Die Rolle der Defensine in der Pathogenese chronisch-entzündlicher Darmerkrankungen

Zusammenfassung

Defensine sind endogene antimikrobielle Peptide mit breitem Wirkungsspektrum. Bereits mikromolare Konzentrationen reichen aus, um gramnegative und grampositive Bakterien, aber auch Mykobakterien sowie Pilze (z. B. Candida), Viren (z. B. Herpes) und Protozoen (z. B. Giardia lamblia) effektiv abzutöten. Als wichtiger Teil des angeborenen Immunsystems werden sie im Darmepithel exprimiert und tragen somit zur Aufrechterhaltung der intestinalen Mucosabarriere bei. Diese scheint bei chronisch entzündlichen Darmerkrankungen defekt zu sein, da einerseits die Immunantwort gegen die „normale” luminale Bakterienflora gerichtet ist, andererseits bei diesen Erkrankungen mucosal-adhärente und invasive Bakterien beobachtet werden. Eine mögliche Erklärung für diese Phänomene beruht auf einer defekten Defensinexpression. Tatsächlich findet sich bei M. Crohn mit Befall des terminalen Ileum, insbesondere bei einer Mutation im NOD2-Gen, eine verminderte α-Defensinexpression (humane Defensine 5 und 6) und im entzündeten Colon eine im Vergleich zur Colitis ulcerosa verminderte β-Defensinantwort (humane β-Defensine 2 und 3). Dies könnte durch Beeinträchtigung der chemischen Mucosabarriere zu einer vermehrten bakteriellen Invasion in die Darmschleimhaut führen und als eigentliche Ursache für die adäquate Entzündungsantwort betrachtet werden. Trotz des noch fehlenden Nachweises, dass diese beeinträchtigte Defensinbildung auch zu einer verminderten antibakteriellen Aktivität der Darmschleimhaut führt, ist ein Defensinmangelsyndrom das derzeit plausibelste Pathogenesekonzept des Morbus Crohn.

Abstract

Defensins are endogenous antimicrobial peptides with a broad activity spectrum. Even at micromolar concentrations gramnegative and grampositive bacteria, but also mycobacteria, as well as fungi (candida), viruses (herpes) and protozoa (giardia lamblia) are destroyed. As part of the innate immune system defensins are expressed by the intestinal epithelium and contribute to the maintenance of the mucosal barrier. This barrier appears to be defective in inflammatory bowel diseases since on one hand, the immune response is directed against the “normal” luminal bacterial flora and on the other hand, mucosal adherent and invasive bacteria have been observed in these diseases. A defective defensin expression may well explain these phenomena. Indeed, Crohn’s disease of the terminal ileum, especially if associated with a NOD2 mutation, is characterised by a diminished α-defensin (human defensin 5 and 6) expression, and in inflamed Crohn’s colitis, in contrast to ulcerative colitis, the β-defensin (human β-defensins 2 and 3) response is reduced. Through a deficient chemical mucosal barrier this defect could lead to increased bacterial invasion into the intestinal mucosa and might well explain an adequate inflammatory response. Although the final proof that this deficient defensin response leads to a reduced antibacterial activity of the intestinal mucosa is still lacking, the most plausible concept of pathogenesis of Crohn’s disease is a defensin deficiency syndrome.

Schlüsselwörter

Morbus Crohn - Pathogenese - angeborene Immunität - Defensine

Key words

Crohn’s disease - pathogenesis - innate immunity - defensins

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