Making Sense of Autoantibodies in Cholestatic Liver Diseases

Marzorati, Simona; Invernizzi, Pietro; Lleo, Ana

doi:10.1016/j.cld.2015.08.003

Cited by 25 publications

(11 citation statements)

References 93 publications

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“…PBC is characterised serologically by autoantibodies specific for mitochondrial, nuclear and centromere antigens, some of which are unique to PBC. 66–78 They are present in ~95% (mitochondrial) and ~30% (nuclear) of patients. Unlike in many other autoimmune diseases, these autoantibodies are, as a result of their sensitivity and specificity, extremely useful in diagnosis and have contributed significantly to the decline in the need for liver biopsy, at least for the purposes of diagnosis.…”

Section: How Is Pbc Diagnosed?mentioning

confidence: 99%

The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines

Hirschfield

Dyson

Alexander

et al. 2018

Gut

269

293

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Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset (<45) and advanced disease at presentation are baseline predictors of poorer outcome. As the disease is increasingly diagnosed through the combination of cholestatic serum liver tests and the presence of antimitochondrial antibodies, most presenting patients are not cirrhotic and the term cholangitis is more accurate. Disease course is frequently accompanied by symptoms that can be burdensome for patients, and management of patients with PBC must address, in a life-long manner, both disease progression and symptom burden. Licensed therapies include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), alongside experimental new and re-purposed agents. Disease management focuses on initiation of UDCA for all patients and risk stratification based on baseline and on-treatment factors, including in particular the response to treatment. Those intolerant of treatment with UDCA or those with high-risk disease as evidenced by UDCA treatment failure (frequently reflected in trial and clinical practice as an alkaline phosphatase >1.67 × upper limit of normal and/or elevated bilirubin) should be considered for second-line therapy, of which OCA is the only currently licensed National Institute for Health and Care Excellence recommended agent. Follow-up of patients is life-long and must address treatment of the disease and management of associated symptoms.

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Section: How Is Pbc Diagnosed?mentioning

confidence: 99%

The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines

Hirschfield

Dyson

Alexander

et al. 2018

Gut

269

293

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“…This provides indirect evidence of the role of the microbiota and abnormal antibody responses to commensal bacteria in disease pathogenesis. 66,67 Furthermore, ANCA detected in bile (IgG isotype) was associated with a 10-fold risk of having PSC and positively correlated with presence of dominant strictures, cholangiographic severity, and number of interventions performed. 68 This suggests that ANCA may be directly pathogenic; however, mechanistic studies have not been performed to verify this.…”

Section: Primary Sclerosing Cholangitismentioning

confidence: 99%

The Contribution of B Cells in Autoimmune Liver Diseases

Taylor

Mack

2019

Semin Liver Dis

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Autoreactive B cells can promote autoimmunity through antigen presentation to autoreactive T cells, production of autoantibodies, generation of cytokines promoting T cell activation and differentiation, and inhibition of regulatory T cells and B cells. Here, the authors highlight studies pertaining to B cell mechanisms associated with disease pathogenesis and outcomes in autoimmune hepatitis and the immune-mediated cholangiopathies (primary biliary cholangitis, primary sclerosing cholangitis, and biliary atresia). The vast majority of investigations focus on autoantibodies and future research endeavors should include deciphering the role of the B cell in T cell activation (through antigen presentation, cytokine/chemokine production, and inhibition of regulation). Targeting B cell mechanisms in the treatment of autoimmune liver diseases is also highlighted.

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“…The detection of autoantibodies such as anti-LKM-1, anti-ANA, and anti-SMA, is an important component of AIH diagnostic criteria developed by IAIHG [15]. However, these autoantibodies are not specific for AIH and can also be detected in many other autoimmune liver diseases, such as primary biliary cirrhosis, primary sclerosing cholangitis [31], and viral hepatitis [32]. Therefore, identifying new biomarkers that are specific to the diagnosis of AIH is crucial.…”

Section: Discussionmentioning

confidence: 99%

Plasma proteomic analysis of autoimmune hepatitis in an improved AIH mouse model

et al. 2020

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Background: The prevalence of autoimmune hepatitis (AIH) is increasing, and its early clinical diagnosis is difficult. The pathogenesis of AIH remains unclear, and AIH-related studies are largely limited because of lack of suitable mouse models. Methods: To obtain a good tool for research on AIH, we first established an improved immune-mediated mouse model that can mimic the pathological process of AIH as in the human body, through repeated injections of human cytochrome P450 2D6 (CYP2D6) plasmid. Next, a proteomic analysis based on isobaric tag (IBT) technology was performed to detect the differentially expressed proteins (DEPs), and related biological functions and pathways in the plasma of AIH and normal mice. Finally, we performed enzyme-linked immunosorbent assay (ELISA) to further confirm the most abundant DEP in the plasma of patients with AIH. Results: Autoantibodies and the characteristic pathology of AIH were observed in our mouse model. Inflammatory infiltration also increased in the livers of AIH mice over time and plateaued by day 42 post the first injection. Chronic hepatitis was most severe on day 35 with the development of fibrosis as well, and the plasma of AIH mice were collected for proteomic analysis. A total of 176 DEPs were found in this experiment, of which 148 DEPs were up-regulated and 28 DEPs were down-regulated. Thirty significant Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways (P < 0.05) were detected. Arginine biosynthesis was found to be the most significant pathway involved in the AIH process. During the Gene Ontology (GO) analysis, most DEPs were found to be involved in the binding, cellular, and metabolic processes. Using ELISA, the most overexpressed DEP, serum amyloid A 1 (SAA1), was confirmed to be increased specifically in the plasma of patients with AIH compared to other chronic hepatitis. Different plasma levels of SAA1 were also found related to different grades of inflammation and stages of fibrosis in the liver of patients with AIH. Conclusions: Our study is the first to describe the proteomics analysis of a true sense of AIH mouse model, which is beneficial for a better understanding of AIH pathogenesis and identifying potential biomarkers for its clinical diagnosis.

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Making Sense of Autoantibodies in Cholestatic Liver Diseases

Cited by 25 publications

References 93 publications

The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines

The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines

The Contribution of B Cells in Autoimmune Liver Diseases

Plasma proteomic analysis of autoimmune hepatitis in an improved AIH mouse model

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