Gastroenterology
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Cellular Mechanism for Severe Viral Hepatitis Identified
(Professor Shin(left) and Professor Jung)
KAIST medical scientists identified a cellular mechanism causing inflammatory changes in regulatory T cells that can lead to severe viral hepatitis. Research on this mechanism will help further understand the nature of various inflammatory diseases and lead to the development of relevant clinical treatments.
It is known that activated immune cells of patients with viral hepatitis destroy hepatocyte, but its regulatory mechanism has not yet been described.
Regulatory T cells inhibit activation of other immune cells and thus are important for homeostasis of the immune system. However, recent studies contradictorily show that immune inhibitory functions of regulatory T cells weaken in inflammatory conditions and the cells secrete inflammatory cytokines in response. Meanwhile, such a phenomenon was not observed in viral hepatitis including types A, B and C.
The team focused on changes in regulatory T cells in patients with viral hepatitis and discovered that regulatory T cells undergo inflammatory changes to secrete inflammatory cytokines (protein secreted by immune cells) called TNF. They also proved regulatory T cells that secrete TNF contribute to the progression of viral hepatitis.
The team confirmed that regulatory T cells of acute hepatitis A patients have reduced immune-inhibitory functions. Instead, their regulatory T cells secrete TNF. Through this research, the team identified a molecular mechanism for changes in regulatory T cells and identified the transcription factor regulating the process. Furthermore, the team found similar changes to be also present in hepatitis B and C patients.
A KAIST immunology research team led by Professors Eui-Cheol Shin and Min Kyung Jung at the Graduate School of Medical Science & Engineering conducted this translational research with teams from Chungnam National University and Yonsei University to identify the mechanism in humans, instead of using animal models. The research was described in Gastroenterology last December.
Professor Shin said, “This is the first research on regulatory T cells that contributes to hepatocyte damage in viral hepatitis.” He continued, “It is significant for identifying the cells and the molecules that can be used as effective treatment targets for viral hepatitis in the future. This research was funded by the Samsung Science and Technology Foundation.
(Figure1: Treg cells from acute hepatitis A (AHA) patients produce tumor necrosis factor (TNF) andhave reduced suppressive activity. These changes are due to a decrease in FoxP3 transcription factor and an increase in RORγt transcription factor. TNF-producing Treg cells are associated with severe liver injury in AHA patients.)
(Figure 2: A higher proportion of Treg cells from patients with acute hepatitis A, compared with healthy controls, produced TNF upon stimulation with anti-CD3 and anti-CD2. This study reports the presence and the significance of TNF-producing Treg cells for the first time in human patients.)
2018.01.18 View 7757 -
Regulatory T Cells Influence Liver Damage of Hepatitis A Patients
Liver damage becomes more severe with the decrease of regulatory T cells
“This research will aid the development of hepatitis A targeted drug,” said a KAIST researcher.
The KAIST Graduate School of Medical Science and Engineering’s Professor Eui-Cheol Shin and his research team have identified the mechanism, explaining how the regulatory T cells are responsible for the body’s immune system and how they have induced liver damage of hepatitis A patients.
The research results were published online in the July 9th edition of ‘Gut,’ the world’s most prominent journal in the field of gastroenterology.
Hepatitis A is an acute form of hepatitis caused by hepatitis A virus. The virus spreads through oral contact and enters the body via digestive organs.
Regulatory T cells play an important role in maintaining the homeostasis of the body’s immune system by inhibiting the activation of other immune cells. In the case of chronic viral infections, regulatory T cells are known to contribute to the duration of the infection, weakening the immune response to virus infections. However, there has been no information on what roles the regulatory T cells perform in the case of acute viral infections.
The research team used the fluorescence flow cytometry technique to determine the number and characteristics of a variety of immune cells, including regulatory T cells, in the blood of hepatitis A patients.
Consequently, the researchers confirmed that the decrease in the regulatory T cells immune inhibitory ability was consistent with a significant reduction in the number of regulatory T cells in the blood of hepatitis A patients. Furthermore, it was identified that the more noticeable decrease of regulatory T cells led to the occurrence of a more severe liver injury.
The analysis of hepatitis A patient’s blood proved that the cause of the decrease in the number and function of regulatory T cells was the increased expression of cell surface protein ‘Fas,’ which induces cell death.
Professor Shin said, “This study is the first case which proposes the mechanism for clinical aspects in not only hepatitis A, but also acute virus infection.” He added on the future prospect of the research that: “In the future, we can prevent tissue damage by inhibiting cell death of regulatory T cells for severe acute viral infections that do not have an effective treatment for the virus itself.”
[Picture]
The picture shows the process of fluorescence flow cytometry technique to study regulatory T cell in the blood of hepatitis A patients.
2014.08.11 View 9643 -
Immune Evasion Mechanism of Hepatitis C Virus Revealed
Professor Ui-Cheol Shin
Inhibiting major histocompatibility complex [MHC] class I protein expression, T cell immune response is evaded.
The research will be a great help to the development of C hepatitis vaccine.
Roughly 1-2% of the population in Korea is known to be infected with Hepatitis C. Most Hepatitis C Virus (HCV) infections progress to a chronic disease and can cause liver cirrhosis or liver cancer, which may lead to death.
Unlike Hepatitis type A or B, there is no vaccine for Hepatitis C Virus and therefore avoiding exposure to the virus is the best known method of prevention. However, a team of researchers at KAIST has produced research results, which may contribute significantly to the vaccine development.
KAIST Graduate School of Medical Sciences & Engineering’ Professor Ui-Cheol Shin and his team have successfully identified why Hepatitis C Virus does not cause an immune response within the human body. The research results were published in the May edition of The Journal of Gastroenterology, a world-renowned journal in the field of gastroenterology.
The immune response occurs to eliminate the virus that has invaded our body. During this process, a major histocompatibility complex [MHC] class I plays a key role in inducing T cell response, which is needed for the elimination of virus-infected cells.
When a cell is infected by a virus, a substance called interferon causes the increased expression of major histocompatibility complex class I. T cell recognizes the increased MHC class I and therefore finds the virus-infected cells.
However, the effect that Hepatitis C Virus has on major histocompatibility complex class I has not been clearly identified until now.
The research team has revealed, using a cell culture for infection systems, that the Hepatitis C Virus suppresses the expression of major histocompatibility complex class I. Also, the mechanism to prove that HCV activates a protein called PKR within the cell to inhibit MHC class I protein expression was identified at a molecular level.
In this study, researchers established the hypothesis that regulating PKR protein in the cell can enhance the T cell immune response, which was then proved through experiments.
Professor Ui-Cheol Shin said, “There are a lot of new drugs to treat Hepatitis C Virus, while its vaccine has not been developed yet. Revealing the HCV immune evasion mechanism will help stimulate momentum for the HCV vaccine development.”
The first author of the journal, Dr. Won-Seok Kang is a graduate from Yonsei College of Medicine. After earning his medical degree, he has continued his training as a ‘doctor-scientist’ at KAIST Graduate School of Medical Sciences & Engineering to study Hepatitis C Virus immune evasion mechanism in this research.
Hepatitis C Virus activates PKR-eIF2a pathway, which inhibits the major histocompatibility complex class I, and therefore weakens the T cell activation to the viral activity.
2014.05.19 View 10455