TITLE

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

AUTHOR(S)
Wehkamp, J.; Harder, J.; Weichenthal, M.; Schwab, M.; Schäffeler, E.; Schlee, M.; Herrlinger, K. R.; Stallmach, A.; Noack, F.; Fritz, P.; M. Schröder, J.; Bevins, C. L.; Fellermann, K.; Stange, E. F.
PUB. DATE
November 2004
SOURCE
Gut;Nov2004, Vol. 53 Issue 11, p1658
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
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 a 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.
ACCESSION #
22269085

 

Related Articles

  • EXPRESSION OF NOD2 BY INTESTINAL EPITHELIAL CELLS IN AN IN VITRO M CELL MODEL. Butler, M.; Winstanley, S.; van Heel, D.; Lombardi, G.; Lechler, R.; Playford, R.; Ghosh, S. // Gut;Apr2004 Supplement 3, Vol. 53, pA64 

    The article cites a study on the expression of NOD2 by intestinal epithelial cells in an in vitro M cell model. NOD2 is a cytosolic detector of peptidoglycans-specifically muramyl dipeptides (MDP)—and is principally expressed by cells of the myeloid lineage (monocytes, macrophages and...

  • NOD2 mutations and Crohn's disease: are Paneth cells and their antimicrobial peptides the link? Grimm, M. C.; Pavli, P. // Gut;Dec2004, Vol. 53 Issue 12, p1558 

    Comments on the relation between NOD2 mutations and Crohn's disease. Evidence that CARD15/NOD2 variants in Crohn's disease are associated with diminished mucosal α-defensin production, resulting in impaired innate immunity; Information on paneth cells; link between intestinal inflammation and...

  • SHIP deficiency causes Crohn's disease-like ileitis. William G Kerr // Gut;Feb2011, Vol. 60 Issue 2, p177 

    BACKGROUND: Inflammatory bowel disease (IBD) can arise from genetic mutations that compromise intestinal epithelial cell integrity or immune regulation. SHIP has previously been shown to play a pivotal role in limiting the number of immunoregulatory cells and their function. AIM: To determine...

  • Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis. Yang, Shuo; Wang, Bingwei; Humphries, Fiachra; Jackson, Ruaidhri; Healy, Marc E; Bergin, Ronan; Aviello, Gabriella; Hall, Barry; McNamara, Deirdre; Darby, Trevor; Quinlan, Aoife; Shanahan, Fergus; Melgar, Silvia; Fallon, Padraic G; Moynagh, Paul N // Nature Immunology;Sep2013, Vol. 14 Issue 9, p927 

    Mutations that result in loss of function of Nod2, an intracellular receptor for bacterial peptidoglycan, are associated with Crohn's disease. Here we found that the E3 ubiquitin ligase Pellino3 was an important mediator in the Nod2 signaling pathway. Pellino3-deficient mice had less induction...

  • MULTIFACTORIAL DISEASE: Opening the flood gates? Alfred, Jane // Nature Reviews Genetics;Jul2001, Vol. 2 Issue 7, p486 

    Deals with two studies which identified linkage mapping of NOD2, a gene involved in Crohn disease (CD). Way by which the immune system might be involved in the etiology of CD; Association of CD to an allele of a chromosome 16 microsatellite marker; Mutations in the leucine-rich repeat region of...

  • Consequence of functional Nod2 and Tlr4 mutations on gene transcription in Crohn’s disease patients. Braat, Henri; Stokkers, Pieter; Hommes, Tijmen; Cohn, Danny; Vogels, Esther; Pronk, Inge; Spek, Arnold; Kampen, Antoine; Deventer, Sander; Peppelenbosch, Maikel; Hommes, Daan // Journal of Molecular Medicine;Aug2005, Vol. 83 Issue 8, p601 

    The concept that mutations in germ-line encoded pattern recognition receptors with immune activating functions are associated with an increased incidence in Crohn’s disease (CD) is gaining acceptance. Whether these mutations have similar or distinct effects on cellular physiology remains...

  • NOD takes its toll but stays in the CARDs in Crohn’s disease. Luft, Friedrich // Journal of Molecular Medicine;Aug2005, Vol. 83 Issue 8, p577 

    Points out to the growing body of evidence implicating nucleotide-binding oligomerization domain (NOD) 2 and toll-like receptor (TLR) 4 mutations in Crohn's disease. Occurrence of inflammatory bowel diseases in areas of the gastrointestinal tract with the highest numbers of luminal bacteria;...

  • Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD 15 3020insC mutation? Buhner, S.; Buning, C.; Genschel, J.; Kling, K.; Herrmann, D.; Dignass, A.; Kuechler, I.; Krueger, S.; Schmidt, H. H.-J.; Lochs, H. // Gut;Mar2006, Vol. 55 Issue 3, p342 

    Background and aim: A genetically impaired intestinal barrier function has long been suspected to be a predisposing factor for Crohn's disease (CD). Recently, mutations of the capsase recruitment domain family, member 15 (CARD15) gene have been identified and associated with CD. We hypothesise...

  • CCR2 expressing CD4+ T lymphocytes are preferentially recruited to the Ileum in Crohn's disease. Connor, S. J.; Paraskevopoulos, N.; Newman, R.; Cuan, N.; Hampartzoumian, T.; Lloyd, A. R.; Grimm, M. C. // Gut;Sep2004, Vol. 53 Issue 9, p1287 

    Background and aims: Chemokine receptors are key determinants of leucocyte trafficking. While the chemokine receptor CCR9 and its chemokine ligand CCL25 (TECK) mediate lymphocyte homing to the healthy small intestine, the chemokine receptors important for recruitment during intestinal...

Share

Read the Article

Courtesy of VIRGINIA BEACH PUBLIC LIBRARY AND SYSTEM

Sign out of this library

Other Topics