Autoimmune Liver Disease Research Articles

Research on gut microbiota characteristics of PBC patients at different ALBI grades based on machine learning

BackgroundThe Albumin-Bilirubin (ALBI) score and grade are widely used to stratify patients with primary biliary cholangitis (PBC) into different disease statuses and risk levels. Recent studies have increasingly highlighted the role of gut microbiota in autoimmune liver diseases. This study aimed to investigate the differences in gut microbiota among PBC patients with varying ALBI grades.MethodsClinical data and stool samples were collected from outpatient and inpatient PBC patients between 2019 and 2022. Gut microbiota profiles were obtained using 16S rDNA sequencing of stool samples. We analyzed alpha diversity, beta diversity, LEfSe analysis and pathway function prediction. Additionally, various machine learning methods—including random forest (RF), lasso, gradient boosting machine (GBM) and support vector machine (SVM)—were employed to identify key features and to build and validate predictive models using bootstrap techniques.ResultsClinical characteristics of ALBI grade 1 patients were comparatively better than those of ALBI grade 2 and 3 patients, including multiple laboratory indices. Gut microbiota analysis revealed that species richness and balance were higher in ALBI grade 1 patients. Both the comparison of the most abundant genera and the linear discriminant analysis (LDA) in LEfSe demonstrated that Lachnospira had a higher abundance and better discriminative ability in ALBI grade 1. Pathway function prediction indicated that sulfur metabolism was upregulated in higher ALBI grades. Furthermore, RF identified 10 specific genera, which were then used to build and validate models for discriminating PBC patients according to their ALBI grades. All three models, developed using different machine learning methods, demonstrated good discrimination ability (mean AUC 0.75–0.80).ConclusionThis study highlights significant differences in gut microbiota profiles among PBC patients with different ALBI grades. The increased abundance of Lachnospira and upregulation of sulfur metabolism pathways are notable in patients with lower ALBI grades. The machine learning models developed based on gut microbiota features offer promising tools for discriminating between PBC patients with varying disease severities, which could enhance the precision of treatment strategies.

Obesity and risk for liver disease: a two-sample Mendelian randomisation study.

The associations between obesity and liver diseases are complex and diverse. To explore the causal relationships between obesity and liver diseases, we applied two-sample Mendelian randomisation (MR) and multivariable MR analysis. The data of exposures (BMI and WHRadjBMI) and outcomes (liver diseases and liver function biomarker) were obtained from the open genome-wide association study database. A two-sample MR study revealed that the genetically predicted BMI and WHRadjBMI were associated with non-alcoholic fatty liver disease, liver fibrosis and autoimmune hepatitis. Obesity was not associated with primary biliary cholangitis, liver failure, liver cell carcinoma, viral hepatitis and secondary malignant neoplasm of liver. A higher WHRadjBMI was associated with higher levels of biomarkers of lipid accumulation and metabolic disorders. These findings indicated independent causal roles of obesity in non-alcoholic fatty liver disease, liver fibrosis and impaired liver metabolic function rather than in viral or autoimmune liver disease.

PD-1+CD8+ T Cell-Mediated Hepatocyte Pyroptosis Promotes Progression of Murine Autoimmune Liver Disease.

The specific mechanisms underlying effector pathways in autoimmune liver disease remain enigmatic and therefore constructing appropriate murine models to investigate disease pathogenesis becomes critical. A spontaneous severe murine model of autoimmune liver disease has been previously established in dnTGFβRII Aire-/- mice, exhibiting disease phenotypes that resemble both human primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH). The data suggests that auto-reactive liver-specific CD8+ T cells are the primary pathogenic cells in liver injury. In this study, these data are advanced through the use of both single-cell sequencing and extensive in vitro analysis. The results identify a specific expanded pathogenic subset of PD-1+CD8+ T cells in the liver, exhibiting strong functional activity and cytotoxicity against target cells. Depletion of PD-1+CD8+ T cells using CAR-T cells effectively alleviates the disease. GSDMD-mediated pyroptosis is found to be aberrantly activated in the livers of model mice, and treatment with a GSDMD-specific inhibitor significantly inhibits disease progression. In vitro experiments reveal that PD-1+CD8+ T cells can induce the pyroptosis of hepatocytes through elevated production of granzyme B and perforin-1. These results provide a novel explanation for the cytotoxic activity of pathogenic liver PD-1+CD8+ T cells in autoimmune liver diseases and offer potential therapeutic targets.

