Between Scylla and Charybdis: the role of the human immune system in the pathogenesis of hepatitis C

Abstract

Hepatitis C virus (HCV) frequently elicits only mild immune responses so that it can often establish chronic infection. In this case HCV antigens persist and continue to stimulate the immune system. Antigen persistence then leads to profound changes in the infected host's immune responsiveness, and eventually contributes to the pathology of chronic hepatitis. This topic highlight summarizes changes associated with chronic hepatitis C concerning innate immunity (interferons, natural killer cells), adaptive immune responses (immunoglobulins, T cells, and mechanisms of immune regulation (regulatory T cells). Our overview clarifies that a strong anti-HCV immune response is frequently associated with acute severe tissue damage. In chronic hepatitis C, however, the effector arms of the immune system either become refractory to activation or take over regulatory functions. Taken together these changes in immunity may lead to persistent liver damage and cirrhosis. Consequently, effector arms of the immune system will not only be considered with respect to antiviral defence but also as pivotal mechanisms of inflammation, necrosis and progression to cirrhosis. Thus, avoiding Scylla - a strong, sustained antiviral immune response with inital tissue damage - takes the infected host to virus-triggered immunopathology, which ultimately leads to cirrhosis and liver cancer - the realm of Charybdis.

Keywords: CD4+ T helper cells; Hepatic stellate cells; Hepatitis C; Hepatocytes; Immunoglobulin; Interferon; Natural killer cells; Regulatory T cells; Retinoic acid inducible gene-I; Toll like receptors.

Figure 1

Central role of natural killer cells in the pathogenesis of hepatitis C. Natural killer (NK) cells regulate fibrosis by killing of activated hepatic stellate cells (HSC), which trigger NK cell activation via natural killer cell receptor with extracellular C-type lectin domains (NKG2D) signalling. The release of granzyme/perforin and cytotoxic cytokines, such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induce tissue damage. Interferon-γ (IFN-γ) released from NK cells can clear hepatitis C virus (HCV) infection from infected hepatocytes without cytolysis. On the other hand NK cell activity is critically dependent on sufficient supply with interleukin 2 (IL-2) from CD4⁺ T cells.

Figure 2

Multiple activities of hepatitis C virus-specific regulatory T cells in chronic hepatitis C. Regulatory T cell (Tregs) inhibit antiviral immunity via release of immunosuppressive factors, such as interleukin 10 (IL-10), transforming growth factor beta (TGF-β) and interleukin 35 (IL-35). Tregs in hepatitis C are also differentiated towards interleukin 8 (IL-8) production. Release of IL-8 binds to its receptors, such as CXCR2 on hepatic stellate cells (HSC), which become activated and produce extracellular matrix (ECM) components. IL-8 down-regulates interferon-stimulated genes in infected cells and induces an interferon (IFN)-refractory state, which also counter-acts antiviral immunity. ISGs: Interferon-stimulated genes.