Crohn's disease--defect in innate defence

Abstract

Crohn's disease may principally involve the whole gastrointestinal tract. Most commonly, the inflammation occurs in the small intestine and/or in the colon with stable disease location over the years. The pathogenesis of both disease phenotypes is complex, the likely primary defect lies in the innate rather than adaptive immunity, particularly in the chemical antimicrobial barrier of the mucosa. Crohn's ileitis is associated with a reduced expression of the Wnt signalling pathway transcription factor T-cell factor 4 (TCF4), which is regulating Paneth cell differentiation. As a result, the alpha-defensins and principal Paneth cell products HD5 and HD6 are deficiently expressed in ileal disease, independent of current inflammation. In contrast, Crohn's colitis is typically associated with an impaired induction of the beta-defensins HBD2 and HBD3 caused by fewer gene copy numbers in the gene locus of the beta-defensins on chromosome 8. This ileal and colonic defect in innate defence mediated by a deficiency of the protective alpha- and beta-defensins may enable the luminal microbes to invade the mucosa and trigger the inflammation. A better understanding of the exact molecular mechanisms behind ileal and colonic Crohn's disease may give rise to new therapeutic strategies based on a stimulation of the protective innate immune system.

Figure 1

Proposed model for the pathogenesis of ileal and colonic Crohn's disease. In the healthy ileal and colonic mucosa, luminal microbes are sufficiently eliminated by an adequate secretion of antimicrobials peptides (A). In ileal Crohn's disease, a reduction of the Wnt transcription factor TCF4 leads to a decreased alpha-defensin secretion. In colonic Crohn´s disease a reduced HBD2 copy number causes a weakened antimicrobial barrier mediated by the beta-defensins. Both changes may allow the luminal microbes to attach and invade in the mucosa triggering the inflammation (B).