Pathophysiologische Mechanismen der chronisch-entzündlichen Darmerkrankungen - ein neues Konzept

Zusammenfassung

Sowohl das bekannte Nord-/Südgefälle als auch epidemiologische Studien in den westlichen Industrieländern belegen die fördernde Rolle der Hygiene bei der Entstehung chronisch-entzündlicher Darmerkrankungen. Vermutlich wird wegen des seltenen Auftretens von Darminfektionen das angeborene Immunsystem nicht ausreichend „trainiert” und durch das spezifische Immunsystem mit deletären Entzündungskaskaden ersetzt. Passend zu einer Störung der angeborenen mukosalen antibakteriellen Barriere finden sich bei entzündlichen Darmerkrankungen häufig mukosal adhärente und teilweise invasive Bakterien. Wichtiger Bestandteil dieser chemischen Barriere des Epithels sind die Defensine als antimikrobielle Peptide mit enormem Wirkungsbereich einschließlich gramnegativen, grampositiven, Mykobakterien, Pilzen (Candida), Viren (Herpes) und Protozoen (Giardia lamblia). Beim Morbus Crohn des Kolon fand sich eine verminderte β-Defensinantwort, welche vermutlich die Mucosabarriere beeinträchtigt und so zu einer vermehrten bakteriellen Invasion in die Darmschleimhaut führt. Beim Morbus Crohn des terminalen Ileum sind die dort wichtigeren α-Defensine in den Panethzellen vermindert exprimiert, insbesondere bei einer Mutation des Transkriptionsfaktors NOD2. Der Defensinmangel kann somit als Trigger für die Entzündungsantwort betrachtet werden. Ob diese verminderte Defensinantwort auch zu einer verminderten antibakteriellen Aktivität der Darmschleimhaut führt, ist noch Gegenstand der Forschung. Dennoch ist ein Defensinmangelsyndrom das derzeit plausibelste Pathogenesekonzept des Morbus Crohn. Die Colitis ulcerosa dagegen zeigt in der Entzündung einen adäquaten Anstieg der bisher bekannten humanen Defensine. Dieses Krankheitsbild ist daher durch obiges Konzept nicht zu erklären, dies schließt aber andere Störungen der angeborenen Abwehr nicht aus.

Abstract

The North-/South Gradient as well as epidemilogical studies in the industrialised countries support a promoting role of good hygiene for chronic inflammatory bowel diseases. Probably innate immunity is not sufficiently trained and adaptive immunity with its deleterious inflammatory cascades has to step in. The finding of mucosal adeherent and invasive bacteria fits with this concept. An important part of this chemical barrier are the defensins with a broad effect against gramnegative and grampositive bacteria, mycobacterias, fungi (candida), viruses (herpes) and protozoa (giardia lamblia). β-defensins are diminshed in Crohn's disease of the colon, which may compromise the mucosal barrier and lead to its bacterial invasion. In terminal ileitis the expression of α-defensins is diminished in the Paneth cells, especially if the transcription factor NOD2 is mutated. The defensin deficiency may therefore trigger the secondary inflammatory events in the mucosa. In contrast to Crohn's disease, ulcerative colitis shows an adequate increase of all known human defensins during inflammation. Hence, other impaired mechanisms of innate defense may be responsible.

Chronisch entzündliche Darmerkrankungen - Morbus Crohn - Colitis ulcerosa - Pathophysiologie - angeborene Immunität - Defensine

Inflammatory bowel disease - Crohn's disease - ulcerative colitis - pathophysiology - innate immunity - defensins

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