IFNγ and CTLA-4 Drive Hepatic CD4 T-Cell Tolerance and Protection From Autoimmunity in Mice.

Background & Aims: The liver has a distinct capacity to induce immune tolerance to hepatic antigens. Although liver tolerance can be advantageous for preventing autoimmune and inflammatory diseases, it also can be detrimental by preventing immune surveillance of infected or malignant cells. Here, we investigated the immune mechanisms that establish hepatic tolerance.

Autoantigen-selected B cells are bystanders in spontaneous T cell-driven experimental autoimmune hepatitis.

Autoreactive B cells are considered pathogenic drivers in many autoimmune diseases; however, it is not clear whether autoimmune B cells are invariably pathogenic or whether they can also arise as bystanders of T cell-driven autoimmune pathology. Here, we studied the B cell response in an autoantigen- and CD4 T cell-driven model of autoimmune hepatitis (AIH), the Alb-iGP_Smarta mouse in which expression of a viral model antigen (GP) in hepatocytes and its recognition by GP-specific CD4 T cells causes spontaneous AIH-like disease. T cell-driven AIH in Alb-iGP_Smarta mice was marked by autoantibodies and hepatic infiltration of plasma cells and B cells, particularly of isotype-switched memory B cells, indicating antigen-driven selection and activation.

Inflammatory type 2 conventional dendritic cells contribute to murine and human cholangitis.

Background & Aims: Primary sclerosing cholangitis (PSC) is a progressive cholangiopathy characterised by fibrotic stricturing and inflammation of bile ducts, which seems to be driven by a maladaptive immune response to bile duct injury. The histological finding of dendritic cell expansion in portal fields of patients with PSC prompted us to investigate the role of dendritic cells in orchestrating the immune response to bile duct injury.

Methods: Dendritic cell numbers and subtypes were determined in different mouse models of cholangitis by flow cytometry based on lineage-imprinted markers.

Harnessing the liver to induce antigen-specific immune tolerance.

Autoimmune diseases develop when the adaptive immune system attacks the body's own antigens leading to tissue damage. At least 80 different conditions are believed to have an autoimmune aetiology, including rheumatoid arthritis, type I diabetes, multiple sclerosis or systemic lupus erythematosus. Collectively, autoimmune diseases are a leading cause of severe health impairment along with substantial socioeconomic costs.

Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liver.

The liver is an immune-privileged organ that can deactivate autoreactive T cells. Yet in autoimmune hepatitis (AIH), autoreactive T cells can defy hepatic control and attack the liver. To elucidate how tolerance to self-antigens is lost during AIH pathogenesis, we generated a spontaneous mouse model of AIH, based on recognition of an MHC class II-restricted model peptide in hepatocytes by autoreactive CD4+ T cells.

Nanoparticle-mediated targeting of autoantigen peptide to cross-presenting liver sinusoidal endothelial cells protects from CD8 T-cell-driven autoimmune cholangitis.

Autoimmune diseases are caused by adaptive immune responses to self-antigens. The development of antigen-specific therapies that suppress disease-related, but not unrelated immune responses in general, is an important goal of biomedical research. We have previously shown that delivery of myelin peptides to liver sinusoidal endothelial cells (LSECs) using LSEC-targeting nanoparticles provides effective protection from CD4 T-cell-driven autoimmune encephalomyelitis.

IL-17A/F enable cholangiocytes to restrict T cell-driven experimental cholangitis by upregulating PD-L1 expression.

Background & Aims: IL-17A-producing T cells are present in autoimmune cholestatic liver diseases; however, little is known about the contribution of IL-17 to periductal immune responses. Herein, we investigated the role of IL-17 produced by antigen-specific CD8 T cells in a mouse model of cholangitis and in vitro in human cholangiocyte organoids.

Methods: K14-OVAp mice express a major histocompatibility complex I-restricted ovalbumin (OVA) peptide sequence (SIINFEKL) on cholangiocytes.

Monocytes as Potential Mediators of Pathogen-Induced T-Helper 17 Differentiation in Patients With Primary Sclerosing Cholangitis (PSC).

Background And Aims: T cells from patients with primary sclerosing cholangitis (PSC) show a prominent interleukin (IL)-17 response upon stimulation with bacteria or fungi, yet the reasons for this dominant T-helper 17 (Th17) response in PSC are not clear. Here, we analyzed the potential role of monocytes in microbial recognition and in skewing the T-cell response toward Th17.

Approach And Results: Monocytes and T cells from blood and livers of PSC patients and controls were analyzed ex vivo and in vitro using transwell experiments with cholangiocytes.

Aryl Hydrocarbon Receptor Activity in Hepatocytes Sensitizes to Hyperacute Acetaminophen-Induced Hepatotoxicity in Mice.

Background & Aims: Acetaminophen (APAP)-induced liver injury is one of the most common causes of acute liver failure, however, a clear definition of sensitizing risk factors is lacking. Here, we investigated the role of the ligand-activated transcription factor aryl hydrocarbon receptor (Ahr) in APAP-induced liver injury. We hypothesized that Ahr, which integrates environmental, dietary, microbial and metabolic signals into complex cellular transcriptional programs, might act as a rheostat for APAP-toxicity.

TNF-Producing Th1 Cells Are Selectively Expanded in Liver Infiltrates of Patients with Autoimmune Hepatitis.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that is believed to be driven by a CD4 T cell response to liver Ags. However, the pathogenic function of CD4 effector T cells in AIH is not fully understood. To characterize liver-infiltrating lymphocytes in AIH, we determined the cytokine production of infiltrating cells obtained from biopsy material by quantitative RT-PCR and flow cytometry.

Liver infiltrating T cells regulate bile acid metabolism in experimental cholangitis.

