B-Cell Dysregulation in Cirrhosis due to Chronic Hepatitis C Infection

慢性丙型肝炎感染引起的肝硬化中的 B 细胞失调

• 批准号: 8633581
• 负责人: David E Kaplan
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633581
• 关键词: Affect; Alcohol consumption; American; Antibodies; Antibody Formation; Antiviral Therapy; Apoptosis; Apoptotic; Automobile Driving; B Cell Proliferation; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Bacterial Infections; Bacterial Translocation; Blood specimen; CD95 Antigens; Cell Survival; Cell physiology; Cells; Cessation of life; Characteristics; Chronic; Chronic Hepatitis C; Cirrhosis; Clinical; Clinical Management; Complement 3d Receptors; Cross-Sectional Studies; Data; Defect; Development; Diabetes Mellitus; Disease; Disease Progression; Etiology; Failure; Frequencies; Functional disorder; Goals; HIV; Health; Health Care Costs; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Homeostasis; Human; Human Identifications; Humoral Immunities; Immune; Immunity; Immunocompromised Host; Immunoglobulin M; Immunoglobulins; In Vitro; Individual; Infection; Intervention; Investigation; Lead; Liver; Liver Cirrhosis; Liver Fibrosis; Lymphocyte Function; Maintenance; Mediating; Memory; Memory B-Lymphocyte; Morbidity - disease rate; Mus; Obesity; Pathogenesis; Patients; Peritonitis; Phenotype; Physiology; Plasma; Play; Population; Portal Hypertension; Predisposition; Prevention strategy; Primary carcinoma of the liver cells; Prospective Studies; Receptors, Antigen, B-Cell; Relative (related person); Research; Resolution; Rest; Risk; Role; Sepsis; Signal Pathway; Staging; Syndrome; T-Lymphocyte; TNFRSF5 gene; TNFRSF6 gene; Therapeutic; Time; Tissue Sample; Tumor Antigens; Vaccines; Veterans; Viral; Viremia; Virus; Virus Diseases; Work; antimicrobial; base; cancer prevention; cohort; cytokine; exhaust; exhaustion; human subject; improved; in vivo; insight; liver transplantation; microbial; mortality; novel; pathogen; public health relevance; receptor; receptor expression; translational study

DESCRIPTION (provided by applicant): Hepatitis C infection affects approximately 3.9 million Americans and disproportionately impacts the health of veterans. Approximately one-third of infected individuals will develop progressive liver fibrosis culminating in cirrhosis. Bacterial infections and sepsis are prominent causes of morbidity and mortality in patients with cirrhosis. Susceptibility to infections in cirrhosis has largely been attributed to increased bacterial translocation across the gut in the setting of reduced innate immune protective mechanisms. Additionally, antibody responses to vaccines have been long established to be inefficient in cirrhotic patients, suggesting a defect in B-cell activation. However, the contribution of B-cell dysfunction to the cirrhotic immunocompromised state has largely remained unexplored. Our novel preliminary data demonstrate that cirrhosis is associated with the disappearance of CD27+ memory B-cells, leading to impaired B-cell activation and reduced capacity of B-cells to stimulate T-cells. Preliminary investigation suggests that soluble factors elevated in cirrhotic plasma may lead to B-cell hyperactivation, that Fas expression is markedly increased on CD27+ B-cells and expression of pro-survival receptors such as CD268/BAFF-R are reduced. We hypothesize that chronic hyperactivation due to gut translocation leads to either activation-induced apoptosis of memory B-cells or conversion to an "exhausted" CD27-CD21- memory B-cells population with weak effector capacity. The objectives of this proposal are to longitudinally confirm the association of B-cell dysfunction and cirrhosis identified in cross-sectional studies, to study the impact of cirrhosis o B-cell proliferation and apoptosis, and to explore approaches to reverse this dysfunction in vivo in translational studies. The research encompasses in vitro studies on B-lymphocyte function using blood and tissue samples donated by human subjects in addition to prospective studies of B-cell memory frequency with and without clinical interventions. First, we will examine if the loss of CD27+ B-cells in cirrhosis reflects specific deletion of innate B1-type B-cells critical for protection against bacterial sepsis. Second, we will examine activation of signal pathways such as NF B downstream of CD40, BAFF-R and TLR9 on the activation of CD27+ B-cells in cirrhosis relative to healthy donors. Lastly, we will longitudinally follow the phenotype and function of B-cells in after pharmacological reduction of bacterial translocation, cure of HCV viremia, and in the peritransplant setting to assess the impact of gut translocation, portal hypertension and viremia on maintenance of B-cell dysfunction in cirrhotic patients. The ultimate goal of these studies is to identify conditions under which cirrhotic patient B-cells function can be improved in vivo to reduce the morbidity and mortality of infectious complications of cirrhosis.

描述（由申请人提供）：