Storage and recall of human B cell memory of influenza over tissues and time

人类 B 细胞对流感的组织和时间记忆的存储和调用

• 批准号: 9219695
• 负责人: Scott Dexter Boyd
• 金额: $ 40.71万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-13 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9219695
• 关键词: Affect; Affinity; Age; Aging; Antibodies; Antibody Affinity; Antibody Repertoire; Antibody Specificity; Antigenic Specificity; Antigens; B-Lymphocytes; Binding; Blood; Blood specimen; Bone Marrow; Cell Lineage; Cell Separation; Cells; Clone Cells; Complex Mixtures; Development; Elderly; Epitopes; Frequencies; Future; Genes; Goals; Hemagglutinin; High-Throughput Nucleotide Sequencing; Human; Humoral Immunities; Immune; Immune system; Immunity; Immunoglobulin M; Impairment; Individual; Infection; Influenza; Influenza Hemagglutinin; Influenza vaccination; Knowledge; Lead; Longitudinal cohort; Memory; Memory B-Lymphocyte; Methods; Molecular; Monoclonal Antibodies; Mutate; Mutation; Organ Donor; Patients; Plasma Cells; Plasmablast; Population; Preparation; Sampling; Selection Criteria; Serum; Shapes; Somatic Mutation; Specificity; Spleen; TFRC gene; Testing; Time; Tissues; Vaccinated; Vaccination; Vaccines; Variant; Virus; Virus Diseases; age group; age related; antigen binding; cohort; experimental study; human subject; improved; influenza virus vaccine; lymph nodes; member; monoclonal antibody production; novel; novel vaccines; pandemic disease; pathogen; predicting response; response; seasonal influenza; vaccination strategy; vaccine response; vaccine trial; young adult

Project Summary Each individual elicits a diverse and complex mixture of different B cell clonal lineages after vaccination or infection, some of which are retained as memory B cells or plasma cells. However, the relationships between antibody specificity and affinity in determining which B cell lineages persist, which cellular compartments they occupy, and what future antigens they are able to recognize are not well understood. Detailed molecular understanding of the changes that decrease vaccine responses in old age has also been an elusive goal. We aim to overcome these barriers by studying a 5-year longitudinal cohort of healthy young adult and elderly human subjects vaccinated with seasonal influenza vaccine, as well as a cohort of deceased organ donors whose spleen, lymph nodes, bone marrow, and blood are sampled. We will compare the antibody repertoires and binding specificities of influenza-specific cells found in memory B cell pools compared to blood plasmablasts and a distinct CD71+ subset of “activated B cells” in the longitudinal cohort, and memory B cells in lymph nodes and spleen compared to bone marrow plasma cell (BMPC) pools in the organ donors. By studying the influenza hemagglutinin (HA) specificity of unmutated ancestors of antibody lineages, and the mutated memory B cell, plasmablast, activated B cell and BMPC progeny, we will determine: the extent to which somatic mutation alters the HA specificity of later members of the clonal lineage; whether future vaccine responses can be predicted from an individual's memory B cell pool; whether BMPCs are subject to different selection criteria than the memory B cells in the lymph nodes, spleen and blood; and the impact of human aging on each of these critical components of humoral immunity. This knowledge will help to shape strategies for improved vaccines for influenza, as well as the whole range of emerging pathogens for which new vaccines need to be developed.

项目摘要 每个个体在接种疫苗后产生不同B细胞克隆谱系的多样和复杂的混合物，或 感染，其中一些被保留为记忆B细胞或浆细胞。然而， 抗体特异性和亲和力在确定哪种B细胞谱系持续存在，哪种细胞区室 占据，以及它们能够识别什么样的未来抗原还不清楚。详细的分子 了解老年人疫苗反应降低的变化也是一个难以实现的目标。我们 旨在通过对健康的年轻人和老年人进行为期5年的纵向队列研究来克服这些障碍 接种季节性流感疫苗的人类受试者，以及死亡器官捐献者队列 采集其脾脏、淋巴结、骨髓和血液样本。我们将比较抗体库 以及与血液相比，在记忆B细胞池中发现的流感特异性细胞的结合特异性 浆母细胞和纵向队列中“活化B细胞”的不同CD 71+亚群，以及记忆B细胞 淋巴结和脾脏中的骨髓浆细胞（BMPC）池相比，在器官供体。 通过研究抗体谱系的未突变祖先的流感血凝素（HA）特异性， 突变的记忆B细胞、浆母细胞、活化的B细胞和BMPC后代，我们将确定： 体细胞突变改变了克隆谱系后来成员的HA特异性;未来的疫苗是否 可以从个体的记忆B细胞库预测反应; BMPC是否受到不同的免疫应答， 选择标准比记忆B细胞在淋巴结，脾脏和血液;和人类的影响， 对这些体液免疫的关键组成部分的影响。这些知识将有助于制定战略 改进流感疫苗，以及新疫苗所针对的所有新兴病原体， 需要加以发展。