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Inflammatory Bowel Disease at the Intersection of Autophagy and Immunity: Insights from Human Genetics

ABSTRACT: Studies using human genetics have identified more than 160 loci that affect the risk of developing inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). Several of these genes have been found to play key roles in the process of autophagy, a lysosome-based degradation pathway. Although historically considered to be a relatively nonselective process of degradation of cytosolic contents, autophagy has recently been revealed to have several selective and immune-specific functions that are relevant to the maintenance of intestinal homeostasis, including xenophagy, mitophagy, antigen presentation, secretion, and inflammasome regulation. In this chapter, we review the evidence that links autophagy-related genes, their immune-specific functions, and possible mechanisms of IBD pathogenesis. We summarize the basic molecular events underlying general and selective autophagy, and present evidence suggesting possible pathogenic mechanisms revealed by studies of IBD-associated risk alleles of ATG16L1 and IRGM. Finally, we review chemical biology-based experimental approaches for identifying autophagy regulatory pathways that may have implications for the development of therapeutics.

SUBMITTER: Hedin C

PROVIDER: S-EPMC7120249 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Project description:Inflammatory bowel diseases (IBDs) are complex, multifactorial disorders that comprise Crohn's disease (CD) and ulcerative colitis (UC). Genome-wide association studies have identified approximately 100 loci that are significantly associated with IBD. These loci implicate a diverse array of genes and pathophysiologic mechanisms, including microbe recognition, lymphocyte activation, cytokine signaling, and intestinal epithelial defense. Consistent with epidemiologic predictions, many IBD-associated loci demonstrate genome-wide significant associations to both CD and UC, notably, genes whose products function in the interleukin-23 pathway, and transcription factors, including NK2 transcription factor related, locus 3 (NKX2-3), SMAD3, STAT3, ZMIZ1, and c-REL. Although CD and UC are both associated with genomic regions that implicate products of genes involved in leukocyte trafficking, there is evidence for association patterns that are distinct between CD and UC. CD-predominant associations include NOD2 and genes that regulate autophagy. In UC, the predominant association signal is on chromosome 6p21, in the major histocompatibility complex region, near HLA class II genes. UC-predominant loci have also implicated genes mediating epithelial defense function. There is a striking overlap of loci between diseases, which could provide comparative insight into mechanisms of disease pathogenesis. Genes that encode factors that function in the interleukin-23 pathway have been associated with a number of chronic inflammatory diseases, notably psoriasis and ankylosing spondylitis. Distinct genetic associations indicate that the colitis associated with primary sclerosing cholangitis is pathophysiologically distinct from UC that is not associated with primary sclerosing cholangitis. As many as 14 susceptibility loci are shared between IBD and celiac disease, indicating significant overlap in pathophysiology. Future genetic studies will be directed toward identifying uncommon variations with potentially greater statistical effects, defining population differences, and more completely accounting for familial transmission of disease.

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Inflammatory Bowel Disease at the Intersection of Autophagy and Immunity: Insights from Human Genetics

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