Pathogenesis Of Autoimmune Liver Diseases Research Articles

Monocyte subpopulations in children with autoimmune liver disease

BackgroundPatients with autoimmune liver diseases require individualized long-term immunosuppressive therapy, whose discontinuation is possible after complete histological remission and that requires repeated liver biopsy. In view of this, the search for non-invasive markers is essential for patients with autoimmune liver disease. PurposeThe purpose of this research is to assess the possibility of predicting the recurrence of autoimmune liver disease in children. MethodThe biological material used in the study was blood serum from 80 children diagnosed with autoimmune hepatitis and autoimmune sclerosing cholangitis. Patients were divided into four groups according to disease activity and therapeutic approach. ResultsThe percentage of monocyte subpopulations was determined by flow cytometry, and disease activity, inflammation, and fibrosis markers were analyzed to study the relationship and diagnostic value of the parameters studied in detail. The results of the study indicate a significant relationship between disease activity and changes in the distribution of the percentage of monocyte subpopulations in the blood. The percentage of intermediate CD14++/CD16+ monocytes was found to correlate with disease activity, and non-classical CD14lowCD16+ monocytes were found to be of high diagnostic value in the diagnosis of disease relapse. ConclusionsThese findings not only expand the understanding of the pathogenesis of autoimmune liver disease but also point to the prospects of using monocyte subpopulations as potential biomarkers for predicting relapse, contributing to the development of more effective clinical management strategies.

Exploring the Pathogenesis of Autoimmune Liver Diseases from the Heterogeneity of Target Cells.

The incidence of autoimmune liver diseases (ALDs) and research on their pathogenesis are increasing annually. However, except for autoimmune hepatitis, which responds well to immunosuppression, primary biliary cholangitis and primary sclerosing cholangitis are insensitive to immunosuppressive therapy. Besides the known effects of the environment, genetics, and immunity on ALDs, the heterogeneity of target cells provides new insights into their pathogenesis. This review started by exploring the heterogeneity in the development, structures, and functions of hepatocytes and epithelial cells of the small and large bile ducts. For example, cytokeratin (CK) 8 and CK18 are primarily expressed in hepatocytes, while CK7 and CK19 are primarily expressed in intrahepatic cholangiocytes. Additionally, emerging technologies of single-cell RNA sequencing and spatial transcriptomic are being applied to study ALDs. This review offered a new perspective on understanding the pathogenic mechanisms and potential treatment strategies for ALDs.

Serum vitamins and homocysteine levels in autoimmune liver disease: A systematic review and meta-analysis.

Vitamins and homocysteine (Hcy) are involved in liver metabolism and related to the pathogenesis of autoimmune liver disease (AILD), but consensus is lacking. This study aims to systematically summarize relevant evidence to clarify the association of serum vitamins and Hcy levels with AILD. The English and Chinese literature was searched until August 29, 2023. Studies were included if they were observational studies of investigating serum vitamins and Hcy levels in patients with AILD and their healthy comparisons. Quality assessment was performed by using the Newcastle-Ottawa Scale, and a meta-analysis was conducted using ReviewManager 5.3. The protocol was registered in the international prospective register of systematic reviews (PROSPERO), with registration number CRD42023455367. A total of 25 case-control studies comprising 3487 patients (1673 patients and 1814 healthy controls) were included for analysis. There were 548 autoimmune hepatitis (AIH) cases, 1106 primary biliary cholangitis (PBC) cases, and 19 primary sclerosing cholangitis (PSC) cases. We found that serum A and E were decreased in both AIH and PBC/PSC; but vitamin C was reduced only in patients with PBC, not AIH. In addition, decreased content of 25(OH)D3 was found in both AIH and PBC. However, levels of 25(OH)D did not differ between the patients and controls, and were independent of disease types and the country. Only one study that met the inclusion criteria reported vitamin B6, B9, B12, and Hcy changes, and found that vitamin B6 and B9 were significantly decreased in patients with PBC, while serum vitamin B12 and Hcy levels were significantly elevated in them. One eligible study each confirmed a reduction in plasma vitamin K1 and 1,25(OH)2D3 in patients with PBC. Most vitamins are deficient in AILD, so appropriate vitamin supplementation should be necessary. Further studies with larger sample sizes are needed to validate these findings.

