https://www.journal-of-hepatology.eu/article/S0168-8278(13)00213-4/pdf

Decoding cell death signals in liver inflammation.

The T-cell biology of the liver is unlike that of any other organ. The local lymphocyte population is enriched in natural killer (NK) and NKT cells, which might have crucial roles in the recruitment of circulating T cells. A large macrophage population and the efficient trafficking of dendritic cells from sinusoidal blood to lymph promote antigen trapping and T-cell priming, but the local presentation of antigen causes T-cell inactivation, tolerance and apoptosis. These local mechanisms might result from the need to maintain immunological silence to harmless antigenic material in food. The overall bias of intrahepatic T-cell responses towards tolerance might account for the survival of liver allografts and for the persistence of some liver pathogens.

Hepatic T cells and liver tolerance

Hepatocellular carcinoma (HCC) is the fifth most common cancer, but the third leading cause of cancer death, in the world, with more than 500,000 fatalities annually. The major etiology of HCC/liver cancer in people is hepatitis B virus (HBV), followed by hepatitis C virus infection (HCV), although nonviral causes also play a role in a minority of cases. Recent molecular studies confirm what was suspected: that HCC tissue from different individuals have many phenotypic differences. However, there are clearly features that unify HCC occurring in a background of viral hepatitis B and C. HCC due to HBV and HCV may be an indirect result of enhanced hepatocyte turnover that occurs in an effort to replace infected cells that have been immunologically attacked. Viral functions may also play a more direct role in mediating oncogenesis. This review considers the molecular and cellular mechanisms involved in primary hepatocellular carcinoma, using a viral perspective.

Molecular viral oncology of hepatocellular carcinoma.

The liver has vital metabolic and clearance functions that involve the uptake of nutrients, waste products and pathogens from the blood. In addition, its unique immunoregulatory functions mediated by local expression of co-inhibitory receptors and immunosuppressive mediators help to prevent inadvertent organ damage. However, these tolerogenic properties render the liver an attractive target site for pathogens. Although most pathogens that reach the liver via the blood are eliminated or controlled by local innate and adaptive immune responses, some pathogens (such as hepatitis viruses) can escape immune control and persist in hepatocytes, causing substantial morbidity and mortality worldwide. Here, we review our current knowledge of the mechanisms of liver targeting by pathogens and describe the interplay between pathogens and host factors that promote pathogen elimination and maintain organ integrity or that allow pathogen persistence.

Living in the liver: hepatic infections

Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver injury and disease-specific cell responses, the progression of fibrotic liver disease follows shared patterns across the main liver disease etiologies. Scientific discoveries within the last decade have transformed the understanding of the mechanisms of liver fibrosis. Removal or elimination of the causative agent such as control or cure of viral infection has shown that liver fibrosis is reversible. However, reversal often occurs too slowly or too infrequent to avoid life-threatening complications particularly in advanced fibrosis. Thus, there is a huge unmet medical need for anti-fibrotic therapies to prevent liver disease progression and HCC development. However, while many anti-fibrotic candidate agents have shown robust effects in experimental animal models, their anti-fibrotic effects in clinical trials have been limited or absent. Thus, no approved therapy exists for liver fibrosis. In this review we summarize cellular drivers and molecular mechanisms of fibrogenesis in chronic liver diseases and discuss their impact for the development of urgently needed anti-fibrotic therapies.

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Hepatitis C Virus Core Protein Inhibits Mitochondrial Electron Transport and Increases Reactive Oxygen Species (ROS) Production

https://altogen.com/wp-content/uploads/2015/10/InVivoTransfection17.pdf

Differential, Type I Interferon-Mediated Autophagic Trafficking of Hepatitis C Virus Proteins in Mouse Liver

Several hepatitis C virus (HCV) proteins have been shown in vitro to interact with host cellular components that are involved in immune regulation. However, there is a paucity of data supporting the relevance of these observations to the in vivo situation. To test the hypothesis that such an interaction suppresses immune responses, we studied a line of transgenic C57BL/6 mice that express the HCV core and envelope proteins in the liver. The potential effects of these proteins on the hepatic immune response were evaluated by challenging these mice with a hepatotropic adenovirus. Both transgenic and nontransgenic mice developed similar courses of infection and cleared the virus from the liver by 28 days postinfection. Both groups of mice mounted similar immunoglobulin G (IgG), IgG2a, interleukin-2, and tumor necrosis factor alpha responses against the virus. Additionally, BALB/c mice were able to clear infection with recombinant adenovirus that does or does not express the HCV core and envelope 1 proteins in the same manner. These data suggest that HCV core and envelope proteins do not inhibit the hepatic antiviral mechanisms in these murine experimental systems and thus favor a model in which HCV circumvents host responses through a mechanism that does not involve general suppression of intrahepatic immune responses.

Hepatitis C Virus Core and Envelope Proteins Do Not Suppress the Host's Ability To Clear a Hepatic Viral Infection

Cre-estrogen receptor-mediated hepatitis C virus structural protein expression in mice.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.24270

Tehsheng Chan

Papers

Hepatitis C Virus Core Protein Inhibits Mitochondrial Electron Transport and Increases Reactive Oxygen Species (ROS) Production

Differential, Type I Interferon-Mediated Autophagic Trafficking of Hepatitis C Virus Proteins in Mouse Liver

Hepatitis C Virus Core and Envelope Proteins Do Not Suppress the Host's Ability To Clear a Hepatic Viral Infection

Cre-estrogen receptor-mediated hepatitis C virus structural protein expression in mice.

Parenchymal expression of CD40 exacerbates adenovirus-induced hepatitis in mice.