Innate immunity includes defensins

COMMENTARY We would like to comment on the comprehensive review of Karantanos and Gazouli in Annals of Gastroenterology [1] about genetics and innate immunity in inflammatory bowel disease (IBD). The authors appreciate the important role of innate immune sensing and the production of antimicrobial peptides in maintaining the integrity of the mucosal barrier. Pertinent studies on the subject are presented and the authors concur with the current understanding of Crohn's disease (CD) as the manifestation of an abnormal immune response to the intestinal microbiome in individuals with genetic susceptibility. Yet, in our view, the body of literature justifies the proposition of an integrative model of pathogenesis for ileal CD (iCD), focusing on the role of the Paneth cell (PC) products, the α-defensins human defensin 5 (HD-5) and HD-6. Associations between PCs and defensins in small intestinal inflammation are plentiful, and we feel that in the interpretation by Karantanos' article, this aspect is not given the due attention. PCs, a characteristic epithelial cell line of the small intestine localized at the bottom of the intestinal crypts, constitutively secrete considerable amounts of antimicrobial peptides (AMP), the expression levels of α-defensins thereby exceeding those of other PC antimicrobials like lysozyme and sPLa2 by a factor of up to 100 [2]. Activation of pattern recognition receptors (e.g. Toll-like receptors, nucleotide-binding oligomerization domain (NOD)-like receptors, RIG-I-like receptors) by pathogen-associated molecular patterns (PAMPs, derived from resident and pathogenic bacteria) leads to the release of PC secretions into the intestinal lumen [3]. Expression of intracellular receptors like NOD2 itself depends on the presence of commensal bacteria [4]. In turn, the composition of microbial species found in the small intestinal lumen can be regulated by the luminal antimicrobials [2,5]. A link between NOD2 and iCD has already been demonstrated by Cuthbert et al [6] in 2002, when the mutations R702W, G908R and 3020insC were identified as strong independent risk factors (in patients of Caucasian descent). NOD2 protein and mRNA were found to be most prominently expressed in the terminal ileum, with localization to crypt base cells and mononuclear cells of the lamina propria [7]. Subsequent work from our group reported decreased α-defensin mRNA levels in ileal biopsy specimens, which were even more pronounced in patients carrying NOD2 mutations [8]. On a functional level, Petnicki-Ocweija et al showed that the bactericidal activity of crypt secretions of the terminal ileum was severely compromised by NOD2 deletion in a murine model …