Dissecting the genetic basis and mechanisms underlying the associations between multiple extrahepatic factors and autoimmune liver diseases

BackgroundAutoimmune liver diseases (AILDs) encompass autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The onset of these diseases is fundamentally influenced by genetic susceptibility. Although various extrahepatic factors are potentially linked to AILDs, the genetic underpinnings and mechanisms of these associations remain unclear. MethodsUtilizing large-scale genome-wide association study (GWAS) data, this study systematically investigated the relationships between extrahepatic autoimmune diseases (EHAIDs), immune cells, and various triggering factors with AILDs. Mendelian randomization (MR) was employed to assess the causal effects of these extrahepatic factors on AILDs, complemented by linkage disequilibrium score (LDSC) regression to uncover shared genetic architecture and causal effects underlying the associations between autoimmune diseases. We employed colocalization, enrichment analysis, and protein-protein interaction (PPI) network to identify the functions of shared loci. Additionally, we proposed that activated immune cells in the circulation may contribute to liver and biliary tract inflammation via migration, mediating the impact of extrahepatic factors on AILDs. This hypothesis was tested using two mediation analysis methods: two-step MR (TSMR) and multivariable MR (MVMR). ResultsCausal associations between multiple extrahepatic factors and AILDs were identified. Notably, CD27+ B cells were found to be a risk factor for PBC, while PSC progression was associated with CD28+ CD8+ T cells exhaustion and increased levels of CD28- CD8+ T cells. Mediation analyses revealed 64 pathways via TSMR and 15 pathways via MVMR, indicating that the effects of extrahepatic factors on AILDs may be mediated by circulating immune cells. The shared genetic architecture also contributed to these associations. Analysis of shared loci and gene functions identified ATXN2 as being shared between PBC and 9 EHAIDs, while SH2B3 and PSMG1 were shared with 6 and 5 EHAIDs, respectively, in PSC. ConclusionsOur research compared three distinct AILDs, enhancing the understanding of their etiology and providing new evidence on risk factors, diagnostic markers, and potential therapeutic targets.

Identification of a novel PDC-E2 epitope in primary biliary cholangitis: Application for engineered Treg therapy

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease, characterized by progressive destruction of small intrahepatic bile ducts and portal inflammation. Treatment options are limited, with reliance on liver transplantation in advanced cases. The adaptive immune response is implicated in disease pathogenesis by the presence of anti-mitochondrial antibodies targeting the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2) in 90–95 % of patients and T cells infiltrating the portal tracts. Here, we examined T cell responses to peptides derived from PDC-E2, with a focus on CD4 T cell responses restricted to HLA Class II DRB4∗01:01, an allele found in 62 % of PBC patients, to uncover PDC-E2 epitopes that could be used for engineered regulatory T cell (Treg; EngTreg) therapy. Using an activation-induced marker assay and single cell RNA-sequencing, we found clonal expansion of CD4 T cells reactive to PDC-E2 epitopes among both T conventional (Tconv) and Tregs. Those T cell receptor (TCR) repertoires were non-overlapping and private and included TCRs specific for a novel PDC-E2 epitope restricted to DRB4∗01:01. CD4 Tconv cells reactive to the PDC-E2 novel epitope showed phenotypic heterogeneity skewed towards T follicular helper cells. Using a TCR specific for this novel PDC-E2 epitope, we created an EngTreg that suppressed PDC-E2-specific polyclonal CD4 Tconv cells from PBC patients. This study advances knowledge of PDC-E2-specific T cell responses and introduces a novel PDC-E2 epitope recognized by both Tconv and Tregs. Generation of EngTreg specific for this epitope provides therapeutic potential for PBC.

