[Barrier- and autophagic functions of the intestinal epithelia: role of disturbances in the pathogenesis of Crohn's disease].
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.
Lapis
Károly
K
Semmelweis Egyetem, Altalános Orvostudományi Kar I. Patológiai és Kísérleti Rákkutató Intézet Budapest. lapkar@t-online.hu
D001343:Autophagy; D000071183:Autophagy-Related Proteins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D003108:Colonic Diseases / Q000503:physiopathology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D023082:Defensins / Q000172:deficiency* / Q000276:immunology; D006801:Humans; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology / Q000503:physiopathology*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D011110:Polymorphism, Genetic; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics
C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; D023082:Defensins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors