Immunohistochemical analysis of inflammation in primary sclerosing cholangitis

Ponsioen, Cyriel Y.; Kuiper, Hilde; Kate, Fiebo J. ten; Wit, Marc van Milligen de; Deventer, Sander J. van; Tytgat, G. N. J.

doi:10.1097/00042737-199907000-00015

Cited by 61 publications

(38 citation statements)

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“…Several immune‐mediated diseases share some of the genetic risk factors, demonstrating an immunologic component to be involved in PSC development. Immunohistochemical studies demonstrated a mixed inflammatory cell infiltrate predominantly consisting of T cells, natural killer cells, and macrophages . Several studies suggested that T cells are the major infiltrating cells in PSC; however, conflicting findings have been reported on the CD4+ or CD8+ T cells being the prevalent subset .…”

Section: Discussionmentioning

confidence: 99%

The ectonucleotidase ENTPD1/CD39 limits biliary injury and fibrosis in mouse models of sclerosing cholangitis

Peng

Rothweiler

Wei

et al. 2017

Hepatology Communications

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The pathogenesis of primary sclerosing cholangitis (PSC) and the mechanistic link to inflammatory bowel disease remain ill‐defined. Ectonucleoside triphosphate diphosphohydrolase‐1 (ENTPD1)/clusters of differentiation (CD) 39, the dominant purinergic ecto‐enzyme, modulates intestinal inflammation. Here, we have explored the role of CD39 in biliary injury and fibrosis. The impact of CD39 deletion on disease severity was studied in multidrug resistance protein 2 (Mdr2)–/– and 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine mouse models of sclerosing cholangitis and biliary fibrosis. Antibody‐mediated CD8+ T‐cell depletion, selective gut decontamination, experimental colitis, and administration of stable adenosine triphosphate (ATP) agonist were performed. Retinoic acid‐induced gut imprinting on T cells was studied in vitro. Over half of Mdr2–/–;CD39–/– double mutants, expected by Mendelian genetics, died in utero. Compared to Mdr2–/–;CD39+/+, surviving Mdr2–/–;CD39–/– mice demonstrated exacerbated liver injury, fibrosis, and ductular reaction. CD39 deficiency led to a selective increase in hepatic CD8+ T cells and integrin α4β7, a T‐cell gut‐tropism receptor. CD8+ cell depletion in Mdr2–/–;CD39–/– mice diminished hepatobiliary injury and fibrosis. Treatment with antibiotics attenuated, whereas dextran sulfate sodium‐induced colitis exacerbated, liver fibrosis in Mdr2–/– mice. Colonic administration of αβ‐ATP into CD39‐sufficient Mdr2–/– mice triggered hepatic CD8+ cell influx and recapitulated the severe phenotype observed in Mdr2–/–;CD39–/– mice. In vitro, addition of ATP promoted the retinoic acid‐induced imprinting of gut‐homing integrin α4β7 on naive CD8+ cells. CD39 expression was relatively low in human normal or PSC livers but abundantly present on immune cells of the colon and further up‐regulated in samples of patients with inflammatory bowel disease. Conclusion: CD39 deletion promotes biliary injury and fibrosis through gut‐imprinted CD8+ T cells. Pharmacological modulation of purinergic signaling may represent a promising approach for the treatment of PSC. (Hepatology Communications 2017;1:957–972)

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Section: Discussionmentioning

confidence: 99%

The ectonucleotidase ENTPD1/CD39 limits biliary injury and fibrosis in mouse models of sclerosing cholangitis

Peng

Rothweiler

Wei

et al. 2017

Hepatology Communications

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“…On one side, there are several lines of evidence supporting classification of PSC as an autoimmune disease [10] . This evidence includes (1) association with other autoimmune diseases in the same individual [11] and first degree relatives [12] , (2) infiltration of T-lymphocytes in the portal tracts [13] with restriction in T cell receptor V gene usage [14] , (3) a statistical association with particular human leukocyte antigen (HLA) haplotypes [15] and (4) the presence of autoantibodies [16] . On the other side, there is no documented effect of immunosuppressants in PSC [2] , and in contrast to the female predominance of many diseases regarded as autoimmune, approximately 2/3 of PSC patients are male [17] .…”