Cardiac morphology and function in patients with primary biliary cholangitis (PBC) without cirrhosis

Abstract Background Primary biliary cholangitis (PBC) is a chronic, autoimmune liver disease causing destruction of the small intralobular bile ducts in the liver. PBC patients can also develop extrahepatic manifestations. Though patients with PBC have often elevated levels of serum lipids, data concerning cardiac involvement is inconsistent and cardiovascular changes may be underdiagnosed. Purpose The purpose of the study was to assess cardiac morphology and function in patients with PBC without cirrhosis and comparison with control subjects. Methods We studied 52 females with PBC, and included in the analysis 22 females without cirrhosis, who were compared to 44 healthy female controls matched for age (53.4 ± 9.2 and 51 ± 8.3 yrs., respectively, p =0.312). Transthoracic echocardiography (TTE) was performed with the analysis of the left ventricular (LV) global longitudinal strain (GLS) and myocardial work. Additionally, impedance cardiography was conducted, with the analysis of the autonomic function using BRS (baroreceptor sensitivity), HRV (heart rate variability) and BPV (blood pressure variability). Results Systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) differed between PBC and control group (128 ± 17 mmHg vs. 116 ± 11 mmHg, p=0.007 and 78± 12 mmHg vs. 75 ± 8 mmHg, p=0.024, and 73.5 ± 12 bpm vs. 71 ± 8 bpm , p=0.024, respectively). PBC group had larger diameter of the cardiac chambers when adjusted for body surface area (BSA), including left atrium (LA/BSA) and right ventricle (RV/BSA), as well as left ventricular mass (LWMI) and relative wall thickness (RWT), with no difference in the left ventricular end diastolic diameter (LVEDD/BSA). LV ejection fraction (EF) measured by bi-plane Simpson method was higher in PBC group. LV diastolic function parameters (E/A, E/e’) differed in patients with PBC when compared with controls, however, without signs of diastolic dysfunction. LV GLS indices (GLSAVG, GLSLAX, GLS4C, GLS2C) were significantly higher in PBC group, as well as global myocardial work indexes: global myocardial work (GWI) and global constructive work (GCW). Non-invasive autonomic assessment showed lower BPV in patients with PBC without cirrhosis, but no differences in baroreceptor sensitivity and HRV. Impedance cardiography did not show differences between both groups. Conclusion Our study shows that PBC patients without cirrhosis are characterized by remodeling and functional changes of the heart, when compared to age-matched controls. These changes could imply hyperkinetic circulation even before the development of cirrhosis in PBC patients.

Autoimmune liver disease revealed by Tuberculosis treatment: report of two cases and literature review

Autoimmune liver disease revealed by Tuberculosis treatment: report of two cases and literature review

Overlap syndrome in liver diseases in children: case report and literature review

In children, autoimmune liver diseases can manifest in a variety of forms, including autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and the co-occurrence of AIH and PSC - the “overlap syndrome.” Early recognition of overlap syndrome is important. Diagnosis of sclerosing cholangitis largely depends on the cholangiographic picture showing single or multiple strictures with dilatation of the biliary tract. The problems of etiology, pathogenesis, diagnosis and treatment of overlap syndrome in children are shown. A clinical example of seronegative autoimmune hepatitis and sclerosing cholangitis as part of a cross syndrome in a child is given.

The Multifaceted Role of Bilirubin in Liver Disease: A Literature Review.

Bilirubin, the primary breakdown product of hemoproteins, particularly hemoglobin, plays a key role in the diagnosis, prognosis, and monitoring of liver diseases. In acute liver diseases, such as acute liver failure, drug-induced liver injury, and viral hepatitis, bilirubin serves as a biomarker reflecting the extent of hepatocyte loss and liver damage. Chronic liver diseases, including alcohol-related liver disease, chronic hepatitis C virus infection, metabolic dysfunction-associated fatty liver disease, and autoimmune liver diseases, are marked by persistent liver injury and inflammation. Bilirubin levels in chronic liver diseases provide insight into liver function, disease severity, and prognosis. As a versatile biomarker, bilirubin offers valuable information on the pathophysiology of liver diseases and aids in guiding clinical decision-making regarding the treatment of liver diseases and their complications. This review aimed to explore the multifunctional role of bilirubin in liver diseases by analyzing its biological functions beyond its role as a biomarker of liver damage.