Assessment of the possible impact of hepatitis viruses on the development and course of autoimmune liver diseases

Despite the well-studied pathogenesis, the etiology of autoimmune liver disease (AILD) remains unknown. To determine the significance of hepatitis A, B, C and E viruses in the development and progression of AILD. A single-center case-control study included 139 patients with AILD: autoimmune hepatitis - AIH (n=46), primary biliary cholangitis - PBS (n=74), primary sclerosing cholangitis - PSC (n=19). Median age 56 years, IQR 48-65 years. 125 patients - without liver disease - control group (median age 55 years, IQR 46-65 years). Testing of blood serum samples for anti-HAV IgG, anti-HEV IgG, HBsAg, anti-HBc IgG, anti-HCV was carried out by solid-phase ELISA. All patients underwent fibroelastography. Needle liver biopsy - 70 patients: AIH (n=37), PBC (n=28) and PSC (n=5). Ab(IgG) to HAV and HBV were detected in patients with AILD significantly more often than in the control group (74.8% vs 54.4%; p<0.001). An increased risk of developing AILD was established in patients with the presence of antibodies to HAV, HBV and HEV (OR 2.491, CI 95% [1.481-4.190]). The highest risk of developing PBC was found in patients with antibodies to HAV and HBV (OR 3.008, 95% CI [1.633-5.542] and OR 2.515, 95% CI [1.242-5.093]). In patients with severe liver fibrosis (F3-F4 according to METAVIR), antibodies to HAV and HBV were detected significantly more often than in patients with F0-F2 [85% vs 65%; p=0.008]. In our work, we have demonstrated the relationship of past hepatitis A, B, E and AILD, as well as the high risk of developing severe fibrosis in patients with AILD and markers of hepatitis A and B viruses indicates the possible involvement of these viruses in the pathogenesis of AILD.

Animal Models for Autoimmune Hepatitis: Are Current Models Good Enough?

Autoimmune liver diseases like autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and IgG4-related cholangitis are chronic inflammatory diseases of the liver with an autoimmune background. The therapy of autoimmune hepatitis targets the autoreactive immune system and is largely dependent on the use of glucocorticoids and cytostatic drugs. In contrast, the treatment of cholestatic autoimmune liver diseases is restricted to the use of secondary or semi-synthetic bile acids, like ursodeoxycholic acid or obeticholic acid. Although the management of the disease using such drugs works well for the majority of patients, many individuals do not respond to standard therapy. In addition, chronic treatment with glucocorticoids results in well-known side effects. Further, the use of bile acids is a symptomatic therapy that has no direct immunomodulatory effect. Thus, there is still a lot of room for improvement. The use of animal models has facilitated to elucidate the pathogenesis of autoimmune liver diseases and many potential target structures for immunomodulatory therapies have been identified. In this review, we will focus on autoimmune hepatitis for which the first animal models have been established five decades ago, but still a precise treatment for autoimmune hepatitis, as obtainable for other autoimmune diseases such as rheumatoid arthritis or multiple sclerosis has yet to be introduced. Thus, the question arises if our animal models are too far from the patient reality and thus findings from the models cannot be reliably translated to the patient. Several factors might be involved in this discrepancy. There is first and foremost the genetic background and the inbred status of the animals that is different from human patients. Here the use of humanized animals, such as transgenic mice, might reduce some of the differences. However, there are other factors, such as housing conditions, nutrition, and the microbiome that might also play an important role. This review will predominantly focus on the current status of animal models for autoimmune hepatitis and the possible ways to overcome discrepancies between model and patient.

May Previous Hepatitis B Virus Infection Be Involved in Etiology and Pathogenesis of Autoimmune Liver Diseases?

