title: ATG16L1 polymorphisms are associated with NOD2-induced hyperinflammation.
abstract: In recent years considerable advances in understanding the pathogenesis of Crohn disease have been achieved, with the identification of susceptibility variants of genes that are part of the autophagy machinery, i.e., ATG16L1 and IRGM. Subsequent functional studies have been conducted to unravel the underlying mechanism of this genetic association. For the ATG16L1 Thr300Ala polymorphism (c.898A > G, rs2241880), it was demonstrated that the risk variant is associated with a reduced capacity of innate immune cells to induce autophagy upon triggering with specific microbial structures such as peptidoglycans, that are specifically recognized by the intracellular pattern-recognition receptor nucleotide oligomerization domain-2 (NOD2). Due to the impaired autophagy activation, autophagosome formation and the subsequent antigen presentation through the major histocompatibility complex are diminished, leading to decreased immune activation. However, these findings arguing for defective host defense mechanisms in individuals bearing the ATG16L1 300Ala variant, and subsequent bacterial persistence in the gut mucosa, provide no conclusive explanation for the excessive inflammation observed in Crohn disease.
authors.affiliation: Department of Medicine, and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Theo S
authors.initials: TS
authors.lastname: Plantinga
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein