In cases of chronic hepatitis B, immune cells in the liver that have the potential to eliminate hepatitis B virus-infected cells remain inactive. Scientists have identified that blood vessel cells in the liver initiate a ‘sleep timer’ mechanism that deactivates these immune cells. This finding could serve as a foundation for developing immunotherapies targeting this process.
Hepatitis B is a prevalent global disease with an estimated 250 million individuals suffering from chronic hepatitis B, as reported by the World Health Organization (WHO). Liver damage is a common health consequence of this chronic condition. Interestingly, the damage often results from the body’s immune response towards infected cells rather than the virus itself. Immune cells trigger inflammatory reactions that can lead to liver tissue scarring known as fibrosis and even liver cancer.
“In chronic hepatitis B, the immune system attempts to eliminate infected liver cells, causing prolonged harm without successfully clearing the virus,” states Professor Percy Knolle, an expert in Molecular Immunology at the Technical University of Munich (TUM). Particularly, in cases of chronic infection, certain immune cells equipped with receptors capable of identifying and destroying the Hepatitis B virus remain inactive.
Role of Blood Vessel Cells in Regulating Immune Response
Professor Knolle’s team, as detailed in Nature, elucidated this phenomenon. The hepatitis B virus predominantly infects hepatocytes, the primary cells in liver tissue. These cells are supplied by small blood vessels lined with endothelial cells. Immune cells entering the liver through the bloodstream can only access infected hepatocytes through specific openings in these endothelial cells. To reach the infected cells and initiate their destruction, immune cells extend projections through these openings, bringing them into close proximity with the endothelial cells.
“Our research shows that endothelial cells induce a molecular ‘sleep timer’ in certain immune cells, specifically cytotoxic T cells capable of identifying hepatitis B virus-infected hepatocytes,” explains Dr. Miriam Bosch, the lead author of the study. “This timer starts once the T cells establish contact with the infected hepatocytes. Prolonged contact leads to decreased activity in the T cells, akin to the volume reducing before the music stops when a sleep timer activates.”
Specifically, endothelial cells employ the cAMP-PKA pathway to deactivate the signaling of receptors on T cells responsible for recognizing the Hepatitis B virus and initiating their activation. Consequently, immune cells no longer launch attacks on infected cells and, crucially, are unable to replicate.
Potential Protective Function
“We propose that this mechanism evolved as a protective measure for the liver,” posits Percy Knolle. “The time limit prevents excessive proliferation of immune cells during an infection, potentially preventing severe damage to the liver when infected hepatocytes are destroyed.” However, in some instances, the timeframe for combatting the virus proves inadequate, resulting in the virus evading immune control. Continuous attacks by new T cells on infected hepatocytes contribute to organ damage in chronic hepatitis B despite the safeguarding mechanism.
“The focus now shifts to exploring methods to influence this mechanism,” notes Percy Knolle. “This could involve targeted immunotherapies where T cells are modified to become unresponsive to signals from endothelial cells. Alternatively, it may be possible to inhibit this mechanism using small molecules directed at this process. However, delivering active compounds specifically to immune cells in the liver to avoid affecting essential processes in other body cells is critical. Researchers believe such therapies could enhance the efficacy of vaccinations and aid in combatting chronic hepatitis B, particularly prevalent in less affluent regions worldwide.”
