[Barrier- and autophagic functions of the intestinal epithelia: role of disturbances in the pathogenesis of Crohn's disease]. / A bélnyálkahártyahám barrier- és autophagiás funkciózavarainak szerepe a Crohn-betegség patogenezisében.

Crohn's disease is a widely known debilitating chronic inflammatory disease, mostly affecting terminal ileum and/or colon. Epidemiological, familial and twin studies suggest that genetic factors play an important role in susceptibility to the disease. Clinical observations suggest that ill-defined environmental factors also play a part. Advances in molecular genotyping technology, statistical methodologies, bioinformatics and the combined use of them in genome wide scanning and association studies resulted in the identification of more than 30 susceptibility genes and loci associated with Crohn's disease and revealed and highlighted a number of new previously unsuspected pathways playing a role in the pathogenesis of Crohn's disease. Close association of the disease with polymorphisms in the genes encoding the pattern recognition receptors particularly the NOD2 protein, the Wnt pathway transcription factor Tcf4 (also known as TCFL2) and the autophagic regulator ATG16L1 have been found. The polymorphisms involved are associated with decreased defensin production (defensin deficiency) which can lead to changes in the composition of the commensal microbial flora, defects in the intestinal barrier functions and bacterial invasion of the mucosa. Other recently recognized consequences of the polymorphisms involving the genes encoding NOD2 and ATG16L1 proteins are that the truncated NOD2 protein is unable to induce autophagy and this protein, just like the ATG16L1 T300A mutant protein, leads to failure adequately to destroy phagocytosed bacteria. The consequence is persisting low level infection, chronic intestinal inflammation, tissue injury and the clinical symptoms of the disease. Thus, Crohn's disease can be seen to be caused by defects in the innate immune defense, in particular defects in bacterial processing and clearance. The accumulated evidence suggests that Crohn's disease is associated with an exaggerated adaptive immune response to the persisting intestinal microbes in genetically susceptible hosts. Intervention in these circumstances should probably be geared to strengthening of the innate immune responses rather than simple attempts to suppress adaptive immunity.

Barrier dysfunction due to distinct defensin deficiencies in small intestinal and colonic Crohn's disease.

Defensins are endogenous antibiotics with broad microbicidal activity. A disturbed antimicrobial defense, as provided by Paneth and other epithelial defensins, seems to be a critical factor in the pathogenesis of inflammatory bowel diseases. Conspicuously, there is a relative lack of Paneth-cell alpha-defensins in ileal Crohn's disease (CD), both in the absence of a pattern recognition receptor nucleotide-binding oligomerization domain 2 (NOD2) frameshift mutation and, even more pronounced, in its presence. This deficit is independent of concurrent active inflammation and cannot be seen in active small intestinal ulcerative colitis (UC; pouchitis) as well as NOD2 wild-type graft vs. host ileitis. After intestinal transplantation, in case of NOD2 mutation, defensins are decreased before the onset of inflammation. In the majority of patients, the Paneth-cell deficiency is mediated by Wnt-TCF4, which suggests a disturbed Paneth-cell differentiation. In contrast, colonic CD is characterized by an impaired induction of mucosal beta-defensins, partly because of a low copy number of the beta-defensin gene cluster. In both ileal and colonic CD, the lack in defensins results in a broadly diminished antibacterial killing by the mucosa, which can also be found independent of inflammation. In summary, the main disease locations can be linked to distinct mechanisms of epithelial barrier dysfunction.

Host-microbe interaction: mechanisms of defensin deficiency in Crohn's disease.

Defensins are endogenous antibiotics with microbicidal activity against Gram-negative and -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 Crohn's disease, an inflammatory disease of the intestinal tract. Different direct and indirect mechanisms leading to a breakdown of antimicrobial barrier function include direct changes in defensin gene numbers (e.g., copy number polymorphism), genetic mutations in pattern-recognition receptors (e.g., nucleotide-binding oligomerization domain 2) and, as described recently, a differentiation problem of epithelial stem cells mediated by the wingless type (Wnt) pathway. Knowledge regarding the regulation and biology of defensins provides an attractive target to open up new therapeutic avenues.

