Evidence from Genetics for a Role of Autophagy and Innate Immunity in IBD Pathogenesis

The early identification of NOD2 (nucleotide-binding oligomerization domain-containing protein 2) as a susceptibility gene for Crohn's disease first catalysed major interest in the role of innate immunity in IBD. This interest has been substantiated by genome-wide association studies with the identification of genetic association between Crohn's disease and variants in two separate autophagy genes, ATG16L1 and IRGM. A variety of disease-predisposing mechanisms have been proposed for the NOD2 mutations, ranging from defects in viral sensing and reduced mucosal defensin production to abnormal autophagy induction. Recent work has also highlighted the complexity of the contribution made by ATG16L1 and IRGM. Thus ATG16 hypomorphic mice show major morphological change in Paneth cells--also observed in humans homozygous for the ATG16L1T300A. Further, these mice developed a Crohn's-like phenotype--but only in the presence of an environmental stressor, an intact gut flora and a specific norovirus trigger. For IRGM, the risk alleles appear to affect mRNA transcription--in one study adversely impacting clearance by macrophages of CD-associated adherent-invasive Escherichia coli. There is now intriguing literature developing on the impact of 'adaptive immunity' genes on innate immune mechanisms. Buoncore et al. Nature 2010;464:1371-1375 recently reported the accumulation of IL-23-responsive innate lymphoid cells in the colon, the former capable of producing IL-17 and interferon γ and mediating innate colitis in mice. Production of Th17 cytokines by analogous cells in humans appeared higher in IBD cases versus controls. Many other genes linked to various components of innate immunity are evident among the >100 confirmed IBD susceptibility loci. Intriguingly, association with epithelial barrier genes seems specific to ulcerative colitis--the converse of NOD2 and the autophagy genes which are Crohn's-specific. These observations correlate nicely with ulcerative colitis being confined to the superficial layers of the colon, while the transmural inflammation of Crohn's disease is caused by defects in cellular innate immunity and bacterial handling in the deeper layers of the gut wall.