Single-cell RNA sequencing reveals the pro-inflammatory roles of liver-resident Th1-like cells in primary biliary cholangitis

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by multilineage immune dysregulation, which subsequently causes inflammation, fibrosis, and even cirrhosis of liver. Due to the limitation of traditional assays, the local hepatic immunopathogenesis of PBC has not been fully characterized. Here, we utilize single-cell RNA sequencing technology to depict the immune cell landscape and decipher the molecular mechanisms of PBC patients. We reveal that cholangiocytes and hepatic stellate cells are involved in liver inflammation and fibrosis. Moreover, Kupffer cells show increased levels of inflammatory factors and decreased scavenger function related genes, while T cells exhibit enhanced levels of inflammatory factors and reduced cytotoxicity related genes. Interestingly, we identify a liver-resident Th1-like population with JAK-STAT activation in the livers of both PBC patients and murine PBC model. Finally, blocking the JAK-STAT pathway alleviates the liver inflammation and eliminates the liver-resident Th1-like cells in the murine PBC model. In conclusion, our comprehensive single-cell transcriptome profiling expands the understanding of pathological mechanisms of PBC and provides potential targets for the treatment of PBC in patients.

Fine-Mapping the Results From Genome-Wide Association Studies of Primary Biliary Cholangitis Using Susie and h2-D2.

The main goal of fine-mapping is the identification of relevant genetic variants that have a causal effect on some trait of interest, such as the presence of a disease. From a statistical point of view, fine mapping can be seen as a variable selection problem. Fine-mapping methods are often challenging to apply because of the presence of linkage disequilibrium (LD), that is, regions of the genome where the variants interrogated have high correlation. Several methods have been proposed to address this issue. Here we explore the 'Sum of Single Effects' (SuSiE) method, applied to real data (summary statistics) from a genome-wide meta-analysis of the autoimmune liver disease primary biliary cholangitis (PBC). Fine-mapping in this data set was previously performed using the FINEMAP program; we compare these previous results with those obtained from SuSiE, which provides an arguably more convenient and principled way of generating 'credible sets', that is set of predictors that are correlated with the response variable. This allows us to appropriately acknowledge the uncertainty when selecting the causal effects for the trait. We focus on the results from SuSiE-RSS, which fits the SuSiE model to summary statistics, such as z-scores, along with a correlation matrix. We also compare the SuSiE results to those obtained using a more recently developed method, h2-D2, which uses the same inputs. Overall, we find the results from SuSiE-RSS and, to a lesser extent, h2-D2, to be quite concordant with those previously obtained using FINEMAP. The resulting genes and biological pathways implicated are therefore also similar to those previously obtained, providing valuable confirmation of these previously reported results. Detailed examination of the credible sets identified suggests that, although for the majority of the loci (33 out of 56) the results from SuSiE-RSS seem most plausible, there are some loci (5 out of 56 loci) where the results from h2-D2 seem more compelling. Computer simulations suggest that, overall, SuSiE-RSS generally has slightly higher power, better precision, and better ability to identify the true number of causal variants in a region than h2-D2, although there are some scenarios where the power of h2-D2 is higher. Thus, in real data analysis, the use of complementary approaches such as both SuSiE and h2-D2 is potentially warranted.

