(A) Domain structure of the ATG16L1 and IRGM proteins. Human ATG16L1 has an N-terminal interaction domain, postulated to be essential for interaction with other autophagy proteins such as ATG5 and ATG12, a coiled-coil domain thought to mediate homodimeric interactions and seven WD repeats. Although proteins with WD repeats demonstrate a very high degree of functional diversity, the structures formed by these repeats are believed to create stable platforms that can coordinate the formation of reversible multi-protein complexes. In contrast, IRGM has just a single identified domain, belonging to the Interferon-Inducible GTPase family. (B) Proposed mechanism for autophagy of intracellular pathogens and subsequent immune events. Responding to uncharacterized signals upon the bacteria-containing vacuole (or the bacterium itself if free in the cytoplasm), the autophagy apparatus initiates an encapsulation process. The double membrane characteristic of autophagy envelops the pathogen, driven by the core autophagic machinery, including the ATG5,12 and 16 complex. Completion of the autophagic vacuole results in dissolution of the ATG complex from the vacuole and the autophagosome is fused with lysosomes (large blue circles) and degrade its contents. Vacuolar contents can then be loaded onto HLA class II molecules or possibly trafficked to compartments where TLR recognition may occur. (C) Potential consequences of autophagy for mucosal homeostasis and immunity. Autophagy is likely to play important roles in both mucosal barrier maintenance and innate and adaptive immunity. As yet, the effects of known human mutations upon these functions is unknown, but the implication of autophagy-related SNPs in CD is likely to reflect subtle alterations in the balance of autophagy versus other immune and homeostatic gut processes.

Crohn’s disease is a complex genetic disorder whereby genetic and non-genetic risk factors contribute to disease susceptibility. Genetic variation in the ATG16L1 and IRGM genes identified in the recent GWA studies, in combination with genetic variation at other genes identified in these and previous studies, likely result in an inappropriate response to the intestinal microbial flora and eventually to a chronic granulomatous inflammatory state.