bacterial Agents
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Wehkamp, J., Harder, J., Weichenthal, M., Schwab, M., Schäffeler, E., Schlee, M., ... Stange, E. F. (2004). NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal α-defensin expression. Gut, 53(11), 1658-1664. https://doi.org/10.1136/gut.2003.032805

NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal α-defensin expression. / Wehkamp, J.; Harder, J.; Weichenthal, M.; Schwab, M.; Schäffeler, E.; Schlee, M.; Herrlinger, K. R.; Stallmach, A.; Noack, F.; Fritz, P.; Schröder, J. M.; Bevins, Charles L; Fellermann, K.; Stange, E. F.

In: Gut, Vol. 53, No. 11, 11.2004, p. 1658-1664.

Research output: Contribution to journalArticle

Wehkamp, J, Harder, J, Weichenthal, M, Schwab, M, Schäffeler, E, Schlee, M, Herrlinger, KR, Stallmach, A, Noack, F, Fritz, P, Schröder, JM, Bevins, CL, Fellermann, K & Stange, EF 2004, 'NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal α-defensin expression', Gut, vol. 53, no. 11, pp. 1658-1664. https://doi.org/10.1136/gut.2003.032805
Wehkamp J, Harder J, Weichenthal M, Schwab M, Schäffeler E, Schlee M et al. NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal α-defensin expression. Gut. 2004 Nov;53(11):1658-1664. https://doi.org/10.1136/gut.2003.032805
Wehkamp, J. ; Harder, J. ; Weichenthal, M. ; Schwab, M. ; Schäffeler, E. ; Schlee, M. ; Herrlinger, K. R. ; Stallmach, A. ; Noack, F. ; Fritz, P. ; Schröder, J. M. ; Bevins, Charles L ; Fellermann, K. ; Stange, E. F. / NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal α-defensin expression. In: Gut. 2004 ; Vol. 53, No. 11. pp. 1658-1664.
@article{e8993486970d40a7b6a473dcc8440ce8,
title = "NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal α-defensin expression",
abstract = "Background: Mutations in NOD2, a putative intracellular receptor for bacterial peptidoglycans, are associated with a subset of Crohn's disease but the molecular mechanism linking this protein with the disease pathogenesis remains unclear. Human α defensins (HD-5 and HD-6) are antibiotic effector molecules predominantly expressed in Paneth cells of the ileum. Paneth cells also express NOD2. To address the hypothesis that the function of NOD2 may affect expression of Paneth cell defensins, we compared their expression levels with respect to NOD2 mutations in Crohn's disease. Methods: Forty five Crohn's disease patients (24 with NOD2 mutations, 21 with wild-type NOD2) and 12 controls were studied. Real time reverse transcription-polymerase chain reaction was performed with mucosal mRNA for HD-5, HD-6, lysozyme, secretory phospholipase A2 (sPLA2), tumour necrosis factor α, interleukin 8, and human hypoxanthine phosphoribosyltransferase (housekeeping gene). Immunohistochemistry with anti-HD-5 and histological Paneth cell staining were performed in 10 patients with NOD2 mutations or wild-type genotypes. Results: Ileal expression of HD-5 and HD-6, but not sPLA2 or lysozyme, were diminished in affected ileum, and the decrease was significantly more pronounced in patients with NOD2 mutations. In the colon, HD-5, HD-6, and sPLA2 were increased during inflammation in wild-type but not in NOD2 mutated patients. In both the colon and ileum, proinflammatory cytokines and lysozyme were unaffected by NOD2 status. Immunohistochemistry identified Paneth cells as the sole source of HD-5. Conclusion: As alpha defensins are important in the mucosal antibacterial barrier, their diminished expression may explain, in part, the bacterial induced mucosal inflammation and ileal involvement of Crohn's disease, especially in the case of NOD2 mutations.",
author = "J. Wehkamp and J. Harder and M. Weichenthal and M. Schwab and E. Sch{\"a}ffeler and M. Schlee and Herrlinger, {K. R.} and A. Stallmach and F. Noack and P. Fritz and Schr{\"o}der, {J. M.} and Bevins, {Charles L} and K. Fellermann and Stange, {E. F.}",
year = "2004",
month = "11",
doi = "10.1136/gut.2003.032805",
language = "English (US)",
volume = "53",
pages = "1658--1664",
journal = "Gut",
issn = "0017-5749",
publisher = "BMJ Publishing Group",
number = "11",

}

TY - JOUR

T1 - NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal α-defensin expression

AU - Wehkamp, J.

