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. 2017 Nov;66(11):1873-1877.
doi: 10.1136/gutjnl-2017-314249. Epub 2017 Jul 21.

Cholangiocytes and the environment in primary sclerosing cholangitis: where is the link?

Steven P O'Hara  1 , Tom H Karlsen  2   3 , Nicholas F LaRusso  1
Affiliations

Cholangiocytes and the environment in primary sclerosing cholangitis: where is the link?

Steven P O'Hara et al. Gut. 2017 Nov.
No abstract available

Keywords: Cholangiocarcinoma; Dietary Factors; Environmental Health; Epithelial Cells; Primary Sclerosing Cholangitis.

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
Model of cholangiocyte activation. (A) Bile ducts are lined by cholangiocytes, specialised epithelia that under normal physiological conditions modify bile through the transport of water, ions and solutes. Portal myofibroblasts are adjacent to bile duct epithelia within the portal tract and are distinct from hepatic stellate cells which line the hepatic sinusoids; both can differentiate to matrix depositing myofibroblasts under injurious conditions. (B) Cholangiocytes exist in a harsh environment and are exposed to a variety of insults such as microbes, pathogen-associated molecular patterns, danger-associated molecular patterns, xenobiotics and bile acid-induced damage during cholestasis (from a variety of potential mechanisms, eg, oxidative stress). Recognition of these insults, for example, via pathogen recognition receptors or damage-associated molecular pattern receptors, promotes an activated cholangiocyte phenotype characterised by increased proliferation and secretion of profibrotic (eg, connective tissue growth factor) and proinflammatory (eg, interleukin 6 and 8) mediators. In this model, the activated cholangiocyte promotes hepatobiliary repair processes and recruits a variety of innate (eg, macrophages) and professional (eg, T cell) immune cells. On persistent insult, some injured cholangiocytes enter the cellular state of senescence, characterised by withdrawal from the cell cycle, and transition to a hypersecretory proinflammatory state, that is, senescence-associated secretory phenotype. On persistence, such an inflammatory/fibrotic environment will lead to sclerosing cholangitis. Reproduced with permission of Kari C. Toverud.
Figure 2
Figure 2
The gut–liver relationship in primary sclerosing cholangitis (PSC). There is bidirectional relationship between the gut and the liver in terms of delivery of a number of endogenous metabolites and bioactive compounds to the gut (eg, bile acids). Reversely, there is an ongoing delivery of compounds from the intestinal environment via portal blood to the liver. In this bilateral concept, the gut microbiota and the liver comprise an integrated physiological machinery under the influence of endogenous as well as external factors, in which the role of cholangiocytes warrants further attention. Reproduced with permission from Ref. 17.
Figure 3
Figure 3
Genome-wide association study outcomes shown as Manhattan plots. In primary sclerosing cholangitis (PSC) and prototypical autoimmune diseases, there is a strong human leucocyte antigen association (chromosome 6). A similar genetic architecture is also seen in diseases elicited by specific environmental exposures (exemplified by drug-induced liver injury and coeliac disease), this contrasts the situation in diseases where a compound environmental insult is involved, exemplified by Crohn’s disease. The figure shows Manhattan plots with results of genome-wide association studies in (A) PSC, (B) flucloxacillin-induced liver injury, (C) coeliac disease and (D) Crohn’s disease. The X axis shows the chromosomal location, the Y axis the -log10 p values of the association statistics. Panel (B) is reproduced with permission from Ref. 19. Panels (A), (C) and (D) plotted from data in Ref. 20.
Figure 4
Figure 4
A coeliac disease model of primary sclerosing cholangitis (PSC) susceptibility. In coeliac disease, the disease-associated human leucocyte antigen (HLA) variants direct the adaptive immune response to gluten. Exposure to gluten, as well as the resulting gluten-specific adaptive immunity, respectively, is required to maintain autoantibody production and immunopathology in coeliac disease. Such observations challenge the concept that autoimmunity requires immune activation towards self-antigens. It may thus be hypothesized that the strong genetic HLA associations in PSC (and other autoimmune diseases) point to specific causal environmental exposures determined by the HLA/antigen (Ag)/T-cell receptor (TCR) interactions. Within this concept, genetic and environmental factors are co-dependent in disease causation with the implication that genetic risk factors may hold clues as to the identity of pathogenic environmental factors. For further reading, see Ref. 47. Reproduced with permission of Kari C. Toverud.
See this image and copyright information in PMC

References

    1. Lazaridis KN, LaRusso NF. Primary Sclerosing Cholangitis. N Engl J Med 2016;375:1161–70. 10.1056/NEJMra1506330 - DOI - PMC - PubMed
    1. Ji SG, Juran BD, Mucha S, et al. . Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nat Genet 2017;49:269–73. 10.1038/ng.3745 - DOI - PMC - PubMed
    1. Ellinghaus D, Jostins L, Spain SL, et al. . Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat Genet 2016;48:510–8. 10.1038/ng.3528 - DOI - PMC - PubMed
    1. Liu JZ, Hov JR, Folseraas T, et al. . Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat Genet 2013;45:670–5. 10.1038/ng.2616 - DOI - PMC - PubMed
    1. Melum E, Franke A, Schramm C, et al. . Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci. Nat Genet 2011;43:17–19. 10.1038/ng.728 - DOI - PMC - PubMed

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