Gut Reactions Gone Awry

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Science  12 Feb 2010:
Vol. 327, Issue 5967, pp. 763
DOI: 10.1126/science.327.5967.763-b

Crohn's disease is a debilitating autoinflammatory disease of the gastrointestinal tract. Genome-wide association studies have demonstrated strong links between Crohn's disease and polymorphisms in genes involved in microbial recognition (NOD2) and autophagy (ATG16L1), which is a broad-spectrum intracellular degradation pathway. How microbial recognition and autophagy might intersect, however, has been unclear.

Travassos et al. and Cooney et al. have found that NOD2 detection of bacterial peptidoglycans results in the recruitment of ATG16L1 to sites of bacterial entry at the plasma membrane. This aids in the formation of autophagosomes, a process that promotes bacterial degradation and leads to the presentation of bacterial antigens to CD4+ T cells. Both groups then went on to connect these events to Crohn's disease. Using cells either from Crohn's disease patients expressing the disease-associated variants of NOD2 or ATG16L1 or from mice homozygous for a NOD2 disease-associated variant, they observed deficits in ATG16L1 localization to the plasma membrane, autophagy induction, antigen presentation, and bacterial clearance. Together, these studies suggest that bacterial persistence, due to impaired autophagic degradation, may be an important driver in the pathogenesis of Crohn's disease.

Nat. Immunol. 11, 55; Nat. Med. 16, 90 (2010).

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