Spontaneous development of an autoimmune hepatitis - primary biliary cholangitis overlap syndrome in dnTGFßRII Aire-/- mice.

Autoimmune regulator (Aire) and TGF-ß signaling play important roles in central tolerance and peripheral tolerance, respectively, by eliminating or suppressing the activity of autoreactive T cells. We previously demonstrated that dnTGFßRII mice develop a defect in peripheral tolerance and a primary biliary cholangitis (PBC)-like disease. We hypothesized that by introducing the Aire gene to this model, we would observe a more severe PBC phenotype. Interestingly, however, we demonstrated that, while dnTGFßRII Aire-/- mice do manifest key histological and serological features of autoimmune cholangitis, they also develop mild to moderate interface hepatitis and show high levels of alanine transaminase (ALT) and antinuclear antibodies (ANA), characteristics of autoimmune hepatitis (AIH). To further understand this unique phenotype, we performed RNA sequencing (RNA-seq) and flow cytometry to explore the functional pathways and immune cell pathways in the liver of dnTGFßRII Aire-/- mice. Our data revealed enrichments of programmed cell death pathways and predominant CD8+ T cell infiltrates. Depleting CD8+ T cells using an anti-CD8α antibody significantly alleviated hepatic inflammation and prolonged the life span of these mice. Finally, RNA-seq data indicated the clonal expansion of hepatic CD8+ T cells. In conclusion, these mice developed an autoreactive CD8+ T-cell-mediated autoimmune cholangitis with concurrent hepatitis that exhibited key histological and serological features of the AIH-PBC overlap syndrome, representing a novel model for the study of tolerance and autoimmune liver disease. © 2023 The Pathological Society of Great Britain and Ireland.

Performance of 2D-shear wave elastography in autoimmune hepatitis-primary biliary cholangitis overlap syndrome.

PURPOSE: To evaluate the diagnostic values of liver stiffness (LS) measured by 2D-SWE, fibrosis index based on the four factors (FIB-4), aspartate aminotransferase to platelet ratio index (APRI), and GGT to PLT ratio (GPR) for assessing liver fibrosis and high-risk esophageal varices (EVs) in patients with autoimmune hepatitis-primary biliary cholangitis (AIH-PBC) overlap syndrome. METHODS: Data of 141 patients were retrospectively collected. Liver fibrosis was staged according to the Scheuer scoring system. The Spearman correlation coefficient was used for correlation analysis. Receiver operating characteristic (ROC) curves were plotted to evaluate the diagnostic performance. RESULTS: LS and FIB-4 were positively correlated with the fibrosis stage (r = 0.555 and 0.198, respectively). LS had significantly higher areas under the ROC curves (AUROCs) values than FIB-4 for predicting advanced fibrosis (0.818 vs. 0.567, P < 0.001), cirrhosis (0.879 vs. 0.637, P < 0.001), whereas LS and FIB-4 similarly predicted significant fibrosis (0.748 vs. 0.638, P = 0.071) and high-risk EVs (0.731 vs. 0.659, P = 0.303). The optimal cut-off values of 2D-SWE for detecting significant fibrosis, advanced fibrosis, cirrhosis, and high-risk EVs were 8.7 kPa, 12.8 kPa, 14.0 kPa, and 11.0 kPa, respectively. LS values were influenced by fibrosis stage, serum GGT, albumin, and total bilirubin levels. The overall concordance rate of the liver stiffness vs. Scheuer stages was 49.65%. CONCLUSIONS: 2D-SWE shows significantly greater diagnostic accuracy than serum fibrosis indexes for diagnosing advanced fibrosis and cirrhosis in patients with AIH-PBC overlap syndrome.

Clinical features of autoimmune liver disease complicated by abdominal lymphadenectasis / 临床肝胆病杂志

Objective To investigate the clinical features of autoimmune liver disease (AILD) complicated by abdominal lymphadenectasis (LA),as well as the clinical significance of LA in AILD.Methods A retrospective analysis was performed for the clinical data of 252 patients who were admitted to The First Affiliated Hospital of Dalian Medical University from January 2005 to April 2016,and among these patients,52 had autoimmune hepatitis (AIH),174 had primary biliary cholangitis (PBC),and 26 had AIH-PBC overlap syndrome (AIH-PBC OS).A total of 78 patients underwent follow-up.According to the presence or absence of LA,these patients were divided into LA group with 70 patients and non-LA (NLA) group with 182 patients.As for general information,laboratory markers,imaging findings,and follow-up results,the normally distributed continuous data were expressed as mean ± SD,and the t-test was used for comparison between groups;the non-normally distributed continuous data were expressed as median,and the Wilcoxon rank sum test was used for comparison between groups.The categorical data were expressed as rates,and the chi-square test,the corrected chi-square test,or the Fisher's exact test was used for comparison of these data between groups.Results There were no significant differences between the two groups in age,sex ratio,proportion of patients who were diagnosed due to abnormal liver function found by physical examination,and incidence rates of other autoimmune diseases.The incidence rate of abdominal LA was 22％ (11/52) in the AIH group,26.4％ (46/174) in the PBC group,and 50％ (13/26) in the AIH-PBC OS group,and the AIH-PBC OS group had a significantly higher incidence rate than the AIH group and the PBC group (x2 =7.693,P =0.021).The LA group had significantly higher levels of alkaline phosphatase and gamma-glutamyl transpeptidase (GGT) than the NLA group (Z =2.944 and 3.169,P =0.003 and 0.002).For the patients with PBC,the LA group had a significantly higher level of GGT than the NLA group (Z =2.136,P =0.033);for the patients with AIH-PBC OS,the LA group had a significantly higher level of total bilirubin thau the NLA group (Z =2.121,P =0.035);for the patients with AIH,there were no significant differences in these indices between the LA group and the NLA group.The LA group had a higher incidence rate of abnormal imaging findings than the NLA group (97.1％ vs 81.9％,x2 =9.863,P =0.002).A total of 78 patients were followed up with a median follow-up time of 18 months.Of all patients in the LA group,6 (23.1％) achieved complete remission,7 (26.9％) achieved incomplete response,1 (3.8％) experienced recurrence,and 12 (46.2％) experienced treatment failure;of all patients in the NLA group,21 (40.4％) achieved complete remission,17 (32.7％) achieved incomplete response,7 (13.5％) experienced recurrence,and 7(13.5％) experienced treatment failure;there was a significant difference in the distribution of treatment outcomes between the LA group and the NLA group (Z =2.406,P =0.016).Conclusion Patients with AIH-PBC OS have a higher incidence rate of abdominal LA than those with AIH and PBC,and patients with AILD complicated by LA may have marked cholestasis and liver impairment and poor treatment response,suggesting that LA might be used to determine disease severity and judge prognosis.