Background & Aims: T cells are central mediators of liver inflammation and represent potential treatment targets in cholestatic liver disease. Whereas emerging evidence shows that bile acids (BAs) affect T cell function, the role of T cells for the regulation of BA metabolism is unknown. In order to understand this interplay, we investigated the influence of T cells on BA metabolism in a novel mouse model of cholangitis.

Inflammatory Phenotype of Intrahepatic Sulfatide-Reactive Type II NKT Cells in Humans With Autoimmune Hepatitis.

Natural Killer T (NKT) cells are CD1d-restricted innate-like T cells that can rapidly release stored cytokines upon recognition of lipid antigens. In mice, type I NKT cells seem to promote liver inflammation, whereas type II NKT cells seem to restrict hepatitis. Here, we aimed at characterizing the role of human type I and type II NKT in patients with autoimmune hepatitis (AIH).

T-cell repertoire profiling by next-generation sequencing reveals tissue migration dynamics of TRBV13-family clonotypes in a common experimental autoimmune encephalomyelitis mouse model.

The experimental autoimmune encephalomyelitis (EAE) model is indispensable for autoimmunity research, but model-specific T cell dynamics are sparsely studied. We used next-generation immunosequencing across lymphoid organs, blood and spinal cord in response to immunization with myelin basic protein (MBP) to study T cell repertoires and migration patterns. Surprisingly, most spinal cord T cells were unique to the individual animal despite the existence of shared MBP-specific clones, suggesting a previously underestimated T cell diversity.

CCL21-expression and accumulation of CCR7 NK cells in livers of patients with primary sclerosing cholangitis.

The pathogenesis of primary sclerosing cholangitis (PSC), an autoimmune liver disease, remains unknown. The aim of this study was to characterize peripheral blood and intrahepatic NK cells from patients with PSC. Peripheral blood samples from patients with PSC, other autoimmune liver diseases, and from healthy control individuals were used, as well as liver tissues from PSC patients undergoing liver transplantation.

Review article: unanswered clinical and research questions in autoimmune hepatitis-conclusions of the International Autoimmune Hepatitis Group Research Workshop.

Background: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that results in substantial morbidity and mortality with many unanswered clinical and research questions. Improved understanding of disease pathogenesis, including the extra-hepatic manifestations of AIH, may allow targeted treatments with greater efficacy and fewer associated adverse events.

Aim: To identify the spectrum of unanswered clinical and research questions facing care providers in the management of patients with autoimmune hepatitis (AIH).

Colitis Promotes a Pathological Condition of the Liver in the Absence of Foxp3 Regulatory T Cells.

Inflammatory bowel disease is associated with extraintestinal diseases such as primary sclerosing cholangitis in the liver. Interestingly, it is known that an imbalance between Foxp3 regulatory T cells (Treg) and Th17 cells is involved in inflammatory bowel disease and also in primary sclerosing cholangitis. To explain these associations, one hypothesis is that intestinal inflammation and barrier defects promote liver disease because of the influx of bacteria and inflammatory cells to the liver.

Dietary and metabolic modulators of hepatic immunity.

The liver is the central metabolic organ of the organism and is thus constantly exposed to gut-derived dietary and microbial antigens. The liver maintains homoeostatic tolerance to these mostly harmless antigens. However, the liver also functions as a barrier organ to harmful pathogens and is thus permissive to liver inflammation.

Can Understanding the Pathogenesis of Autoimmune Hepatitis Lead to Rational Therapy?

The pathogenesis of autoimmune hepatitis is still poorly understood and therefore, the therapy administered to treat this condition is broadly targeted immunosuppression. However, the aim of therapy in the future should be more specific; it should be a therapy that interrupts the pathogenetic cascade at defined checkpoints. Even though these checkpoints are not yet defined, possible targets of immunotherapy are emerging.

Activation of the Akt-CREB signalling axis by a proline-rich heptapeptide confers resistance to stress-induced cell death and inflammation.

Cell stress of various kinds can lead to the induction of cell death and a damaging inflammatory response. Hence, a goal of therapeutic cell-stress management is to develop agents that might effectively regulate undesirable cell death and inflammation. To that end, we developed a synthetic peptide of seven amino acids based on structural mimicry to a functional domain of p53, a key factor in the responses of cells to stressful stimuli.

IL-10 Receptor Signaling Is Essential for TR1 Cell Function In Vivo.

IL-10 is essential to maintain intestinal homeostasis. CD4 T regulatory type 1 (T1) cells produce large amounts of this cytokine and are therefore currently being examined in clinical trials as T cell therapy in patients with inflammatory bowel disease. However, factors and molecular signals sustaining T1 cell regulatory activity still need to be identified to optimize the efficiency and ensure the safety of these trials.

Dysfunction of hepatic regulatory T cells in experimental sclerosing cholangitis is related to IL-12 signaling.

Background & Aims: Reduced numbers of regulatory T cells (Treg) have been reported in patients with primary sclerosing cholangitis (PSC); therefore, Treg expansion might serve as a therapeutic approach. Here, we explored whether treatment with IL-2/IL-2 monoclonal antibody complex (IL-2/IL-2Ab complex) could provide in vivo Treg expansion and treatment of experimental sclerosing cholangitis.

Methods: Treg were expanded by repeated injection of IL-2/IL-2Ab complex in mouse models of cholangitis (Mdr2, DDC) or colitis (dextran sulfate sodium [DSS]) as control.

IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice.

Unlabelled: Hepatocellular carcinoma (HCC) is one of the most frequent tumors worldwide with rising incidence. The inflammatory cytokine, interleukin-6 (IL-6), is a critical mediator of HCC development. It can signal through two distinct pathways: the IL-6 classic and the IL-6 trans-signaling pathway.