More than 170 million people worldwide are infected with hepatitis C virus (HCV) and the majority are unable to resolve the infection and remain persistently infected. A significant number of these individuals will go on to develop severe complications including liver fibrosis, cirrhosis, and hepatocellular carcinoma. HCV is a leading cause of liver failure and transplantation in the United States with approximately 15,000 HCV-associated deaths each year. Persistent infection is characterized by a poor antiviral T cell immune response. The early CD4+ T cell exhaustion, CTL viral epitope escape, dendritic cells (DC) dysfunction and viral evasion of immune recognition contribute to persistent viral infection. However, the immunological function of B cells and antibody responses during chronic HCV infection remains elusive. The chronic HCV infection is characterized by progressive liver fibrosis largely mediated by a nonparenchymal cell population known as hepatic stellate cells (HSC), which mainly store vitamin A (e.g. retinoids) in the liver. HSC reside in the space between the endothelial layer and parenchymal hepatocytes, and this anatomical position enables HSC to interact both with the infected hepatocytes and infiltrating immune cells. During chronic HCV infection, HSC transition from a state of quiescence to activation. Although many studies have described the effect of this HSC transition on fibrogenesis, the correlation between HSC frequency and B cell phenotype and function in the liver during chronic hepatitis C infection is unclear. The objective of this study is to understand the molecular interaction between HSC and B cells during HCV infection and determine how these interactions would affect the outcome of immune responses in the liver. We will approach these questions from four different directions: (i) to determine HSC-B cell interaction in vitro and identify the key molecules that instruct the fate of the B cells using primary murine HSC and B cells; (ii) to determine the specific role of B cells in liver fibrosis using in vivo murine models of liver fibrosis; (iii) characterize the B cell subsets phenotypes and functions in the liver and peripheral blood of chronically infected human HCV patients; and (iv) to compare the effects of chronic HCV infection to non-alcoholic steatohepatitis (NASH) and alcoholic (ETOH) liver diseases on consequent modulations in B cell functions. Overall, our goal is to understand the role of HSC and B cells in hepatic fibrosis during chronic liver diseases and their contribution to hepatic as well as extra-hepatic manifestations in humans. As B cells are primary cells that produce immunoglobulins, a number of novel cell-based therapies can be explored by targeting B cell function during chronic HCV infection.
This proposed work is designed to study the molecular interactions between hepatic stellate cells (HSC) and intrahepatic B cells in the liver during chronic hepatitis C virus (HCV) infection. A better understanding of the role of HSC and B cells in the process of hepatic fibrogenesis during chronic liver disease is necessary in order to explore therapeutic interventions targeting important molecules involved in the liver fibrosis and HCV- associated disorders.
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