Inflammatory bowel disease

Reduced -defensin expression is associated with inflammation and not NOD2 mutation status in ileal Crohn’s disease

L A Simms^1,2, J D Doecke², M D Walsh², N Huang^1,2, E V Fowler^1,3, G L Radford-Smith^1,4

¹ Inflammatory Bowel Disease Laboratory, Royal Brisbane and Women’s Hospital Foundation, Brisbane, Australia
² Queensland Institute of Medical Research, Brisbane, Australia
³ School of Medicine, The University of Queensland, Brisbane
⁴ Department of Gastroenterology, Royal Brisbane and Women’s Hospital, Brisbane, Australia

Lisa A Simms, Inflammatory Bowel Disease Laboratory, Queensland Institute of Medical Research, Brisbane 4029, Australia; Lisa.Simms{at}qimr.edu.au

Background and aims: Reduced ileal Paneth cell -defensin expression has been reported to be associated with Crohn’s disease, especially in patients carrying NOD2 mutations. The aim of this study was to independently assess whether NOD2, -defensins and Crohn’s disease are linked.

Methods: Using quantitative real-time polymerase chain reaction (RT-PCR), we measured the mRNA expression levels of key Paneth cell antimicrobial peptides (DEFA5, DEFA6, LYZ, PLA2G2A), inflammatory cytokines [interkelukin 6 (IL6) and IL8], and a marker of epithelial cell content, villin (VIL1) in 106 samples from both affected ileum (inflamed Crohn’s disease cases, n = 44) and unaffected ileum (non-inflamed; Crohn’s disease cases, n = 51 and controls, n = 11). Anti-human defensin 5 (HD-5) and haematoxylin/eosin immunohistochemical staining was performed on parallel sections from NOD2 wild-type and NOD2 mutant ileal Crohn’s disease tissue.

Results: In Crohn’s disease patients, DEFA5 and DEFA6 mRNA expression levels were 1.9- and 2.2-fold lower, respectively, in histologically confirmed inflamed ileal mucosa after adjustment for confounders (DEFA5, p<0.001; DEFA6, p = 0.001). In contrast to previous studies, we found no significant association between -defensin expression and NOD2 genotype. HD-5 protein data supports these RNA findings. The reduction in HD-5 protein expression appears due to surface epithelial cell loss and reduced Paneth cell numbers as a consequence of tissue damage.

Conclusions: Reduction in -defensin expression is independent of NOD2 status and is due to loss of surface epithelium as a consequence of inflammatory changes rather than being the inciting event prior to inflammation in ileal Crohn’s disease.

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