Autoantibodies in Autoimmune Liver Disease—Clinical and Diagnostic Relevance

Sebode, Marcial; Weiler‐Normann, Christina; Liwinski, Timur; Schramm, Christoph

doi:10.3389/fimmu.2018.00609

Cited by 112 publications

(161 citation statements)

References 152 publications

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“…PBC is an autoimmune liver disease in which an autoantibody to the pyruvate dehydrogenase complex of mitochondria leads to damage to the bile ducts . This abnormality can be detected in up to 95% of patients with PBC .…”

Section: Pbcmentioning

confidence: 99%

“…Autoimmune liver diseases consist of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis, juvenile autoimmune hepatitis and variant syndromes . Although a growing body of evidence indicates that individuals with particular genetic backgrounds may develop autoimmune liver diseases with accumulating environmental triggers, the pathogenesis behind these conditions is still incompletely elucidated .…”

Section: Introductionmentioning

confidence: 99%

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Unmet needs in autoimmune liver diseases

Chang

Tanaka

Gershwin

2019

J of Digest Diseases

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Section: Pbcmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Unmet needs in autoimmune liver diseases

Chang

Tanaka

Gershwin

2019

J of Digest Diseases

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“…Patients show increased serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), increased γ‐globulin concentrations and usually the generation of autoantibodies with specificities for different liver antigens. Historically, type 1 AIH has been characterized by the presence of anti‐nuclear and/or anti‐smooth muscle autoantibodies, whereas type 1 liver/kidney microsomal (LKM‐1) and/or liver cytosol type 1 autoantibodies have been considered as the hallmark of type 2 AIH . AIH is associated with specific HLA alleles, is more common in females and affects all ages though with a higher occurrence and a more aggressive course of type 2 AIH in children .…”

Section: Introductionmentioning

confidence: 99%

“…In some patients, hepatocellular damage and cholestasis coexist and have developed either simultaneously or consecutively . For example, 14%‐18% of patients with classical AIH show features of cholestatic diseases, designated AIH‐PBC or AIH‐PSC overlap syndrome.…”

Section: Introductionmentioning

confidence: 99%

Effects of adenovirus‐induced hepatocyte damage on chronic bile duct inflammation in a sclerosing cholangitis mouse model

Fuchs

Bayer

Taubert

et al. 2019

Liver International

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Background & Aims: Four major autoimmune diseases target the liver. They develop because of bile duct destruction, leading to chronic cholestasis or result from hepatocyte damage like autoimmune hepatitis (AIH). Interestingly, some patients simultaneously show features of both cholangitis and AIH. Our goal was to mimic such concurrent characteristics in a mouse model that would help deciphering mechanisms possibly involved in an inflammatory crosstalk between cholestatic disease and hepatitis.Methods: Mdr2 −/− mice, which spontaneously develop sclerosing cholangitis because of accumulation of toxic bile salts, were infected with adenovirus (Ad) encoding human Cytochrome P4502D6 (hCYP2D6), the major target autoantigen in type-2 AIH, to trigger hepatocyte injury. Wild type FVB mice were controls. Results:Resulting Ad-Mdr2 −/− mice presented with cholangitis, fibrosis and cellular infiltrations that were higher than in Mdr2 −/− or Ad-FVB mice. Increased levels of antineutrophil cytoplasmic antibodies but similar anti-hCYP2D6 antibody titres were detected in Ad-Mdr2 −/− compared to Mdr2 −/− and Ad-FVB mice respectively. IFNγexpressing hCYP2D6-specific CD4 T cells declined, whereas hCYP2D6-specific CD8 T cells increased in Ad-Mdr2 −/− compared to Ad-FVB mice. The overall T cell balance in Ad-Mdr2 −/− mice was a combination of a type 17 T cell response typically found in Mdr2 −/− mice with a type 1 dominated T cell response characteristic for Ad-FVB mice.Simultaneously, the type 2 T cell compartment was markedly reduced. Conclusions:Experimental hepatitis induction in a mouse with sclerosing cholangitis results in a disorder which represents not simply the sum of the individual characteristics but depicts a more complex entity which urges on further analysis. K E Y W O R D S autoimmune hepatitis, autoimmune liver disease, primary sclerosing cholangitis S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Fuchs S, Bayer M, Taubert R, et al. Effects of adenovirus-induced hepatocyte damage on chronic bile duct inflammation in a sclerosing cholangitis mouse model.

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“…Autoantibodies play an important role in AIH diagnosis, but do not show clinical specificity. They may not be present in several special patients with AIH but can be detected in other autoimmune diseases [16]. As AIH is a systemic disease and the blood sample is much easier to obtain from the human body, identifying new biomarkers in the serum/plasma is an urgent requirement for early clinical diagnosis of AIH.…”

mentioning

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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Autoantibodies in Autoimmune Liver Disease—Clinical and Diagnostic Relevance

Cited by 112 publications

References 152 publications

Unmet needs in autoimmune liver diseases

Unmet needs in autoimmune liver diseases

Effects of adenovirus‐induced hepatocyte damage on chronic bile duct inflammation in a sclerosing cholangitis mouse model

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

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