Why Doesn’t Primary Biliary Cholangitis Respond to Immunosuppressive Medications?

Molinaro, Antonio; Marschall, Hanns‐Ulrich

doi:10.1007/s11901-017-0345-y

Cited by 16 publications

(13 citation statements)

References 64 publications

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“…45 In a context of reduced liver AE2 expression and AE2 deficiency, there may occur defective bicarbonate umbrella and subsequent entry of protonated bile salts into cholangiocytes (concisely and nicely reviewed in ref. 12 ). Entry of highly hydrophobic bile salts can promote reactive oxygen species (ROS) production, and lead to enhanced inflammatory cytokine and chemokine responses.…”

Section: Discussionmentioning

confidence: 99%

“…Notwithstanding these features of autoimmunity in PBC, the therapeutic regimes with potent immunosuppressants have shown little efficacy, which is particularly intriguing if compared with the substantial benefit obtained in most patients with early PBC undergoing therapy with ursodeoxycholic acid (UDCA). [12][13][14][15][16] Since the hydrophilic bile acid UDCA is known to induce bicarbonate-rich choleresis, we have been postulating that primary or secondary abnormalities in the mechanisms responsible for biliary bicarbonate secretion might have a pathogenic role in PBC. [17][18][19][20][21] Indeed, positron-emission-tomography studies showed that untreated patients with PBC failed to increase biliary bicarbonate in response to secretin, while treatment with UDCA for a few months could reverse this defect.…”

Section: Introductionmentioning

confidence: 99%

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Promoter hypermethylation of the AE2/SLC4A2 gene in PBC

et al. 2019

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Graphical abstract Highlights• Patients with PBC have higher AE2 CpG methylation in upstream AE2a and/or AE2b2/AE2b1 promoter regions in liver and PBMCs.Background & Aims: Patients with primary biliary cholangitis (PBC) exhibit reduced AE2/SLC4A2 gene expression in the liver and peripheral blood mononuclear cells (PBMCs). AE2 encodes a Cl -/HCO 3 exchanger involved in biliary bicarbonate secretion and intracellular pH regulation. Reduced AE2 expression in PBC may be pathogenic, as Ae2-knockout mice reproduce characteristic PBC features. Herein, we aimed to identify CpG-methylation abnormalities in AE2 promoter regions that might contribute to the reduced gene transcription in PBC livers and PBMCs.Methods: CpG-cytosine methylation rates were interrogated at 1-base pair resolution in upstream and alternate AE2 promoter regions through pyrosequencing of bisulphite-modified genomic DNA from liver specimens and PBMCs. AE2a and alternative AE2b1 and AE2b2 mRNA levels were measured by real-time PCR. Human lymphoblastoid-T2 cells were treated with 5-aza-2´deoxycytidine for demethylation assays.Results: AE2 promoters were found to be hypermethylated in PBC livers compared to normal and diseased liver specimens.Receiver operating characteristic (ROC) curve analysis showed that minimal CpG-hypermethylation clusters of 3 AE2a-CpG sites and 4 alternate-AE2b2-CpG sites specifically differentiated PBC from normal and diseased controls, with mean methylation rates inversely correlating with respective transcript levels. Additionally, in PBMCs a minimal cluster of 3 hypermethylated AE2a-CpG sites distinguished PBC from controls, and mean methylation rates correlated negatively with AE2a mRNA levels in these immune cells. Alternate AE2b2/AE2b1 promoters in PBMCs were constitutively hypermethylated, in line with absent alternative mRNA expression in diseased and healthy PBMCs. Demethylation assays treating lymphoblastoid-T2 cells with 5aza-2´-deoxycytidine triggered AE2b2/AE2b1 expression and upregulated AE2a-promoter expression.Conclusions: Disease-specific hypermethylation of AE2 promoter regions and subsequent downregulation of AE2-gene expression in the liver and PBMCs of patients with PBC might be critically involved in the pathogenesis of this complex disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Promoter hypermethylation of the AE2/SLC4A2 gene in PBC

et al. 2019

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“…Patients without AMA can develop PBC, whereas a proportion of patients with AMA do not [10]. Furthermore, immunosuppression has proven to be of little utility for PBC patients, whereas bile modulation therapy with ursodeoxycholic acid and more recently with the potent FXR receptor agonist obeticholic acid, have become the standard of care [11]. Nevertheless, the common perception remains that PBC patients have autoimmune destruction of bile ducts [8] but this assumption is prevalent (and rarely challenged) even though pertinent validation is lacking.…”

Section: Primary Biliary Cholangitismentioning

confidence: 99%

Modelling Recurrent Primary Biliary Cholangitis and Primary Sclerosing Cholangitis as Infectious Diseases Following Liver Transplantation

Dong¹,

Montaño-Loza²,

Mason³

2019

obm transplant

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Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are idiopathic and progressive autoimmune hepatobiliary disorders that lead to liver failure and a need for liver transplantation in a proportion of individuals with poorly controlled disease. It is currently thought that an environmental agent triggers disease in a genetically susceptible host and to date, xenobiotics, bacteria and a human betaretrovirus have all been linked with PBC. However, there is no consensus on which agents predominates. These disease processes are poorly understood and there are disparate hypotheses concerning the pathogenesis. One theory suggests that the disease is mediated by autoimmunity, whereas others have speculated that they are infectious disease processes that only manifest in individuals with diminished immunity. Clinically, the triggers of disease are difficult to study because of the indolent onset and chronic nature of the disorders. Notably, observations from liver transplantation provide a unique insight into the development of PBC and PSC. Both biliary disorders may reoccur in up to 30%-50% of patients following liver transplantation and many of the factors that influence recurrence have been well described. Prior to transplantation, immunosuppression is not routinely used to treat PBC and PSC because specific treatments have not been shown to have utility or have caused undue side effects. Following

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“…ACA recognize six centromere polypeptides belonging to the kinetochore proteins: Therapy PBC treatment is currently based on UDCA, which is the only approved drug. Its mechanism of action is incompletely understood and possibly dependent on the various phases of the disease 5,92 .…”

Section: Association With Rheumatic Diseasesmentioning

confidence: 99%

Rheumatic Manifestations in Autoimmune Liver Disease

Selmi

Generali

Gershwin

2018

Rheumatic Disease Clinics of North America

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Autoimmune liver diseases coexist with rheumatic disorders in approximately 30% of cases and may also share pathogenic mechanisms. Autoimmune liver diseases result from an immune-mediated injury of different tissues, with autoimmune hepatitis (AIH) targeting hepatocytes, and primary biliary cholangitis (PBC) and primary sclerosing cholangitis targeting cholangiocytes. Sjogren syndrome is diagnosed in 7% of AIH cases and serologic autoimmunity profiles are a common laboratory abnormality, particularly in the case of serum antimitochondrial (PBC) or anti-liver kidney microsomal antibodies (AIH). Therapeutic strategies may overlap between rheumatic and autoimmune liver diseases and practitioners should be vigilant in managing bone loss.

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Why Doesn’t Primary Biliary Cholangitis Respond to Immunosuppressive Medications?

Cited by 16 publications

References 64 publications

Promoter hypermethylation of the AE2/SLC4A2 gene in PBC

Promoter hypermethylation of the AE2/SLC4A2 gene in PBC

Modelling Recurrent Primary Biliary Cholangitis and Primary Sclerosing Cholangitis as Infectious Diseases Following Liver Transplantation

Rheumatic Manifestations in Autoimmune Liver Disease

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