[Chronic inflammatory bowel diseases (IBD): novel pathophysiological concepts and their clinical relevance]. / Chronisch-entzündliche Darm- erkrankungen (CED): Neue pathophysiologische Erkenntnisse--Folgerungen für die Klinik.

Despite many years of intensive research the pathogenesis of inflammatory bowel diseases is still enigmatic. All efforts to identify the cause of Crohn's disease and ulcerative colitis in a dysregulation of specific immune mechanisms have failed. This review presents a novel pathogenetic concept, based on the expression of natural mucosal antibiotic peptides. These so called defensins are part of innate immunity and defend the mucosa as antimicrobial peptides against intraluminal potentially pathogenic and invasive bacteria. In contrast to ulcerative colitis, Crohn's disease is characterised by a diminished defensin expression. This defect may represent the molecular pathogenesis of this disease.

Defensin deficiency, intestinal microbes, and the clinical phenotypes of Crohn's disease.

Crohn's disease is a chronic, inflammatory disease of the intestinal mucosa. Although intestinal bacteria are implicated in disease pathogenesis, the etiology is still unclear. The main location of disease is the small intestine (ileum) and the colon. Ileal disease has been linked to a mutation in the NOD2 gene. Defensins are antimicrobial peptides and in the ileum, are mainly expressed in Paneth cells, epithelial cells that also express NOD2. In the colon, defensins are expressed by enterocytes or metaplastic Paneth cells. Crohn's disease patients with ileal involvement, compared with controls or Crohn's patients without ileal involvement, have diminished expression of ileal Paneth cell defensins. This decrease is even more pronounced in Crohn's patients displaying a NOD2 mutation. In contrast, Crohn's disease of the colon is characterized by an impaired induction of beta-defensins in enterocytes. The colonic expression of the constitutive beta-defensin 1 is also decreased in the inflamed colonic mucosa, but this decrease is less specific to Crohn's disease, as it can also be found in ulcerative colitis patients. In conclusion, the regional localizations of Crohn's disease, ileal or colonic disease, can be linked to different defensin profiles. Crohn's disease of the ileum is associated with diminished defensin expression in Paneth cells. Crohn's disease of the colon is associated with diminished beta-defensin expression in enterocytes. Thus, it can be speculated that decreased defensin levels lead to a weakened intestinal barrier function to intestinal microbes and might be crucial in the pathophysiology of Crohn's disease.

[The role of defensins in the pathogenesis of chronic-inflammatory bowel disease]. / Die Rolle der Defensine in der Pathogenese chronisch-entzündlicher Darmerkrankungen.

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 alpha-defensin (human defensin 5 and 6) expression, and in inflamed Crohn's colitis, in contrast to ulcerative colitis, the beta-defensin (human beta-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.

Crohn's disease: a defensin deficiency syndrome?

This comprehensive review promotes the novel concept that a defensin deficiency, i.e. lack of mucosal peptide antibiotics, may play a pivotal role in the aetiopathogenesis of Crohn's disease. Such an impaired function of this chemical barrier is consistent with the epidemiological relationship of good domestic hygiene with the incidence of inflammatory bowel diseases. The disregulated adaptive immune system, formerly believed to be the major cause in the development of Crohn's disease, may reflect only the primary break of the mucosal defence since the immune response is mostly directed against lumenal bacteria. Recent work has identified five different defensins expressed in colonic mucosa. In contrast to ulcerative colitis, Crohn's disease is characterised by an impaired induction of human beta defensins 2 and 3. This deficient induction may be due to changes in the intracellular transcription by NFkappaB and the intracellular peptidoglycan receptor NOD2, mutated in Crohn's disease. These findings are consistent with the mucosal attachment of lumenal bacteria in inflammatory bowel diseases and the frequent occurrence of other infectious agents. The hypothesis of an impaired mucosal antibacterial activity is also consistent with the benefit from antibiotic or probiotic treatment in certain inflammatory bowel disease states.