In chronic hepatitis B, the liver contains immune cells that could destroy cells infected with the hepatitis B virus, but are inactive. A team at the Technical University of Munich (TUM) has discovered that cells in the blood vessels of the liver set off a “sleep timer” that switches off the immune cells. An attack on this mechanism could be a starting point for immunotherapies.

Hepatitis B and the Consequences

Hepatitis B is a widespread disease. According to estimates by the World Health Organization (WHO), 250 million people worldwide suffer from chronic hepatitis B. The most common health consequence of chronic hepatitis B is liver damage. Often it is not the virus itself, but the body’s immune response to the infected cells that is responsible for the damage: immune cells trigger inflammatory processes that can lead to fibrosis – scarring of the liver tissue – and liver cancer.

In chronic hepatitis B, the body’s own immune system tries to destroy the infected liver cells, which leads to long-term damage and still cannot get rid of the virus. Particularly in chronic infections, some immune cells whose receptors could recognize and destroy the hepatitis B virus are inactive.

New Ways to effectively Treat a Chronic Hepatitis B Infection

A team led by Prof. Knolle describes the reason for this in Nature. The hepatitis B virus specifically infects hepatocytes. These cells make up the majority of liver tissue. They are supplied by small blood vessels that are lined with endothelial cells. Immune cells that enter the liver via the blood only reach the infected hepatocytes through special openings in these endothelial cells. They eject projections through these openings in order to reach the infected hepatocytes and trigger their destruction. In doing so, they are forced into close contact with the endothelial cells.

The researchers show that the endothelial cells set off a kind of molecular timer in certain immune cells – cytotoxic T cells that can recognize hepatocytes infected with the hepatitis B virus,” says Dr. Miriam Bosch, first author of the study. The timer starts to run as soon as the T cells come into contact with the infected hepatocytes. The longer the T cells are in contact with the endothelial cells, the weaker their activity becomes – comparable to the volume of music, which decreases before the sleep timer stops it completely.

Specifically, the endothelial cells use the cAMP-PKA pathway to switch off the signal transmission of the receptors with which the T cells recognize the hepatitis B virus and through which they are activated. As a result, the immune cells no longer attack the infected cells and, above all, can no longer multiply. The researchers believe that this mechanism has evolved to protect the liver. The time limit prevents the immune cells from multiplying too much during an infection and potentially causing severe damage to the liver when the infected hepatocytes are destroyed.mIn some cases, however, the time window for fighting the virus is apparently too short and the virus escapes the control of the immune system. As new T cells are constantly attacking the infected hepatocytes, chronic hepatitis B leads to organ damage despite the protective mechanism, and the search is now beginning for ways to influence this mechanism.

In this way, we could support the immune system in effectively combating a chronic hepatitis B infection. On the one hand, targeted immunotherapies are conceivable in which T cells are manipulated in such a way that they are no longer receptive to the signals from the endothelial cells. On the other hand, it could also be possible to switch off the mechanism using small molecules that target this mechanism. However, it is crucial that the active substances are delivered specifically to immune cells in the liver so that no vital processes in other cells of the body are affected. The researchers believe that such therapies could enhance the effect of vaccinations and thus help to combat chronic hepatitis B, which is particularly widespread in poorer regions of the world.