B-077 F-actin as a New Marker Antigen on an Established Multiparametric Immunoassay Profile for Liver Diseases

Abstract Background Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are severe diseases with heterogenous manifestations, which affect people of all populations and age groups. Diagnosis and differentiation from other liver diseases such as primary sclerosing cholangitis (PSC) remain a substantial challenge for hepatologists. Since AIH and PBC are caused by different sets of autoantibodies, we previously developed a line blot for the parallel detection of all relevant parameters. We now added the AIH-specific antigen filamentous actin (F-actin) to this established liver immunoassay profile. Methods Sera from 15 patients with AIH, 15 patients with overlap AIH/PBC or AIH/PSC, 32 patients with PSC, 53 patients with PBC, 4 patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), 30 patients with hepatitis B infection and 79 patients with hepatitis C infection as well as sera from 150 blood donors were examined using the EUROLINE line immunoassay system (EUROIMMUN autoimmune liver diseases 9 Ag plus F-actin (IgG); contains the PBC-relevant antigens AMA-M2, M2-3E (BPO), Sp100, PML and gp210, the AIH-associated antigens LKM-1, LC-1 and SLA/LP and F-actin as well as Ro52). The newly included F-actin antigen was polymerized from human globular actin (G-actin) and assessed by sedimentation analysis and dynamic light scattering. The scan software EUROLineScan (EUROIMMUN) was used to automatically determine presence and intensity of the resulting bands on the blot. Results Quality assessment revealed successful polymerization of F-actin. Autoantibodies against this newly developed F-actin antigen were detected in 53.3% of sera from AIH patients and 40% of AIH+PBC/AIH+PSC overlap patients. 93% of these positive sera did not contain other autoantibodies associated with AIH. Only one PSC patient (3.1%), two patients with hepatitis C (2.5%) and two blood donors (1.3%) also showed anti-F-actin positivity. All tested sera of PBC, NAFLD/NASH and hepatitis B patients were evaluated as anti-F-actin negative. Conclusions The addition of F-actin to the established multiparametric EUROLINE profile for the simultaneous and monospecific detection of AIH- and PBC-relevant autoantibodies is a great advance for routine diagnostics of patients with symptoms associated with various liver diseases.

Increased attention to women with drug-induced liver injury: Risk factors and early intervention

A recent study by Yu-Ting and colleagues has unveiled the clinical characteristics and risk factors of acute drug-induced liver injury (DILI). Upon reading the article, we found that there are some differences between female and male patients with DILI in terms of clinical and pathological features, especially in the number of patients, the degree of liver inflammation, and the risk of autoimmune liver disease. Therefore, it is necessary to pay attention to female patients with DILI and their outcomes, and to intervene appropriately in advance. This article analyzes the reasons for the differences between female and male patients with DILI and makes recommendations for patient prognosis.

Laboratory diagnostics of autoimmune liver diseases in primary care settings - short review

Elevated liver enzymes (ELE) are common in Germany. Primary care physicians are paramount in the early detection of liver diseases. The aim of this article is to provide an overview of autoimmune liver disease for primary care physicians (PCP) with a focus on laboratory diagnostics. The national and international guidelines and review articles serve as a reference, supplemented by the current prevalence data from the German Zentralinstitut of the kassenärztliche Vereinigung (ZI). In 2022, of the approximately 59 million PCP patients aged 20 years and older, around 50-60/100 000 received a confirmed diagnosis of autoimmune hepatitis or primary biliary cholangitis (according to ICD-10-GM diagnosis). The diagnoses were made 2 to 6 times more frequently in women than in men. Primary sclerosing cholangitis occurred in around 10/100 000 people treated by PCPs; women were affected up to twice as often, especially from the age of 60. Data on etiology, clinical, laboratory and diagnostic parameters, treatment options and prognosis data for the 3 disease entities are presented concisely in this article. Laboratory diagnostics is the central step in the diagnosis of autoimmune liver diseases. However, general laboratory screening for ELE is not advisable. Rather, it is important to recognize, that no validated key figures are yet available for these markers in the primary care setting. The interpretation of these laboratory values is therefore complex. It is therefore advisable to consider determining these specific laboratory parameters, taking into account the common (and less common) causes that can lead to ELE.

