Wehkamp J, Stange E F, Fellermann K
Dr. Margarete Fischer-Bosch - Institute of Clinical Pharmacology, and Robert Bosch Hospital; Internal Medicine I, Auerbachstr. 112, 70376 Stuttgart, Germany.
Gastroenterol Clin Biol. 2009 Jun;33 Suppl 3:S137-44. doi: 10.1016/S0399-8320(09)73149-5.
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.
防御素是一种内源性抗生素，对革兰氏阴性菌和革兰氏阳性菌、真菌、包膜病毒及原生动物具有杀菌活性。由潘氏细胞和其他上皮细胞防御素提供的抗菌防御功能紊乱，似乎是炎症性肠病发病机制中的一个关键因素。值得注意的是，在回肠克罗恩病中，无论是否存在模式识别受体NOD2突变，尤其是在存在该突变的情况下，潘氏细胞β-防御素HD-5和HD-6相对缺乏。这种缺陷与同时存在的活动性炎症无关，会导致黏膜的抗菌杀伤能力减弱。克罗恩病黏膜不仅对不同大肠杆菌的杀伤能力显著不足，而且清除金黄色葡萄球菌及厌氧微生物的能力也受损。因此，这种抗菌屏障功能障碍似乎范围广泛，并不局限于单一菌株。除了直接控制屏障功能外，潘氏细胞防御素还调节粪便细菌菌群的组成。在大多数患者中，潘氏细胞缺陷是由WNT信号介导的，这表明回肠克罗恩病中潘氏细胞分化受到干扰。相比之下，结肠克罗恩病的特征是黏膜β-防御素的诱导受损，部分原因是β-防御素基因簇的拷贝数较低。因此，细菌利用防御素缺乏形成的生态位似乎是合理的。这将代表对克罗恩病理解的范式转变，并为未来的治疗策略提供一个靶点。
