Cd39 ~ + ~ The Foxp3 + Regulatory T Cells (treg) And Hepatitis B Slow Expedited Liver Failure (aclf) Correlation

Hepatitis B caused by the hepatitis B virus (HBV), is a worldwide disease and a high incidence in developing countries. According to statistics, about 280 million people worldwide are chronically infected with HBV, among which 100 million are Chinese. There are around 20 million Chinese each year get Hepatitis who are chronically infected with HBV, and around 300 thousand people who die of liver failure, cirrhosis and cancer caused by the hepatitis B virus infection. China incurs high medical expenses for the treatment of hepatitis B patients each year. Hepatitis B has become a public health problem that needs to be resolved urgently.Acute on chronic liver failure is developed from chronic hepatitis. Many factors may lead to the acute exacerbation of liver damage. As a result, a large number of liver cells necrosis leads to liver failure, hepatic encephalopathy, hepatorenal syndrome, gastrointestinal bleeding, infection and other serious complications. The mortality rate is extremely high. Present study shows that the pathogenesis of acute on chronic liver failure include HBV viral replication, host immune reactions, infection and other factors, but the exact mechanism remains to be further studied. In recent years, clinical studies suggest that patients with immune dysfunction may be one of the main mechanisms.Regulatory T cells (Treg) are a group of cells which are responsible for immunoregulation. Their characteristic phenotypes are CD4, CD25 and FoxP3. Treg have two distinctive characteristics including immunity non-reactivity and immunity suppression. Studies have confirmed that the changes of the number and function of Treg cells are associated with many diseases, such as autoimmune diseases, cancer and infectious diseases. Recent studies have found that the role of immunoregulation by Treg cells is mainly concentrated in CD39+Fxop3+Treg subset. As a member of the ectonucleoside triphosphate diphosphohydrolase family, CD39 can degrade ATP/ADP. A notable amount of extracellular ATP is an indicator of tissue destruction. Seeing that the intracellular ATP concentration is rather high, a significant amount of ATP will be released upon cell damage. The presence of extracellular ATP will be sensed by purinergic P2 receptors, which would then induce proinflammatory responses. CD39 inactivates ATP, thus it inhibits the inflammatory responses induced by the ATP. Present studies found that CD39 is primarily expressed on Treg cells'membranes, and it plays an important role in the immunoloregulation function of Treg cells. Studies have confirmed that immunity suppression of CD39+Foxp3+Treg cells are remarkable stronger than that of CD39-Foxp3+Treg cells. Numeral or functional abnormalities of CD39+Foxp3+Treg cells are linked to a variety of diseases. It has been confirmed that the number of Treg cells in patients with different degrees of MS has no significant difference from that in healthy individuals. However, the ratio of Treg cells expressing CD39 to total Treg cells shows a remarkable difference. Both MS patients in stable conditions and healthy individuals have a significantly higher number than what is found in recurrent patients.HBV chronic infection is characterized by its weak virus-specific immune response. The chronic active state of hepatitis B may be related to abnormal immune tolerance, but the reasons for this abnormailty are unclear. Treg cells can inhibit the functions of effective T cells. Recent studies have found that Treg cells play an important role in anti-HBV specific immune response, which leads to liver injury. Currently, whether CD39+Treg cells are involved in the pathogenesis of acute on chronic liver failure still remains unknown. There has been no domestic or foreign article published concerning this topic.To investigate the relationship between CD39+Treg cells and the pathogenesis of acute on chronic liver failure , we did the following: 1) analyzed CD39+Treg cells'phenotypes; 2) looked into functional characteristics of human peripheral blood; 3) compared the CD39+Treg cells to CD4+T cells ratio of patients with acute on chronic liver failure to that of healthy people; 4) compared the CD39+Treg cells to CD4+T cells ratio of dead patients to that of survival patients. Our studies include the three aspects shown below.I. Phenotype identification of human peripheral blood CD39+FoxP3+ Treg cells.To investigate the relationship between CD39+Treg cells and acute on chronic liver failure associated with chronic HBV infection, we first examined the Treg cells phenotypes of human peripheral blood. FACS results showed that using CD39 as a marker, FoxP3+Treg cells could be divided into two groups: CD39+FoxP3+Treg cells and CD39-FoxP3+Treg cells. CTLA-4, HLA-DR, CD45RO and Ki-67 surface markers of CD39+FoxP3+Treg cells were significantly higher than those of CD39-FoxP3+Treg cells. This finding provides the fundamentals for our next experiment about cell function.II. Function analysis of human peripheral blood CD39+FoxP3+Treg cells Besides phenotype identification, determining whether Treg cells have immunosuppression function in vivo or in vitro environment is more important. In this part of the experiment,we monitored the suppressive capacity of CD39+FoxP3+ Treg cells and CD39-FoxP3+Treg cells in regards to proliferation of PBMC and IFN-γsecretion of PBMC. Results showed that CD39+FoxP3+Treg cells were more effective than CD39+FoxP3+Treg cells in suppressing PBMC proliferation and IFN-γsecretion of PBMC.III. Comparing the number of CD39+FoxP3+Treg cells in healthy people and that in patients suffering from acute on chronic liver failure associated with chronic HBV infectionTo determine whether CD39+FoxP3+Treg cells are closely related with acute on chronic liver failure associated with chronic HBV infection, we compared the CD39+ FoxP3+Treg cells to CD4+T cells ratio of patients with acute on chronic liver failure to that of healthy people, and compared the CD39+FoxP3+Treg cells to CD4+T cells ratio of survival patients to that of dead patients. Our findings show that the ratio of patients with acute on chronic liver failure associated with chronic HBV infection is significantly higher than that of healthy people, and the ratio of survival patients is significantly higher than that of the dead patients.In this study, we observed the changes of CD39+FoxP3+Treg in patients with acute on chronic liver failure associated with chronic HBV infection, and validate its immunosuppression function. Our study provides a new thread for futher study of pathogenesis of acute on chronic liver failure associated with chronic HBV infection.