Paediatric-onset autoimmune liver disease: Insights from a monocentric experience

BackgroundAutoimmune liver disease (AILD) encompasses autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC) and primary sclerosing cholangitis (PSC). A unified disease process evolving over time through these entities has been recently suggested. From this perspective, this study aimed to compare the characteristics of childhood-onset AILD at baseline and after a medium-to-long term follow-up period. MethodsPaediatric-onset cases of AILD diagnosed between 1992 and 2023 at a tertiary-care centre were reviewed. Patients transitioned to adult-care by the time of data collection were asked for clinical updates. ResultsFifty-five patients were included (AIH = 20, ASC =22, PSC =13). AIH, ASC and PSC exhibited increasing age at the onset (AIH to PSC, p < 0.01). The area under the receiver operating characteristic curve for gamma-glutamyltranspeptidase (GGT) combined with alkaline phosphatase/aspartate aminotransferase (ALP/AST) ratio in predicting sclerosing cholangitis was 0.94, with a sensitivity of 86 % and a specificity of 94 %. At the last follow-up (median duration 5,8 years, interquartile range [IQR] 2,9–10,2, n = 45), 15 patients (33 %) developed portal hypertension, 2 patients (4 %) underwent liver transplantation, no patient died. ConclusionA cohort of childhood-onset AILD managed at a single centre reveals a temporal trend in the onset of AIH, ASC and PSC, with progressively older ages. Elevated GGT levels combined with a high ALP/AST ratio predict the diagnosis of sclerosing cholangitis. The occurrence of liver-related adverse events in one-third of patients highlights the progressive nature of paediatric-onset AILD.

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.

Predictors of survival in autoimmune liver disease overlap syndromes.

Survival in patients with autoimmune liver disease overlap syndromes (AILDOS) compared to those with single autoimmune liver disease is unclear. To investigate the survival of patients with AILDOS and assess the accuracy of non-invasive serum models for predicting liver-related death. Patients with AILDOS were defined as either autoimmune hepatitis and primary biliary cholangitis overlap (AIH-PBC) or autoimmune hepatitis and primary sclerosing cholangitis overlap (AIH-PSC) and were identified from three tertiary centres for this cohort study. Liver-related death or transplantation (liver-related mortality) was determined using a population-based data linkage system. Prognostic scores for liver-related death were compared for accuracy [including liver outcome score (LOS), Hepascore, Mayo Score, model for end-stage liver disease (MELD) score and MELD incorporated with serum sodium (MELD-Na) score]. Twenty-two AILDOS patients were followed for a median of 3.1 years (range, 0.35-7.7). Fourteen were female, the median age was 46.7 years (range, 17.8 to 82.1) and median Hepascore was 1 (range, 0.07-1). At five years post enrolment, 57% of patients remained free from liver-related mortality (74% AIH-PBC, 27% AIH-PSC). There was no significant difference in survival between AIH-PBC and AIH-PSC. LOS was a significant predictor of liver-related mortality (P < 0.05) in patients with AIH-PBC (n = 14) but not AIH-PSC (n = 8). A LOS cut-point of 6 discriminated liver-related mortality in AIH-PBC patients (P = 0.012, log-rank test, 100% sensitivity, 77.8% specificity) (Harrell's C-statistic 0.867). The MELD score, MELD-Na score and Mayo Score were not predictive of liver-related mortality in any group. Survival in the rare, AILDOS is unclear. The current study supports the LOS as a predictor of liver-related mortality in AIH-PBC patients. Further trials investigating predictors of survival in AILDOS are required.

TIPE2 protein restrains invariant NKT activation and protects against immune-mediated hepatitis in mice.

