Pathway paradigms revealed from the genetics of inflammatory bowel disease

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Inflammatory bowel disease (IBD) is a complex genetic disease that is instigated and amplified by the confluence of multiple genetic and environmental variables that perturb the immune- microbiome axis. The challenge of dissecting pathological mechanisms underlying IBD has spawned the development of transformative approaches in human genetics and functional genomics. Here, we describe IBD as a model disease in the context of leveraging human genetics to dissect cellular and molecular pathway interactions that control homeostasis of the mucosal immune system. Finally, we synthesize emerging insights from multiple experimental approaches into pathway paradigms and discuss future prospects for disease subtype classification and therapeutic intervention.

Related collections

Most cited references 89

Record: found
Abstract: found
Article: not found

Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production.

Tatsuya Saitoh, Naonobu Fujita, Myoung Ho Jang … (2008)

Systems for protein degradation are essential for tight control of the inflammatory immune response. Autophagy, a bulk degradation system that delivers cytoplasmic constituents into autolysosomes, controls degradation of long-lived proteins, insoluble protein aggregates and invading microbes, and is suggested to be involved in the regulation of inflammation. However, the mechanism underlying the regulation of inflammatory response by autophagy is poorly understood. Here we show that Atg16L1 (autophagy-related 16-like 1), which is implicated in Crohn's disease, regulates endotoxin-induced inflammasome activation in mice. Atg16L1-deficiency disrupts the recruitment of the Atg12-Atg5 conjugate to the isolation membrane, resulting in a loss of microtubule-associated protein 1 light chain 3 (LC3) conjugation to phosphatidylethanolamine. Consequently, both autophagosome formation and degradation of long-lived proteins are severely impaired in Atg16L1-deficient cells. Following stimulation with lipopolysaccharide, a ligand for Toll-like receptor 4 (refs 8, 9), Atg16L1-deficient macrophages produce high amounts of the inflammatory cytokines IL-1beta and IL-18. In lipopolysaccharide-stimulated macrophages, Atg16L1-deficiency causes Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-dependent activation of caspase-1, leading to increased production of IL-1beta. Mice lacking Atg16L1 in haematopoietic cells are highly susceptible to dextran sulphate sodium-induced acute colitis, which is alleviated by injection of anti-IL-1beta and IL-18 antibodies, indicating the importance of Atg16L1 in the suppression of intestinal inflammation. These results demonstrate that Atg16L1 is an essential component of the autophagic machinery responsible for control of the endotoxin-induced inflammatory immune response.

0 comments Cited 682 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease

Katrina M de Lange, Loukas Moutsianas, James Lee … (2017)

Genetic association studies have identified 215 risk loci for inflammatory bowel disease 1–8, which have revealed fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals, and meta-analyzed with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new loci, three of which contain integrin genes that encode proteins in pathways identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4, ITGB8) and at previously implicated loci (ITGAL, ICAM1). In all four cases, the expression increasing allele also increases disease risk. We also identified likely causal missense variants in the primary immune deficiency gene PLCG2 and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new common variant associations continue to identify genes relevant to therapeutic target identification and prioritization.

0 comments Cited 522 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis

Christopher S. Smillie, Moshe Biton, Jose Ordovas-Montanes … (2019)

Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4+ enterocytes, microfold-like cells, and IL13RA2+IL11+ inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and co-regulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.