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）： 丙型肝炎感染影响约390万美国人，对退伍军人的健康影响不成比例。大约三分之一的感染者会发展为进行性肝纤维化，最终导致肝硬化。细菌感染和败血症是肝硬化患者发病和死亡的主要原因。肝硬化对感染的易感性在很大程度上归因于先天免疫保护机制降低时肠道细菌移位增加。此外，对疫苗的抗体应答长期以来一直被认为在腹泻患者中是无效的，这表明B细胞活化存在缺陷。然而，B细胞功能障碍对免疫功能低下状态的贡献在很大程度上仍未被探索。我们新的初步数据表明，肝硬化与CD 27+记忆B细胞的消失有关，导致B细胞活化受损和B细胞刺激T细胞的能力降低。初步研究表明，血小板减少血浆中可溶性因子升高可能导致B细胞过度活化， Fas在CD 27 + B细胞上的表达显著增加，促存活受体如CD 268/BAFF-R的表达降低。我们推测，由于肠道易位导致的慢性过度活化导致激活诱导的记忆B细胞凋亡或转化为效应能力弱的“耗尽”CD 27-CD 21记忆B细胞群。本提案的目的是纵向确认在横断面研究中确定的B细胞功能障碍和肝硬化的关联，研究肝硬化对B细胞增殖和凋亡的影响，并探索在体内转化研究中逆转这种功能障碍的方法。该研究包括使用人类受试者捐赠的血液和组织样本对B淋巴细胞功能进行的体外研究，以及在有和没有临床干预的情况下对B细胞记忆频率进行的前瞻性研究。首先，我们将研究损失是否 肝硬化中CD 27 + B细胞的减少反映了先天性B1型B细胞的特异性缺失，这些细胞对于预防细菌性脓毒症至关重要。第二，我们将检查信号通路的激活，例如CD 40下游的NF B、BAFF-R和TLR 9对肝硬化中相对于健康供体的CD 27 + B细胞的激活。最后，我们将纵向跟踪B细胞的表型和功能，在药物减少细菌易位后，治愈HCV病毒血症，并在围移植设置，以评估肠道易位，门静脉高压症和病毒血症对维持B细胞功能障碍的影响，在消化道疾病患者。这些研究的最终目标是确定在何种条件下，可以改善阿尔茨海默病患者B细胞的功能， 降低肝硬化感染并发症的发病率和死亡率。