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)： 丙型肝炎感染影响了大约390万美国人，并对退伍军人的健康造成了不成比例的影响。大约三分之一的感染者会发展成进行性肝纤维化，最终发展为肝硬变。细菌感染和败血症是肝硬变患者发病率和死亡率的主要原因。肝硬变对感染的易感性在很大程度上归因于肠道内细菌移位的增加，即天然免疫保护机制的减弱。此外，长期以来，对疫苗的抗体反应在肝硬变患者中被证实是无效的，这表明B细胞激活存在缺陷。然而，B细胞功能障碍在肝硬变免疫功能受损状态中的作用在很大程度上仍未被探讨。我们新的初步数据表明，肝硬变与CD27+记忆性B细胞的消失有关，导致B细胞活化受损，B细胞刺激T细胞的能力降低。初步研究表明，肝硬变血浆中可溶性因子升高可能导致B细胞过度激活， CD27+B细胞Fas表达明显增加，CD268/BAFF-R等促生存受体表达降低。我们假设，肠道易位引起的慢性过度激活导致激活诱导记忆B细胞的凋亡，或者转化为效应能力较弱的“耗尽”的CD27-CD21记忆B细胞群。这项建议的目的是纵向证实横断面研究中确定的B细胞功能障碍与肝硬变的关系，研究肝硬变对B细胞增殖和凋亡的影响，并在翻译研究中探索体内逆转这种功能障碍的方法。这项研究包括使用受试者捐赠的血液和组织样本进行的B淋巴细胞功能的体外研究，以及在有和没有临床干预的情况下对B细胞记忆频率的前瞻性研究。首先，我们将检查损失是否 CD27+B细胞在肝硬变中的表达反映了先天B1型B细胞的特异性缺失，这对预防细菌性败血症至关重要。其次，我们将检测CD40下游的核因子B、BAFF-R和TLR9等信号通路的激活对CD27+B细胞活化的影响。最后，我们将纵向跟踪B细胞在药物减少细菌易位、治愈丙型肝炎病毒血症后以及在移植围手术期的表型和功能，以评估肠道易位、门脉高压和病毒血症对维持肝硬变患者B细胞功能障碍的影响。这些研究的最终目标是确定在哪些条件下肝硬化患者的B细胞功能可以得到改善 活体治疗可降低肝硬变感染性并发症的发病率和死亡率。