The immunobiology of primary sclerosing cholangitis

Aoki, Christopher A.; Bowlus, Christopher L.; Gershwin, M. Eric

doi:10.1016/j.autrev.2004.09.003

Cited by 75 publications

(56 citation statements)

References 122 publications

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“…To gain preliminary insights into the expression of the AID gene in human bile duct epithelium, expression of AID mRNA transcripts was first analyzed by RT-PCR in several cholangiocarcinoma-derived cells in the absence or presence of TNF-␣, a proinflammatory cytokine that plays a central role in the pathogenesis of human sclerosing cholangitis. [17][18][19] We found that endogenous AID mRNA expression was enhanced by TNF-␣ stimulation in RBE and SSP-25 cells, whereas only small amounts were detectable in the quiescent cells (Fig. 1A).…”

Section: Resultsmentioning

confidence: 87%

Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma

et al. 2008

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Chronic inflammation plays a critical role in oncogenesis in various human organs. Epidemiological studies have demonstrated that patients with primary sclerosing cholangitis have a predisposition to develop cholangiocarcinoma (CC). However, the molecular mechanisms that account for the development of bile duct carcinomas are not well defined. We recently provided evidence that activation-induced cytidine deaminase (AID), a member of the DNA/ RNA editing enzyme family, is implicated in human tumorigenesis via its mutagenic activity. We found here that ectopic AID production is induced in response to tumor necrosis factor-␣ ( C holangiocarcinoma (CC) is an epithelial neoplasm that originates from the bile duct and can occur at any level of the biliary tree. 1,2 The incidence CC is increasing worldwide; it is the second most common primary hepatobiliary malignancy. 2 Although most CC arise in the absence of apparent risk factors, chronic inflammation of the biliary epithelium plays a critical role for their development. 2 In fact, primary sclerosing cholangitis (PSC) is the commonest predisposing condition for cholangiocarcinogenesis, and the prevalence of CC in patients with PSC ranges from 9% to 23%, with a cumulative annual risk of 1.5% per year of the disease. 1 Other risk factors for cholangiocarcinogenesis are also associated with chronic biliary tract inflammation, including chronic choledocholithiasis, liver fluke infestation, hepatolithiasis, Caroli's disease, and hepatitis C viral infection. 1 It has been hypothesized that the increased risk of CC in these conditions occurs because of chronic epithelial inflammation leading to cell proliferation, along with enhanced production of endogenous mutagens in the bile. 1 However, the precise molecular mechanism that accounts for the development of CC on the basis of chronic biliary tract inflammation remains unsolved.

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Section: Resultsmentioning

confidence: 87%

Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma

et al. 2008

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“…We studied two diseases targeted to bile ducts, PBC and PSC. Autoimmune and infectious etiologies have been proposed for both conditions but no definitive pathogenic mechanism has been reported for either disease (49,50). Both diseases are characterized by chronic inflammation focused on the biliary epithelium and both show a slow progression to fibrosis and cirrhosis.…”

Section: Discussionmentioning

confidence: 99%

Epithelial Inflammation Is Associated with CCL28 Production and the Recruitment of Regulatory T Cells Expressing CCR10

Eksteen

Miles

Curbishley

et al. 2006

The Journal of Immunology

158

143

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Mucosal tissues require constant immune surveillance to clear harmful pathogens while maintaining tolerance to self Ags. Regulatory T cells (Tregs) play a central role in this process and expression of αEβ7 has been reported to define a subset of Tregs with tropism for inflamed tissues. However, the signals responsible for recruiting Tregs to epithelial surfaces are poorly understood. We have isolated a subset of CCR10-expressing CD25+CD4+Foxp3+ Tregs with potent anti-inflammatory properties from chronically inflamed human liver. The CCR10+ Tregs were detected around bile ducts that expressed increased levels of the CCR10 ligand CCL28. CCL28 was secreted by primary human cholangiocytes in vitro in response to LPS, IL-1β, or bile acids. Exposure of CCR10+ Tregs to CCL28 in vitro stimulated migration and adhesion to mucosal addressin cell adhesion molecule-1 and VCAM-1. Liver-derived CCR10+ Tregs expressed low levels of CCR7 but high levels of CXCR3, a chemokine receptor associated with infiltration into inflamed tissue and contained a subset of αEβ7+ cells. We propose that CXCR3 promotes the recruitment of Tregs to inflamed tissues and CCR10 allows them to respond to CCL28 secreted by epithelial cells resulting in the accumulation of CCR10+ Tregs at mucosal surfaces.

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“…However, in contrast to other autoimmune diseases, PSC is more frequently encountered in male subjects, and it does not respond to immunosuppressive therapy (O'Mahony & Vierling, 2006). One hypothesis that aims to explain the increased incidence of PSC in IBD patients postulates that the transportation of bacterial endotoxins from the inflamed colonic mucosa to the liver via the portal circulation stimulates the Kupffer cells (Fausa et al, 1991;Aoki et al, 2005). However, another study showed that there is no evidence of altered intestinal permeability or bacterial overgrowth in PSC patients (Björnsson et al,2000).…”

Section: Pathogenesismentioning

confidence: 99%

Inflammatory Bowel Disease and Primary Sclerosing Cholangitis

Erkan¹

2011

Ulcerative Colitis - Epidemiology, Pathogenesis and Complications

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The immunobiology of primary sclerosing cholangitis

Cited by 75 publications

References 122 publications

Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma

Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma

Epithelial Inflammation Is Associated with CCL28 Production and the Recruitment of Regulatory T Cells Expressing CCR10

Inflammatory Bowel Disease and Primary Sclerosing Cholangitis

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