NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal  -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 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 A 2 (sPLA 2 ), tumour necrosis factor a, 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 sPLA 2 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 sPLA 2 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.

CARD15 Mutations and Perianal Fistulating Crohn’s Disease: Correlation and Predictive Value of Antibiotic Response

“…However, we know that CARD15 plays a role in bowel immunity by participating in recognition of intestinal bacteria [21][22][23][24]. Thus, we can speculate that, in CARD15 wild-type patients, endogenous antimicrobial activity may synergize with antibiotics to enhance their action, while in patients with CARD15 mutations this synergy does not occur.…”

“…Since CARD15 mutations increase susceptibility to CD and appear to change the host response to luminal bacteria, it is reasonable to speculate on a possible connection between this gene and perianal fistulas [19][20][21][22][23][24]. However, there are few studies on the correlation between CARD15 mutations and development of Crohn 0 s perianal fistulas, and they provided conflicting data [25,26].…”

TIR, CARD and PYRIN: three domains for an antimicrobial triad

“…Nod2 is preferentially expressed in myeloid cells but is also expressed in Paneth cells. 65 Interestingly, a recent study revealed diminished a defensin expression in Paneth cells from Crohn's patients with Nod2 mutations, 66 suggesting that defective sensing by Nod2 protein could lead to a diminished mucosal protection due to a decreased production of these antimicrobial effectors.…”

Rôle de la cellule épithéliale dans l’homéostasie intestinale et les maladies inflammatoires chroniques de l’intestin

“…La sécrétion des peptides antimicrobiens est diminuée chez les patients MICI notamment chez les sujets porteurs de certaines mutations de gènes, tels que les gènes NOD2 (nucleotide-binding oligomerization domain containing 2) et TLR4 [31,32]. Des anomalies de fonction des cellules de Paneth ont été rapportées chez des patients atteints de MC et homozygotes pour l'allèle T300A du gène Atg16L1 impliqué dans l'autophagie [33].…”