Chronic Hepatitis B virus (HBV) infection affects 250 million patients worldwide. Dr. Baruch S. Blumberg discovered the Hepatitis B virus for which he won the Nobel Prize in Physiology and Medicine in 1976. According to WHO, there are about 1.2 million new cases every year, totaling up to 254 million people in 2022. The infection can be acute (short and severe) or chronic (long-term). Chronic hepatitis B can lead to cirrhosis and liver cancer.
The Discovery
Prof. Percy Knolle and Dr. Miriam Bosch, along with an interdisciplinary research team, have discovered a mechanism to switch off immune cells present in the liver that have the ability to destroy virus-infected hepatocytes.
“In chronic hepatitis B, the body’s immune system tries to destroy infected liver cells, thereby causing long-term damage, and still does not get rid of the virus,” says Percy Knolle, Professor of Molecular Immunology at Technical University of Munich.
The immune cells present in the blood inside the liver enter into hepatocytes by passing through special openings (fenestrations) in endothelial cells. These endothelial cells line the blood vessel wall. Immune cells and other molecules and nutrients pass through fenestrations between endothelial cells and enter into extracellular space and into liver cells. Due to this mechanism, the immune cells remain in contact with endothelial cells for a significant amount of time before reaching the viral-infected hepatocytes.
“We show that the endothelial cells start a kind of molecular sleep timer in certain immune cells – cytotoxic T cells that can detect hepatocytes infected with the hepatitis B virus,” says Dr. Miriam Bosch, first author of the study. “The timer starts running as soon as the T cells get 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 decreasing before the sleep timer stops it altogether.
However, scientists believe that this mechanism exists to protect the liver from its own immunity. “We think that this mechanism evolved to protect the liver,” says Percy Knolle. “The time limit prevents immune cells from proliferating too much during an infection and potentially critically damaging the liver when destroying infected hepatocytes.” Chronic Hepatitis B infection potentially leads to cirrhosis and liver cancer as the virus infects hepatocytes and our CD8+ T-cells keep attacking and destroying viral-infected hepatocytes.
Therapeutic approaches
With this discovery, we can target this mechanism to our advantage and reduce the time period for immune cells. Endothelial cells use cyclic AMP-protein Kinase A pathway to regulate immune cell priming against chronic Hepatitis B infection. This pathway from the endothelial cells can be targeted to decrease the switch-off mechanism. This can be done by manipulating T cells to become unresponsive to this mechanism or by small molecules that target this mechanism. Delivering small molecules to only liver immune cells is essential so as to not disrupt other vital organs. This can help in boosting vaccination and therapies to combat chronic hepatitis B infection.
How does Hepatitis B get transmitted?
Hepatitis B gets transmitted in various ways such as:
1. Mother-to-child transmission (vertical transmission): This is the most common transmission route worldwide, particularly in regions with high prevalence. It occurs during childbirth when the mother passes the virus to her baby.
2. Sexual transmission: Unprotected sexual contact with an infected person can lead to transmission of the virus.
3. Parenteral transmission: Sharing of needles, syringes, or other drug-injection equipment; tattooing and piercing; exposure to infected blood through injuries; and use of improperly sterilized medical or dental equipment.
4. Household transmission: Close household contact with an infected person can also be a source of transmission, though less common
What happens in chronic Hepatitis B infection vs acute
Hepatitis B infection can be acute or chronic depending upon the duration of the infection inside the human body. In acute Hepatitis B, there is an initial prodrome of symptoms resembling serum sickness such as:
- Nausea
- Vomiting
- Weight loss
- Bone pain
- Rash, etc.
These symptoms will progress to jaundice, fever, and right upper abdominal pain in many cases. The majority of cases will run their course for 2-3 weeks with complete clinical and labs recovery by 16 weeks. However, in a few cases, and especially in old people/neonates and people with comorbidities such as Diabetes mellitus and Hypertension, the acute infection can progress to liver failure or chronic Hepatitis B infection.
A chronic Hepatitis B infection is defined as an infection persisting longer than 6 months. The function of the liver declines and the likelihood of complications such as cirrhosis and liver cancer rises exponentially. The Hepatitis D virus can cause acute infection on chronic hepatitis B infection which is called superinfection.
How to know if you have Hepatitis B infection
Hepatitis B infection is diagnosed via signs/symptoms and laboratory values. There is a high amount of aminotransferases in the blood which can be identified by ordering liver function tests (LFTs) for your blood. There are several specific antigens and antibodies for Hepatitis B infection such as:
- HBsAg: It is a Hepatitis B surface antigen that marks the disease phase of the virus. Persistence of HbsAg more than 6 months after the acute illness indicates chronic Hepatitis B infection.
- Anti-HBs: It is an antibody against HbsAg. The presence of it indicates recovery from hepatitis B infection (disappearance of HBsAg). It is also present among vaccinated individuals against hepatitis b infection.
- Anti-HBc: It is an antibody against Hepatitis B core antigen. If the antibody is IgM, it marks the acute hepatitis B infection. If the antibody is IgG, it marks the chronic Hepatitis B infection.
- HBeAg: It is an antigen secreted by infected liver cells into blood circulation. It indicates active viral replication and hence, infectivity of the virus.
- Anti-HBe: It is an antibody against HBeAg. Its presence indicates decreased HBeAg and therefore, low transmissibility.
How do immune cells work in chronic Hepatitis B infection
Adaptive immune cells consist of B cells and T cells. An antigen-presenting cell (APC) would engulf the virus or viral antigens and present those antigens on their surface using Major Histocompatibility Complexes (MHCs).
Various immune cells from adaptive and innate immunity would recognize these antigens and release cytokines and immunoglobins that neutralize and kill hepatitis B. Out of these, one of the major mechanisms of immunity is performed by CD8+ T-cells that release enzymes that destroy the HBV-infected hepatocytes. This leads to hepatocyte destruction and liver damage seen in chronic Hepatitis B infection which can lead to scarring and fibrosis. This eventually progresses to cirrhosis and liver cancer.
Source: Technical University of Munich
Journal reference:
Bosch, M., Kallin, N., Donakonda, S., Zhang, J. D., Wintersteller, H., Hegenbarth, S., Heim, K., Ramirez, C., Fürst, A., Lattouf, E. I., Feuerherd, M., Chattopadhyay, S., Kumpesa, N., Griesser, V., Hoflack, J., Mogler, C., Swadling, L., Pallett, L. J., Meiser, P., . . . Knolle, P. A. (2024). A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection. Nature, 1-9. https://doi.org/10.1038/s41586-024-07630-7
