Controversy over NOD2, inflammation, and defensins

Abstract

Bevins CL, Stange EF, Wehkamp J. Decreased Paneth cell defensin expression in ileal Crohn’s disease is independent of inflammation, but linked to the NOD2 1007fs genotype. Gut. 2009;58:882–883; discussion 883–884. Several years ago, Bevins, Stange, Wehkamp and colleagues1 reported decreased human α-defensin 5 and 6 expression in ileal Crohn’s disease (CD) patients harboring the NOD21007fs variant (encoded by NOD23020insC, “snp13”) and hypothesized that decreased Paneth cell antimicrobial activity might contribute to disease pathogenesis in ileal CD. Simms et al2 recently challenged this model by reporting that decreased α-defensin expression is a consequence of inflammation per se and unrelated to the NOD2 polymorphic state, implying that altered antimicrobial function might be secondary to active CD rather than a contributor to intestinal inflammation. This apparent contradiction has now been addressed by Bevins et al3 in a letter published in Gut, which triggered a counter-response by Simms et al4 and a consequent reply by Wehkamp et al.5 Specifically, Bevins et al3 remark that Simms et al have not stratified for the NOD21007fs variant but pooled all 3 major NOD2 variants. Moreover, they pointed to the fact that stratification with regard to inflammation in the ileum did not affect HD5 expression in the Wehkamp et al1 study, nor was human defensin-5 (HD5) regulation observed in non-CD ileal inflammation as deduced from measurements in pouchitis mucosa. Bevins et al speculated that a mix of surgical and biopsy specimens in the CD group might have been a detrimental confounder for the analysis in the Simms et al study, since the control group solely consisted of biopsy specimens. In their response, Simms et al4 now provide a stratification of HD5 and HD6 mRNA levels by NOD2 genotypes, which does not show significant differences including that associated with the NOD21007fs variant. Moreover, these authors claim varying results in the other group’s previous articles with regard to defensin levels, and reject the idea that sample bias might have contributed to the divergent results since statistical analyses included adjustment for confounders including sample type.4 Simms et al bring up another potential confounder distinguishing the Wehkamp et al study from the Simms et al study, namely, medical treatment, as 5-aminosalicylates and immunosuppressants, which were used differentially in the 2 study cohorts, and might have vastly different effects on intestinal bacteria.4