Clonal Dynamics of the antibody response

抗体反应的克隆动力学

• 批准号: 10521309
• 负责人: Gabriel D Victora
• 金额: $ 62.83万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10521309
• 关键词: 2019-nCoV; Affinity; Antibodies; Antibody Affinity; Antibody Response; Antibody titer measurement; Antibody-Producing Cells; Antibody-mediated protection; Antigens; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocytes; Biology; Bone Marrow; COVID-19 pandemic; Cell Maintenance; Cellular biology; Chronic; Clone Cells; Color; Data; Effectiveness; Epitopes; Funding; Goals; Grant; HIV; Hepatitis C virus; Home; Immune response; Immune system; Immunity; Immunization; Infection; Infection Control; Influenza; Influenza Hemagglutinin; Influenza vaccination; Investigation; Laboratories; Logic; Maps; Measures; Memory; Memory B-Lymphocyte; Methods; Modeling; Molecular; Mutate; Mutation; Parabiosis; Phase; Plasma Cells; Plasmablast; Play; Population; Property; Publications; Reaction; Research; Role; SARS-CoV-2 spike protein; Serum; Shapes; Source; Specificity; Structure; Structure of germinal center of lymph node; System; Testing; Time; Vaccination; Vaccines; Viral; Virus; Virus Diseases; Waxes; Work; cross reactivity; design; imprint; improved; neutralizing antibody; novel; pathogen; plasma cell differentiation; protective efficacy; response; seasonal influenza; stem; tool; universal vaccine; vaccination strategy

PROJECT SUMMARY Generating an appropriate antibody response is critical for protection against reinfection and for the effectiveness of vaccination, particularly in the context of viral diseases. In addition to well-studied quantitative parameters such as antibody titer and affinity, other, more qualitative parameters related to the clonal composition of the response also play critical roles in antibody-mediated protection. These include antigen and epitope specificity, which is key to viral neutralization capacity and antibody breadth, and overall clonal diversity, which strongly influences the degree of immunodominance and therefore the ability of viruses to escape immunity by mutation. Despite their importance, such “ecological” aspects of GC biology remain poorly understood and systematically understudied at the mechanistic level. Our long-term goal is to develop a mechanistic understanding of how the competitive waxing and waning of B cell clones at the various stages of the immune response shapes the ultimate composition, specificity, and protective efficacy of serum antibody. In our previous studies, using multicolor “Brainbow”-based B cell fate- mapping models, we focused on the germinal center (GC) and memory phases of the response, revealing how highly diverse early responders are funneled towards oligoclonality, first progressively by GC selection (including in chronic gut-associated GC) and then dramatically by secondary boosting. We now propose to extend our work using these same tools to investigate the clonal dynamics of prolonged selection in long-lived virus-induced GCs (Aim 1) and of the progressive differentiation of plasmablasts and plasma cells from GC precursors (Aim 2). We also propose a new “molecular fate-mapping” system to determine how clonal dynamics impact the ultimate composition of serum antibody (Aim 3). This allows us to investigate the B cell biology of serum-level phenomena such as antigenic imprinting/original antigenic sin, immunodominance, and viral escape. We expect our findings will provide greater mechanistic understanding of how the composition and protective effectiveness of serum antibody is determined by the dynamics of B cell clonal competition, with implications for the design of effective vaccination strategies for influenza, HIV, and SARS-CoV-2.

项目摘要 产生适当的抗体反应对于防止再感染和有效性至关重要 疫苗接种，特别是在病毒疾病的情况下。除了研究良好的定量参数外 例如抗体滴度和亲和力，其他与克隆组成相关的更多定性参数 反应在抗体介导的保护中也起着关键作用。这些包括抗原和表位特异性， 这是病毒神经化能力和抗体宽度以及总体克隆多样性的关键，这是强烈的 影响免疫主持的程度，因此影响病毒通过突变逃避免疫力的能力。 尽管它们的重要性，但GC生物学的这种“生态”方面仍然对 在机械水平上进行了研究。 我们的长期目标是对B的竞争打蜡和B的竞争方式建立机械理解 免疫反应的各个阶段的细胞克隆塑造了最终组成，特异性和 血清抗体的保护效率。在我们以前的研究中，使用基于多色的“ brainbow” B细胞命运 映射模型，我们专注于生发中心（GC）和响应的记忆阶段，揭示了如何 高度多样化的早期响应者被吸引到寡聚性，首先是由GC选择逐渐（包括 在慢性肠道相关的GC中），然后通过次级增强大幅度。我们现在建议扩展我们的工作 使用这些相同的工具来研究长期病毒诱导的GC中长时间选择的克隆动力学 （AIM 1）以及与GC前体的等离子体和血浆细胞的进行性分化（AIM 2）。我们 还提出了一个新的“分子脂肪映射”系统，以确定克隆动力如何影响最终 血清抗体的组成（AIM 3）。这使我们能够研究血清水平现象的B细胞生物学 例如抗原烙印/原始抗原罪，免疫主持和病毒逃生。 我们希望我们的发现将对构图和保护的方式提供更多的机械理解 血清抗体的有效性取决于B细胞克隆竞争的动力学，对 影响力疫苗，艾滋病毒和SARS-COV-2的有效疫苗接种策略的设计。