The route from acute to chronic
Hepatitis C often progresses from a mild acute stage to become a chronic, life-threatening disease. An LMU team now reports that defective expression of a specific transcription factor plays a crucial role in this transition.
Most of those who have the misfortune to become infected with hepatitis C virus (HCV) will never get rid of the pathogen without therapy. In more than two-thirds of all cases, the infection becomes chronic, and the risk of incurring severe liver damage and developing liver cancer increases significantly. By comparison, the hepatitis B virus (HBV) appears quite harmless. Almost all HBV infections in adults are effectively resolved by the immune system, and the frequency of progression to the chronic stage is far lower. What factors account for this striking difference in outcomes? Why is it that, in the majority of cases, the immune system fails to mount an effective response against the C-type virus, and is incapable of eliminating the pathogen? Hepatitis is an insidious illness, and the early symptoms are relatively unspecific, so that most victims fail to realize that they have been infected at all.
In collaboration with colleagues in Munich, Freiburg and Edinburgh, LMU researchers led by Dr. med. Peter Kurktschiev and Privatdozent Dr. med. Norbert Grüner, who have dual appointments at LMU’s Institute of Immunology and Department of Medicine II, have now pinpointed one major difference in how the immune system responds to HBV and HCV. The team found that patients infected with HBV who went on to recover fully from their illness had high levels of the protein T-bet in a particular class of immune cells during the early acute phase of the illness. Strikingly, a similarly high level of T-bet was found in early-phase patients who had contracted hepatitis C but subsequently eradicated the virus. On the other hand, patients who went on develop chronic hepatitis C were deficient in T-bet early in infection.
The transcription factor T-bet regulates the activity of a specific set of genes in immune cells, and is known to play a central role in orchestrating the immune response to viral infections. Not only does it control the differentiation of so-called CD4+ T cells (otherwise known as T helper cells), it is also required for the proliferation of virus-specific populations of CD8+ T cells. The latter function as so-called killer cells that recognize and destroy infected cells, and they secrete an immune modulator (cytokine) called gamma interferon, which further stimulates the immune system to attack the pathogen. In the case of chronic hepatitis C, the team confirmed the relative lack of functional killer T cells specific for HCV. Furthermore, they were able to show that HCV-specific killer cells from non-responding patients could be induced to express T-bet, proliferate and produce gamma interferon in the test-tube by adding the cytokines interleukin-2 and interleukin-12. “The fact that two signal molecules are necessary to activate the CD8+ cells suggests that a stepwise process allows the immune system to adjust its response to pathogens,” says Kurktschiev.
The new results are potentially of clinical relevance: The level of T-bet expressed in CD8+ T-cells may provide doctors with a reliable marker that allows them to assess whether an acute HCV infection is likely to become chronic or undergo spontaneous resolution, as Kurktschiev points out. One could then dispense with the conventional antiviral therapy for the latter class of infected individuals.
In addition, the researchers demonstrated that in vitro activation of CD8+ cells with a combination of IL-2 and IL-12 allows them to use significantly lower doses of the cytokines than are required in previously tested treatment regimes. This finding too is of considerable interest for future therapies, as both interleukins can provoke unpleasant side-effects. (The Journal of Experimental Medicine 2014)