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Reduced alpha-defensin expression is associated with inflammation and not NOD2 mutation status in ileal Crohn’s disease
  1. Lisa A Simms (lisa.simms{at}qimr.edu.au)
  1. Queensland Institute of Medical Research, Australia
    1. James D Doecke (james.doecke{at}qimr.edu.au)
    1. Queensland Institute of Medical Research, Australia
      1. Michael D Walsh (michael.walsh{at}qimr.edu.au)
      1. Queensland Institute of Medical Research, Australia
        1. Ning Huang (ning.huang{at}qimr.edu.au)
        1. Queensland Institute of Medical Research, Australia
          1. Elizabeth V Fowler (beth.fowler{at}qimr.edu.au)
          1. The University of Queensland, Australia
            1. Graham L Radford-Smith (graham.radford-smith{at}qimr.edu.au)
            1. Royal Brisbane and Women's Hospital, Australia

              Abstract

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

              Methods: Using quantitative RT-PCR, we measured the mRNA expression levels of key Paneth cell antimicrobial peptides (DEFA5, DEFA6, LYZ, PLA2G2A), inflammatory cytokines (IL6, IL8), and a marker of epithelial cell content, villin (VIL1) in 106 samples from both affected ileum (inflamed CD cases, n=44) and unaffected ileum (non-inflamed; CD 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 CD tissue.

              Results: In CD 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 alpha-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 alpha-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 CD.

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