Viral infections, especially with hepatotropic viruses, may trigger autoimmune liver diseases (AILDs) and deteriorate their course. However, association of previous hepatitis B virus (HBV) infection (presence of anti-HBc with or without anti-HBs or HBV DNA in serum) with AILDs is poorly studied so far. The aim of the study was to assess the prevalence of previous hepatitis B virus infection markers and its clinical significance in patients with autoimmune liver diseases. The study was based on the data obtained from 234 consecutive HBsAg-negative patients with AILDs [81 with autoimmune hepatitis (AIH), 122 with primary biliary cholangitis (PBC) and 31 with primary sclerosing cholangitis (PSC)] and 131 subjects of the control group without liver diseases. Blood samples of the enrolled patients were tested for anti-HBc and HBV DNA. Samples of liver tissue were examined by standard morphologic protocol and, in anti-HBc positive subjects, for HBV DNA. We assessed estimated risks of AILDs according to anti-HBc positivity and association of anti-HBc positivity with stage of liver fibrosis. Anti-HBc was detected in 14.5% participants in the control group vs 26.1% (p = 0.016) in patients with AILDs (including 27.1% subjects with PBC (p = 0.021 vs control group), in 29% of PSC and 23.5% in AIH. HBV DNA was detected in three patients with PBC and in one with AIH. Positive anti-HBc test result was associated with higher risk of AILDs-odds ratio (OR) = 2.078 [95% confidence interval (CI) 1.179-3.665], especially in PBC: OR (95% CI) 2.186 (1.165-4.101). Odds of advanced stage of liver fibrosis (F3-F4 by METAVIR) in anti-HBc-positive subjects with PBC were also higher compared to those who had no previous HBV infection: OR (95% CI) 2.614 (1.153-5.926). Significant proportions of patients with AILDs are anti-HBc positive, and some of them have OBI. Among patients with AILDs, anti-HBc-positivity is most widespread in the PBC group and in subjects with advanced stage of liver fibrosis. Our data may support the idea of an important role of previous HBV infection in the etiology and pathogenesis of AILDs (namely PBC).

О роли вирусов гепатита в этиологии и патогенезе аутоиммунных заболеваний печени

О роли вирусов гепатита в этиологии и патогенезе аутоиммунных заболеваний печени

The Effects of Androgens on T Cells: Clues to Female Predominance in Autoimmune Liver Diseases?

The immune system responds differently in women and in men. Generally speaking, adult females show stronger innate and adaptive immune responses than males. This results in lower risk of developing most of the infectious diseases and a better ability to clear viral infection in women (1–5). On the other hand, women are at increased risk of developing autoimmune diseases (AID) such as rheumatoid arthritis, multiple sclerosis (MS), systemic lupus erythematosus (SLE), Sjögren's syndrome, and the autoimmune liver diseases autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) (6). Factors contributing to the female sex bias in autoimmune diseases include environmental exposure, e.g., microbiome, behavior, and genetics including X chromosomal inactivation of genes. Several lines of evidence and clinical observations clearly indicate that sex hormones contribute significantly to disease pathogenesis, and the role of estrogen in autoimmune diseases has been extensively studied. In many of these diseases, including the autoimmune liver diseases, T cells are thought to play an important pathogenetic role. We will use this mini-review to focus on the effects of androgens on T cells and how the two major androgens, testosterone and dihydrotestosterone, potentially contribute to the pathogenesis of autoimmune liver diseases (AILD).

Autoimmune hepatitis associated Hepatitis C virus infection treated with fi rst generation direct-acting antivirals

The hepatitis C virus (HCV) infection has been associated with autoimmune diseases, probably due to the interaction between HCV E2 envelope protein and CD-81 receptor of B lymphocyte and thus, can infl uence the pathogenesis of autoimmune liver diseases [1,2]. Therefore, it seems reasonable to consider the benefi cial effect of direct-acting antivirals (DAAs) for HCV in patients with chronic HCV infection and autoimmune hepatitis (HAI), although evidence is scarce.

THU-019-Impact of metabolic stress on the pathogenesis of autoimmune liver disease in subjects bearing missense variant of negative immune regulator Lnk/Sh2b3

THU-019-Impact of metabolic stress on the pathogenesis of autoimmune liver disease in subjects bearing missense variant of negative immune regulator Lnk/Sh2b3

Dysbiosis of oral microbiota and its association with salivary immunological biomarkers in autoimmune liver disease.

