Defensin-immunology in inflammatory bowel disease

Abstract

Defensins are endogenous antibiotics with microbicidal activity against Gram-negative and Gram-positive bacteria, fungi, enveloped viruses and protozoa. A disturbed antimicrobial defense, as provided by Paneth- and other epithelial cell defensins, seems to be a critical factor in the pathogenesis of inflammatory bowel diseases. Conspicuously, there is a relative lack of Paneth cell beta-defensins HD-5 and HD-6 in ileal Crohn's disease, both in the absence of a pattern recognition receptor NOD2 mutation and, even more pronounced, in its presence. This deficit is independent of concurrent active inflammation and results in a diminished antibacterial killing by the mucosa. The Crohn's disease mucosa has not only a significant lack in killing different Escherichia coli but also an impaired ability in clearing Staphylococcus aureus as well as anaerobic micro-organisms. Thus, this dysfunction in antibacterial barrier seems to be broad and is not restricted to a single bacterial strain. In addition to directly controlling barrier function, Paneth cell defensins also regulate the composition of the bacterial stool flora. In the majority of patients, the Paneth cell deficiency is mediated by WNT signalling which suggests a disturbed Paneth cell differentiation in ileal Crohn's disease. In contrast, colonic Crohn's disease is characterised by an impaired induction of mucosal beta-defensins, partly due to a low copy number of the beta-defensin gene cluster. Therefore it seems plausible that bacteria take advantage of a niche formed by defensin deficiency. This would represent a paradigm shift in understanding Crohn's disease and provides a target for future therapeutic strategies.