AU - Harder, J.

AU - Weichenthal, M.

AU - Schwab, M.

AU - Schäffeler, E.

AU - Schlee, M.

AU - Herrlinger, K. R.

AU - Stallmach, A.

AU - Noack, F.

AU - Fritz, P.

AU - Schröder, J. M.

AU - Bevins, Charles L

AU - Fellermann, K.

AU - Stange, E. F.

PY - 2004/11

Y1 - 2004/11

N2 - Background: Mutations in NOD2, a putative intracellular receptor for bacterial peptidoglycans, are associated with a subset of Crohn's disease but the molecular mechanism linking this protein with the disease pathogenesis remains unclear. Human α defensins (HD-5 and HD-6) are antibiotic effector molecules predominantly expressed in Paneth cells of the ileum. Paneth cells also express NOD2. To address the hypothesis that the function of NOD2 may affect expression of Paneth cell defensins, we compared their expression levels with respect to NOD2 mutations in Crohn's disease. Methods: Forty five Crohn's disease patients (24 with NOD2 mutations, 21 with wild-type NOD2) and 12 controls were studied. Real time reverse transcription-polymerase chain reaction was performed with mucosal mRNA for HD-5, HD-6, lysozyme, secretory phospholipase A2 (sPLA2), tumour necrosis factor α, interleukin 8, and human hypoxanthine phosphoribosyltransferase (housekeeping gene). Immunohistochemistry with anti-HD-5 and histological Paneth cell staining were performed in 10 patients with NOD2 mutations or wild-type genotypes. Results: Ileal expression of HD-5 and HD-6, but not sPLA2 or lysozyme, were diminished in affected ileum, and the decrease was significantly more pronounced in patients with NOD2 mutations. In the colon, HD-5, HD-6, and sPLA2 were increased during inflammation in wild-type but not in NOD2 mutated patients. In both the colon and ileum, proinflammatory cytokines and lysozyme were unaffected by NOD2 status. Immunohistochemistry identified Paneth cells as the sole source of HD-5. Conclusion: As alpha defensins are important in the mucosal antibacterial barrier, their diminished expression may explain, in part, the bacterial induced mucosal inflammation and ileal involvement of Crohn's disease, especially in the case of NOD2 mutations.

AB - Background: Mutations in NOD2, a putative intracellular receptor for bacterial peptidoglycans, are associated with a subset of Crohn's disease but the molecular mechanism linking this protein with the disease pathogenesis remains unclear. Human α defensins (HD-5 and HD-6) are antibiotic effector molecules predominantly expressed in Paneth cells of the ileum. Paneth cells also express NOD2. To address the hypothesis that the function of NOD2 may affect expression of Paneth cell defensins, we compared their expression levels with respect to NOD2 mutations in Crohn's disease. Methods: Forty five Crohn's disease patients (24 with NOD2 mutations, 21 with wild-type NOD2) and 12 controls were studied. Real time reverse transcription-polymerase chain reaction was performed with mucosal mRNA for HD-5, HD-6, lysozyme, secretory phospholipase A2 (sPLA2), tumour necrosis factor α, interleukin 8, and human hypoxanthine phosphoribosyltransferase (housekeeping gene). Immunohistochemistry with anti-HD-5 and histological Paneth cell staining were performed in 10 patients with NOD2 mutations or wild-type genotypes. Results: Ileal expression of HD-5 and HD-6, but not sPLA2 or lysozyme, were diminished in affected ileum, and the decrease was significantly more pronounced in patients with NOD2 mutations. In the colon, HD-5, HD-6, and sPLA2 were increased during inflammation in wild-type but not in NOD2 mutated patients. In both the colon and ileum, proinflammatory cytokines and lysozyme were unaffected by NOD2 status. Immunohistochemistry identified Paneth cells as the sole source of HD-5. Conclusion: As alpha defensins are important in the mucosal antibacterial barrier, their diminished expression may explain, in part, the bacterial induced mucosal inflammation and ileal involvement of Crohn's disease, especially in the case of NOD2 mutations.

UR - http://www.scopus.com/inward/record.url?scp=7244257312&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=7244257312&partnerID=8YFLogxK

U2 - 10.1136/gut.2003.032805

DO - 10.1136/gut.2003.032805

M3 - Article

C2 - 15479689

AN - SCOPUS:7244257312

VL - 53

SP - 1658

EP - 1664

JO - Gut

JF - Gut

SN - 0017-5749

IS - 11

ER -