The gut microbiota has recently been recognized to play a role in the pathogenesis of autoimmune liver disease (AILD), mainly primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH). This study aimed to analyze and compare the composition of the oral microbiota of 56 patients with AILD and 15 healthy controls (HCs) and to evaluate its association with salivary immunological biomarkers and gut microbiota. The subjects included 39 patients with PBC and 17 patients with AIH diagnosed at our hospital. The control population comprised 15 matched HCs. Salivary and fecal samples were collected for analysis of the microbiome by terminal restriction fragment length polymorphism of 16S rDNA. Correlations between immunological biomarkers measured by Bio-Plex assay (Bio-Rad) and the oral microbiomes of patients with PBC and AIH were assessed. Patients with AIH showed a significant increase in Veillonella with a concurrent decrease in Streptococcus in the oral microbiota compared with the HCs. Patients with PBC showed significant increases in Eubacterium and Veillonella and a significant decrease in Fusobacterium in the oral microbiota compared with the HCs. Immunological biomarker analysis showed elevated levels of inflammatory cytokines (IL-1β, IFN-γ, TNF-α, IL-8) and immunoglobulin A in the saliva of patients with AILD. The relative abundance of Veillonella was positively correlated with the levels of IL-1β, IL-8 and immunoglobulin A in saliva and the relative abundance of Lactobacillales in feces. Dysbiosis of the oral microbiota is associated with inflammatory responses and reflects changes in the gut microbiota of patients with AILD. Dysbiosis may play an important role in the pathogenesis of AILD.

A molecular marker of disease activity in autoimmune liver diseases with histopathological correlation; FoXp3/RORγt ratio.

Autoimmune liver diseases (AILDs) encompass a group of diseases with variable clinicopathological manifestations. Th17 and Treg cells have roles in the pathogenesis of AILDs with a balance shifted towards a relative increase in activity of the Th17 cells. In this study, the balance between the transcription factors of Treg and Th17 cells (FoXp3 and RORγt) was sought as a molecular marker of disease activity and to highlight the pathogenesis. The peripheral blood samples of 46 treatment-naive patients were collected and RNA was extracted. Real time PCR was performed and the ratio of gene expression was calculated. Histopathology of 18 patients was obtained and the activity score of these biopsies were also corroborated with their respective molecular (FoXp3/RORγt) (FRGT=FoXp3-ROR Gamma T) ratio. The FRGT ratio in healthy individuals was close to 1 and in disease the ratio changed significantly. This ratio (FRGT) was not significantly different in different varieties of AILD or in adult or paediatric form of the disease. However, the ratio remained consistently below 1 (mean 0.3) in acute disease and high (mean 224.7) in chronic or asymptomatic form of the disease (p < 0.001). The histopathological activity score also significantly correlated with the ratio. This signified the relative excess of Th17 (RORγt) in active disease as compared to Treg (FoXp3) and the reverse in chronic form. This ratio can be an important peripheral molecular marker to assess the disease activity without the necessity of performing a liver biopsy.

Oral bacterial load in autoimmune liver diseases: possible role or coincidence?

Background and aims: Several factors seem be involved in the pathogenesis of autoimmune liver disease (ALD), such as bacteria or bacterial components. Some studies highlighted the role of an oral bacterium, P. gingivalis, in the pathogenesis of rheumatoid arthritis and in the induction of NASH. We evaluated if there was a correlation between oral bacteria and some features of ALD.

Chronic inflammatory liver disease in mice expressing a CD28-specific ligand (P4099)

Abstract Inflammation of the normally tolerant liver microenvironment precedes the development of chronic liver disease. Study of the pathogenesis of autoimmune liver diseases, such as autoimmune hepatitis (AIH), has been hampered by a lack of autochthonous chronic animal models. Through our studies of T cell costimulation, we generated transgenic mice expressing a ligand specific for the CD28 receptor, which normally shares ligands with the related inhibitory receptor CTLA-4. The mice spontaneously develop chronic inflammatory liver disease with several pathologies found in AIH, including elevated serum aminotransferases in the context of normal alkaline phosphatase and bilirubin levels, lymphocytic inflammation, focal necrosis, oval cell hyperplasia, and fibrosis. The prevalence of IFN-γ-producing CD8(+) T cells in the livers of transgenic mice suggests a role for autoimmune cytotoxicity in the chronic disease state. The CD28 ligand-specific transgenic mice will facilitate evaluation of CD8(+) T cell function in liver disease pathologies found in AIH.

