In the realm of chronic hepatitis B, the liver plays host to immune cells that possess the potential to destroy hepatitis B virus infected cells, yet remain inactive. A groundbreaking discovery made by a team of scientists from the Technical University of Munich (TUM) has unveiled a remarkable phenomenon where cells within the blood vessels of the liver initiate a “sleep timer” that effectively disables these immune cells. This newfound insight holds the key to potentially revolutionizing immunotherapies for the treatment of chronic hepatitis B.
Hepatitis B is a prevalent global health issue, with an estimated 250 million individuals grappling with chronic hepatitis B worldwide, as reported by the World Health Organization (WHO). The primary health complication arising from chronic hepatitis B is liver damage, where the body’s immune response to infected cells triggers inflammatory processes that can culminate in liver fibrosis and ultimately, liver cancer.
“In chronic hepatitis B, the body’s immune system launches an attack on infected liver cells, leading to prolonged damage without ultimately eradicating the virus,” explains Professor Percy Knolle, a distinguished figure in the field of Molecular Immunology at TUM. Notably, within chronic infections, certain immune cells equipped with receptors capable of identifying and eliminating the Hepatitis B virus remain dormant.
The Role of Blood Vessel Cells in Limiting Immune Response
Professor Knolle’s team, featured in a recent publication in Nature, delves into the mechanisms at play. The hepatitis B virus specifically targets hepatocytes, the predominant cell type within liver tissue. These hepatocytes are nourished by intricate blood vessels lined with endothelial cells, providing a gateway for immune cells traveling through the bloodstream to reach infected hepatocytes via specialized openings in the endothelial cells. Through these apertures, immune cells extend protrusions to connect with infected hepatocytes, instigating their destruction and prompting intimate contact with endothelial cells in the process.
“Our research illustrates how endothelial cells initiate a molecular ‘sleep timer’ within specific immune cells – cytotoxic T cells tasked with identifying hepatocytes infected with the hepatitis B virus,” notes Dr. Miriam Bosch, the study’s lead author. “This timer commences once T cells engage with infected hepatocytes, gradually diminishing their activity akin to the gradual fade-out of music before reaching a complete halt.”
Specifically, endothelial cells employ the cAMP-PKA pathway to deactivate signal transmission from receptors that enable T cells to recognize the Hepatitis B virus and trigger their activation. Consequently, immune cells lose their ability to target infected cells and crucially, become unable to proliferate.
Presumed Protective Function of the Mechanism
“We hypothesize that this mechanism serves as a protective measure for the liver,” asserts Percy Knolle. “The time constraint prevents excessive proliferation of immune cells during an infection, which could potentially inflict significant damage on the liver while combating infected hepatocytes.” Nevertheless, in certain scenarios, the window for combatting the virus appears to be too brief, allowing the virus to elude immune surveillance. As new T cells persist in attacking infected hepatocytes, chronic hepatitis B ensues, resulting in organ damage despite the protective mechanism.
“The pursuit now shifts towards manipulating this mechanism,” states Percy Knolle. “In doing so, we may fortify the immune system’s ability to combat chronic hepatitis B infections effectively.” This endeavor opens up the possibility of targeted immunotherapies where T cells undergo manipulation to resist signals from endothelial cells. Additionally, the potential exists for the development of small molecules that target and disable this mechanism. Vital to this approach is the precise delivery of active agents exclusively to immune cells in the liver, thereby averting disruption to essential processes in other cells across the body. Researchers are optimistic that such therapeutic interventions could enhance the efficacy of vaccinations, bolstering efforts to combat chronic hepatitis B more effectively, particularly in underserved regions worldwide.
