Project description:Autoimmune hepatitis is an interface hepatitis characterized by the progressive destruction of the liver parenchyma, the cause of which is still obscure. Interleukin (IL)-17A is a major driver of autoimmunity, which can be produced by innate immune cells against several intracellular pathogens. Here, we investigated the involvement of IL-17A in a mice model of immune-mediated hepatitis with the intestine exposed to Salmonella typhimurium. Our results showed more severe Concanavalin (Con) A-induced liver injury and gut microbiome dysbiosis when the mice were treated with a gavage of S. typhimurium. Then the Natural Killer (NK) T cells were over-activated by the accumulated IL-17A in the liver in the Con A and S. typhimurium administration group. IL-17A could activate NKT cells by inducing CD178 expression via IL-4/STAT6 signaling. Furthermore, via the portal tract, the laminae propria mucosal-associated invariant T (MAIT) cell-derived IL-17A could be the original driver of NKT cells’ over-activation in intragastric administration of S. typhimurium and Con A injection. In IL-17A deficient mice, Con A-induced liver injury and NKT cells activation was alleviated. However, when AAV-sh-mIL-17a was used to specifically knock down IL-17A in liver, it seemed that hepatic IL-17a knock down did not significantly influence the liver injury. Our results suggested that, under Con A-induction, laminae propria MAIT-derived IL-17A activated hepatic NKT, and this axis could be a therapeutic target in autoimmune liver disease.
Project description:The etiology of autoimmune hepatitis is poorly understood but likely involves Th1 cells producing IFN-γ. BALB/c background TGF-β1-/- mice rapidly develop fulminant Th1-mediated autoimmune hepatitis. Our aims are to profile liver gene expression in TGF-β1-/- mice, to identify gene expression pathways dependent on IFN-γ as possible targets for rational therapy, and to test potential targets directly in vivo in mice. Keywords: Comparative analysis of gene expression in livers of WT, TGFB1 & IFN knockout mice DNA microarray analyses were applied to liver RNA from TGF-β1-/- mice, TGF-β1-/- /IFN-γ-/- mice, and TGF-β1+/+ littermate controls. 3 mice from each group were analyzed in this study.
Project description:The etiology of autoimmune hepatitis is poorly understood but likely involves Th1 cells producing IFN-γ. BALB/c background TGF-β1-/- mice rapidly develop fulminant Th1-mediated autoimmune hepatitis. Our aims are to profile liver gene expression in TGF-β1-/- mice, to identify gene expression pathways dependent on IFN-γ as possible targets for rational therapy, and to test potential targets directly in vivo in mice. Keywords: Comparative analysis of gene expression in livers of WT, TGFB1 & IFN knockout mice
Project description:To investigate the function of miRNAs in liver, we obtained liver tissues from nonsteatotic individuals and fatty livers from patients with nonalcoholic fatty liver disease (NAFLD). Patients due to excessive alcohol consumption, autoimmune liver disease, viral hepatitis and diabetes were excluded. Nonsteatotic livers were collected from the normal region of the livers from donors who received liver resection due to liver hemangioma, and were defined as those with NASH activity scores of 0 We then performed miRNA sequencing using livers from two NAFLD patients and two nonsteatotic individuals.
Project description:Autoimmune hepatitis (AIH) is caused by an immune disorder that is characterized by hypergammaglobulinemia, autoantibodies, and chronic active hepatitis on liver histology. This present study was designed to analyze the characteristics of AIH peripheral blood mononuclear cells (PBMCs) through single-cell RNA sequencing (scRNA-seq, 10x Genomics Gene Expression 3' Chromium V 2.0) and to explore the potential molecular mechanism of AIH.
Project description:Autoimmune regulator (Aire) and TGF-β signaling play an important role in central tolerance and peripheral tolerance respectively, by eliminating or suppressing the activity of autoreactive T cells. We have previously demonstrated that dnTGFβRII mice develop a defect in peripheral tolerance and a primary biliary cirrhosis (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 demonstrate that while dnTGFβRII Aire-/- mice do manifest key histologic and serologic 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-seq and flow cytometry to explore the functional pathways and immune cell pathways in the liver of dnTGFβRII 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 lifespan of these mice. Finally, RNA-seq data indicated the clonal expansion of hepatic CD8+ T cells. In conclusion, these mice develop an autoreactive CD8+ T cell mediated autoimmune cholangitis with concurrent hepatitis that exhibits key histological and serological features of the AIH-PBC overlap syndrome, representing a novel model for the study of tolerance and autoimmune liver disease.
Project description:The liver in newborn animals undergo a maturation process in order to adapt to a plethora of changes and challenges in the extra-uterine life. The influx of regulatory T cells during 1-2-week period protect the animals from autoimmune hepatitis and govern the transformation of a neonatal liver to a crucial metabolic organ in adults.