Cutting Edge: Chronic Inflammatory Liver Disease in Mice Expressing a CD28-Specific Ligand

Inflammation of the normally tolerant liver microenvironment precedes the development of chronic liver disease. Study of the pathogenesis of autoimmune liver diseases, such as autoimmune hepatitis (AIH), has been hampered by a lack of autochthonous chronic animal models. Through our studies of T cell costimulation, we generated transgenic mice expressing a ligand specific for the CD28 receptor, which normally shares ligands with the related inhibitory receptor CTLA-4. The mice spontaneously develop chronic inflammatory liver disease with several pathologies found in AIH, including elevated serum aminotransferases in the context of normal alkaline phosphatase and bilirubin levels, lymphocytic inflammation, focal necrosis, oval cell hyperplasia, and fibrosis. The prevalence of IFN-γ-producing CD8(+) T cells in the livers of transgenic mice suggests a role for autoimmune cytotoxicity in the chronic disease state. The CD28 ligand-specific transgenic mice will facilitate evaluation of CD8(+) T cell function in liver disease pathologies found in AIH.

Activated natural killer T cells producing interferon-gamma elicit promoting activity to murine dendritic cell-based autoimmune hepatic inflammation

As natural killer (NK) T cells play an important role in the development of autoimmune diseases, they should have significant roles for the pathogenesis of autoimmune liver disease. Implication of the NK T cells in the generation of autoimmune-related hepatic inflammation was investigated using a novel mouse model. Immunization of mice with dendritic cells (DCs) loaded with hepatocyte-mimicking hepatocellular carcinoma cells (DC/Hepa1-6) induces cytotoxic T lymphocytes (CTL) capable of killing hepatocytes. Subsequent administration of interleukin (IL)-12, a potent interferon-gamma (IFN-γ) inducer, to the immunized mice generates autoimmune hepatic inflammation (AHI), as reported previously. Upon onset of the AHI response, the number of intrahepatic CD3(+) NK1 · 1(+) NK T cells increased markedly, along with a decrease in the number of splenic NK T cells, augmented expression of CXCR6 on intrahepatic NK T cells and CXCL16 in hepatic tissue, suggesting that NK T cells were recruited into the inflamed liver. The NK T cells were strongly positive for CD69 and produced IFN-γ, but not IL-4. AHI activity was attenuated markedly in CD1d(-/-) NK T cell-deficient mice, indicating that NK T cells play a pivotal role in the development of AHI. Mice treated with DC/Hepa1-6 and alpha-galactosylceramide, a potent NK T cell activator, also exhibited similar hepatic inflammation, in which activated NK T cells producing IFN-γ and CD8(+) T cells cytotoxic to hepatocytes were induced in liver-infiltrating mononuclear cells. Activated NK T cells producing IFN-γ potentiate DC-based AHI in the mouse model.

Dendritic Cells in Autoimmune Liver Diseases

Dendritic cells (DC) are professional antigen presenting cells that maintain immune tolerance to self-antigens by controlling the pathogenicity of autoreactive T cells, and a lack of immune tolerance against self-antigens results in autoimmune diseases. Therefore, DCs play an essential role in the induction and/or maintenance of autoimmunity. In the present review, we focus on the role of DCs in the pathogenesis of autoimmune liver diseases. In addition, recent developments in DC-based immunotherapy using regulatory (tolerogenic) DCs in autoimmune diseases will be discussed. Keywords: Autoimmune liver disease, dendritic cells, tolerance, antigen presenting cells, autoimmune diseases, immunotherapy, autoimmune hepatitis, biliary cirrhosis, IgG4-Related Sclerosing Cholangitis, Regulatory dendritic cells

