title: Crohn's disease: loss of tolerance or a disorder of autophagy?
abstract: Crohn's disease (CD) is characterized by a breakdown of the intestinal epithelial barrier function leading to an uncontrolled immune response to bacterial antigens. Available data demonstrate that appropriate response and early host defense against invading bacteria are crucial to maintain tolerance towards commensal bacteria. When the mechanisms of early removal of invading bacteria are disturbed, a loss of tolerance and a full-blown adaptive immune reaction, which is mounted against the usually harmless commensal flora, are induced. Dysfunction of autophagy caused by genetic variations within CD susceptibility genes, such as ATG16L1 and IRGM, results in defective handling of intracellular and invading bacteria and causes prolonged survival and defective clearance of those microbes. Dysfunction of ATG16L1 and IRGM has also been shown to cause aberrant Paneth cell function and uncontrolled secretion of proinflammatory cytokines finally resulting in increased susceptibility to bacterial infection and the onset of colitis. Interestingly, autophagy can also be regulated by other CD susceptibility genes, such as NOD2 (nucleotide oligomerization domain 2) or PTPN2 (protein tyrosine phosphatase nonreceptor type 2) and the presence of the CD-associated variations within these genes results in similar effects. Taken together, more and more evidence suggests a close functional correlation between loss of tolerance and defective autophagy in CD patients. Therefore, most likely, the onset of CD is triggered by both a loss of tolerance as well as a dysfunction of autophagy, which finally results in the onset of chronic intestinal inflammation.
authors: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
authors: Marianne R
authors: MR
authors: Spalinger
authors: Gerhard
authors: G
authors: Rogler
authors: Michael
authors: M
authors: Scharl
mesh_terms: D001343:Autophagy; D002352:Carrier Proteins / Q000378:metabolism; D003424:Crohn Disease / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D007108:Immune Tolerance; D019879:Paneth Cells / Q000473:pathology; D051192:Receptors, Pattern Recognition / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D051192:Receptors, Pattern Recognition