Section: Introductionmentioning

confidence: 99%

Autoantibodies in primary sclerosing cholangitis

Hov¹,

Boberg²,

Karlsen³

2008

WJG

144

107

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The aetiology of primary sclerosing cholangitis (PSC) is not known and controversy exists as to whether PSC should be denominated an autoimmune disease. A large number of autoantibodies have been detected in PSC patients, but the specificity of these antibodies is generally low, and the frequencies vary largely between different studies. The presence of autoantibodies in PSC may be the result of a nonspecific dysregulation of the immune system, but the literature in PSC points to the possible presence of specific antibody targets in the biliary epithelium and in neutrophil granulocytes. The present review aims to give an overview of the studies of autoantibodies in PSC, with a particular emphasis on the prevalence, clinical relevance and possible pathogenetic importance of each individual marker.

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“…Since PSC develops predominantly in patients with IBD and may arise long after colectomy, it was suggested that long‐lived immune cells migrating from the gut to the liver play a role. Indeed, T cells displaying the gut‐homing phenotype characterized by expression of integrin α4β7 and CCR9 are found in livers of patients with PSC but not other liver diseases. Liver antigen‐presenting cells (APCs) lack the capability to inscribe this phenotype in T cells, since this mechanism requires retinoic acid and is specifically located in the gut‐associated lymphoid tissue (GALT) .…”

mentioning

confidence: 99%

CD8 T cells primed in the gut-associated lymphoid tissue induce immune-mediated cholangitis in mice

et al. 2013

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The pathogenesis of primary sclerosing cholangitis (PSC) remains poorly understood. Since PSC predominantly occurs in patients with inflammatory bowel disease, autoimmunity triggered by activated T cells migrating from the gut to the liver is a possible mechanism. We hypothesized that T cells primed in the gut‐associated lymphoid tissue (GALT) by a specific antigen migrate to the liver and cause cholangitis when they recognize the same antigen on cholangiocytes. We induced ovalbumin‐dependent colitis in mice that express ovalbumin in biliary epithelia (ASBT‐OVA mice) and crossed ASBT‐OVA mice with mice that express ovalbumin in enterocytes (iFABP‐OVA mice). We analyzed T‐cell activation in the GALT and crossreactivity to the same antigen in the liver as well as the effects of colitis per se on antigen‐presentation and T‐cell activation in the liver. Intrarectal application of ovalbumin followed by transfer of CD8 OT‐I T cells led to antigen‐dependent colitis. CD8 T cells primed in the GALT acquired effector function and the capability to migrate to the liver, where they caused cholangitis in a strictly antigen‐dependent manner. Likewise, cholangitis developed in mice expressing ovalbumin simultaneously in biliary epithelia and enterocytes after transfer of OT‐I T cells. Dextran sodium sulfate colitis led to increased levels of inflammatory cytokines in the portal venous blood, induced activation of resident liver dendritic cells, and promoted the induction of T‐cell‐dependent cholangitis. Conclusion: Our data strengthen the notion that immune‐mediated cholangitis is caused by T cells primed in the GALT and provide the first link between colitis and cholangitis in an antigen‐dependent mouse model. (Hepatology 2014;59:601–611)

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Immunohistochemical analysis of inflammation in primary sclerosing cholangitis

Cited by 61 publications

References 0 publications

The ectonucleotidase ENTPD1/CD39 limits biliary injury and fibrosis in mouse models of sclerosing cholangitis

The ectonucleotidase ENTPD1/CD39 limits biliary injury and fibrosis in mouse models of sclerosing cholangitis

Autoantibodies in primary sclerosing cholangitis

CD8 T cells primed in the gut-associated lymphoid tissue induce immune-mediated cholangitis in mice

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