Concanavalin A (ConA) administration induces a rapid and severe liver injury in mice, and invariant natural killer T (iNKT) cells are recognized to be the key effector cells in this process. However, the underlying regulatory mechanisms are not well defined. We found that iNKT cells constitutively expressed TIPE2 (Tumor necrosis factor-α-induced protein 8-like 2, or TNFAIPL2). Genetic TIPE2 ablation strongly sensitized mice to ConA-induced hepatitis, accompanied with hyperactivation of iNKT cells. Moreover, Tipe2-/- mice were also more susceptible to α-galactosylceramide (αGalCer)-induced liver injury, with elevated serum ALT level and enhanced proinflammatory cytokine production. CD1d signaling blockade or iNKT cell elimination through antibodies reduced the effect of TIPE2 deficiency on liver injury. Mechanistic studies revealed that TIPE2 in iNKT cells functioned as a negative regulator, limiting iNKT cell activity and cytokine production through PIP3- AKT/mTOR pathway. TIPE2-mediated protection from liver injury was further validated by the administration of adeno-associated viruses expressing TIPE2, which effectively ameliorated ConA-induced hepatic injury. However, TIPE2 was dispensable in two other liver injury models, including D-GalN/LPS and APAP-induced hepatitis. Our findings reveal a new role of TIPE2 in the attenuation of iNKT cell-mediated hepatic injury. We propose that TIPE2 serves as an important regulator of immune homeostasis in the liver, and might be exploited for the therapeutic treatment of autoimmune liver diseases.

Incidence and risk factors for chronic rejection in pediatric liver transplantation.

Chronic rejection (CR) is a progressive immunological injury that frequently leads to long-term liver allograft dysfunction and loss. Although CR remains an important indication for retransplantation, as transplant immunosuppression has evolved, its prevalence in adults undergoing liver transplantation (LT) has declined. However, the incidence and factors that lead to CR in pediatric LT are poorly defined. Therefore, we sought to systematically measure CR's incidence and assess both the risk factors for developing CR and outcomes in a large cohort of pediatric recipients of LT. In this single-center study, we retrospectively analyzed and compared relevant recipient characteristics, surgical details, immunosuppression, graft, and patient survival in the CR and control groups over a 17-year period. After a median time of 1.9 years after LT, 19/356 recipients of LT (5.3%) developed CR in our cohort. Posttransplant lymphoproliferative disorder ( p = 0.01), infections ( p = 0.02), autoimmune liver diseases (HR = 7.3, p = <0.01), Black race (HR = 11.5, p = 0.01), and 2 or more episodes of T cell mediated rejection (HR = 5.1, p = <0.01) were associated with CR development. The retransplantation rate among CR cases was 15.8% at a median follow-up time of 4.1 years. Overall, patient survival was lower in the CR group (78.9%) versus controls (91.1%). While CR incidence in our pediatric cohort was lower than previously reported rates of >12%, the CR group had a higher graft failure rate that required retransplantation and lower overall patient survival. Thus, identifying risk factors may warrant specialized immunosuppression protocols and closer posttransplantation monitoring to reduce the risk of morbidity and mortality from CR.

Primary Biliary Cholangitis in Men: A Case Report

Primary biliary cholangitis (PBC) is a rare chronic autoimmune liver disease, especially in men, that causes progressive inflammation and destruction of the intrahepatic bile ducts. This leads to hepatic fibrosis that can progress to cirrhosis. PBC diagnosis is suggested by cholestatic jaundice in the absence of abnormalities in intrahepatic and extrahepatic bile ducts, with alkaline phosphatases (ALP) &gt; 1.5 times the upper limit of normal and gamma-glutamyl transferase (GGT) &gt; 3 times the upper limit of normal, with or without elevated bilirubin levels. Confirmation is made through immunological tests, and liver biopsy (PBH) is necessary if tests are negative. The disease is often diagnosed at an advanced stage. Poor prognostic factors include early diagnosis, male gender, severe symptoms, and biological abnormalities such as elevated bilirubin levels. Specific autoantibodies, such as anti-gp210 and anti-sp100, also predict unfavorable disease progression. The first-line treatment is ursodeoxycholic acid (UDCA), which helps slow disease progression and improve symptoms. If UDCA is ineffective, other options include obeticholic acid (OCA) or fibrates like bezafibrate, often used in combination with UDCA. Liver transplantation is the only curative treatment for severe cases. Research is ongoing for new treatments, including PPAR agonists and bile acid transporter inhibitors.