Natural killer cells take two tolls to destruct bile ducts

Pit cells were first described by Wisse et al.1 in 1976. Later, Kaneda et al.2 referred to this cell type as “natural killer (NK) cells” due to their resemblance to large granular lymphocytes that are known to possess NK cell activity. In 1984, Kaneda et al.3 also observed that in autoimmune hepatitis, these pit cells (now known as liver-specific NK cells) were frequently seen in close contact with hepatocytes that eventually showed degenerative or immature features, providing the first evidence that NK cells may contribute to hepatocellular damage in autoimmune hepatitis. Although more than 2 decades have since passed and the accumulating evidence indicates that NK cells are involved in the pathogenesis of many types of human autoimmune diseases,4 little is known about the role of NK cells in autoimmune liver disease specifically. To date, there are several studies reporting that NK cell functions are dysregulated in autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis (PBC). These data show that in patients with PBC, there was increased cell-killing activity and decreased cytokine production in NK cells5 and that there appeared to be a genetic link between NK cell receptor ligand expression and susceptibility to primary sclerosing cholangitis.6 However, the mechanism by which NK cells are activated and contribute to the pathogenesis of autoimmune liver disease was largely unknown until Shimoda et al.7 published their recent data in this issue of Hepatology.

Enzymes as Target Antigens of Liver-Specific Autoimmunity: The Case of Cytochromes P450s

Characterization of liver-specific autoantigens has given a fresh impetus to research in the pathogenesis of autoimmune liver diseases, viral-triggered and drug-induced autoimmunity affecting the liver. Intriguing is the fact that most of the liver-specific autoantigens are enzymes of key importance for cell's homeostasis. Detection of autoantibodies against the respective antigens is carried out for diagnostic and research purposes using indirect immunofluorescence, immunoblotting, enzyme-linked immunosorbent assays, radioimmunoassay, immunoprecipitation or assays determining inhibition of enzyme activity. In patients with autoimmune hepatitis, a liver disorder of unknown etiology and pathogenesis, disease-specific autoantibodies are frequently directed against drug metabolizing enzymes of phase 1, namely cytochrome P450 2D6 (CYP2D6). The same and other members of these families of enzymes (CYPs) have also been described as targets of liver-specific autoimmunity in chronic hepatitis C virus (HCV)-infected patients, patients with autoimmune hepatitis as part of the autoimmune polyglandular syndrome type-1 (APS-1) and drug-induced autoimmunity. How these enzymes become 'self targets' is not yet established. An antigen release following hepatocyte injury could provide the stimulus for an immune response towards epitopes on these enzymes but the highly-specific, antigen-restricted initiation of the observed autoimmune response is against such an explanation. Accordingly, in this review we will focus on the pathogenic role -if any- of autoimmune responses against liver-related CYPs in autoimmune hepatitis, HCV infection, APS-1 and drug-induced autoimmunity. Learning more about the specificity of antibody responses against these enzymes may help us better understand the mechanisms underlying liver autoimmunity and may facilitate the development of therapeutic and preventive interventions.

Differential priming of CD8 and CD4 T-cells in animal models of autoimmune hepatitis and cholangitis

The pathogenesis of autoimmune liver diseases is poorly understood. Animal models are necessary to investigate antigen presentation and priming of T-cells in the context of autoimmunity in the liver. Transgenic mouse models were generated in which the model antigen ovalbumin is expressed in hepatocytes (TF-OVA) or cholangiocytes (ASBT-OVA). Transgenic OT-I (CD8) or OT-II (CD4) T-cells specific for ovalbumin were adoptively transferred into TF-OVA and ASBT-OVA mice to induce in vivo priming of antigen-specific T-cells. T-cell migration and activation, as well as induction of liver inflammation, were studied. OT-I T-cells preferentially located to the liver of both mouse strains whereas no migration of OT-II T-cells to the liver was observed. OT-I T-cells proliferated in the liver of TF-OVA mice and the liver and liver draining lymph nodes of ASBT-OVA mice. OT-II CD4 T-cells were activated in spleen and liver draining lymph node of TF-OVA mice but not in ASBT-OVA mice. Transfer of OT-I T-cells led to histologically distinct inflammatory conditions in the liver of ASBT-OVA and TF-OVA mice and caused liver injury as determined by the elevation of serum alanine aminotransferase. An antigen expressed in hepatocytes is presented to CD8 and CD4 T-cells, whereas the same antigen expressed in cholangiocytes is presented to CD8 but not CD4 T-cells. In both models, activation of CD8 T-cells occurs within the liver and causes liver inflammation. The models presented here are valuable to investigate the priming of T-cells in the liver and their role in the development of autoimmune disease of the liver.