Role of Inflammatory B cells in Liver Fibrosis and Chronic HCV Infection

描述(申请人提供)：全球有超过1.7亿人感染丙型肝炎病毒(丙型肝炎病毒)，大多数人无法消除感染并持续感染。这些人中的相当一部分人将继续发展严重的并发症，包括肝纤维化、肝硬变和肝细胞癌。在美国，丙型肝炎病毒是导致肝功能衰竭和移植的主要原因，每年约有15,000人死于与丙型肝炎病毒相关的死亡。持续性感染的特点是抗病毒T细胞免疫反应差。早期的CD4+T细胞耗竭、CTL病毒表位逃逸、树突状细胞(DC)功能障碍和病毒逃避免疫识别是导致病毒持续感染的原因之一。然而，慢性丙型肝炎病毒感染过程中B细胞的免疫功能和抗体反应仍不清楚。慢性丙型肝炎病毒感染的特点是进行性肝纤维化，主要由一种称为肝星状细胞(HSC)的非实质细胞群介导，HSC主要在肝脏中储存维生素A(如维甲酸)。HSC位于内皮层和实质肝细胞之间，这一解剖位置使HSC既能与感染的肝细胞相互作用，又能与浸润性免疫细胞相互作用。在慢性丙型肝炎病毒感染过程中，HSC从静止状态转变为激活状态。虽然许多研究已经描述了这种HSC转变对纤维化形成的影响，但在慢性丙型肝炎感染期间，HSC频率与B细胞表型和肝脏功能之间的相关性尚不清楚。本研究的目的是了解丙型肝炎病毒感染过程中HSC和B细胞之间的分子相互作用，并确定这些相互作用将如何影响肝脏免疫反应的结果。我们将从四个不同的方向探讨这些问题：(I)确定HSC-B细胞在体外的相互作用，并利用原代小鼠HSC和B细胞确定决定B细胞命运的关键分子；(Ii)使用体内小鼠肝纤维化模型确定B细胞在肝纤维化中的特定作用；(Iii)表征慢性感染的人类丙型肝炎患者肝脏和外周血中B细胞亚群的表型和功能；以及(Iv)比较慢性丙型肝炎与非酒精性脂肪性肝炎(NASH)和酒精性肝病(Etoh)对随后B细胞功能调节的影响。总体而言，我们的目标是了解HSC和B细胞在慢性肝病期间肝纤维化中的作用，以及它们对人类肝脏和肝外表现的贡献。由于B细胞是产生免疫球蛋白的主要细胞，因此可以通过靶向慢性丙型肝炎病毒感染期间的B细胞功能来探索一些基于细胞的新疗法。

DESCRIPTION (provided by applicant): 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.