The Development and Function of Plasmodium-specific memory B cells

疟原虫特异性记忆 B 细胞的发育和功能

• 批准号: 9235529
• 负责人: MARION PEPPER
• 金额: $ 59.67万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-16 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9235529
• 关键词: Address; Affect; Affinity; Antibodies; Antibody Formation; Antibody-Producing Cells; Antigen Presentation; Antigens; Autoimmune Diseases; B-Lymphocytes; Blood; Cell Communication; Cell physiology; Cells; Communicable Diseases; Cytokine Signaling; Development; Disease; Flow Cytometry; Frequencies; Generations; Goals; Gold; Human; Humoral Immunities; Immune; Immune Sera; Immunization; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin-Secreting Cells; Immunologics; Infection; Kinetics; Knowledge; Lead; Ligands; Maintenance; Malaria; Mediating; Memory; Memory B-Lymphocyte; Merozoite Surface Protein 1; Methods; Modeling; Molecular; Mus; Parasite Control; Parasitemia; Parasites; Perception; Phenotype; Plasma Cells; Plasmablast; Plasmodium; Plasmodium chabaudi; Plasticizers; Play; Population; Population Heterogeneity; Proteins; Reaction; Receptor Activation; Receptors, Antigen, B-Cell; Research; Role; Serum Immunologic; Signal Transduction; Source; Structure of germinal center of lymph node; T-Lymphocyte; Tertiary Protein Structure; Testing; Time; Vaccination; Vaccines; Work; base; cytokine; emergency service responder; global health; immunoregulation; innovation; magnetic beads; malaria infection; mouse model; nanoparticle; neutralizing antibody; novel; pathogen; receptor; receptor expression; response; secondary infection; tool; vaccine development

Memory B cells and long-lived plasma cells are responsible for producing neutralizing antibodies that can effectively eliminate a pathogen. Understanding the function of these cells in response to infection and how they can be induced and maintained by vaccination is therefore critical to eradicating diseases that are global health burdens. Malaria, caused by Plasmodium spp, is a major global health burden that is in urgent need of a vaccine. Over fifty years ago it was shown that transfer of human immune serum can neutralize Plasmodium parasites during the blood stage of infection. Little is known however about the Plasmodium-specific B cells that produce these antibodies due to the difficulties of studying low frequency antigen-specific B cells. Additionally, it is not understood how recently described populations of heterogeneous memory B cell (MBC) subsets induced by protein immunization form or function in response to infection. To clarify functional roles for distinct MBC subsets during malaria infection, tetramers were generated that identify Plasmodium-specific MBCs in both humans and mice. Multiparameter flow cytometry and single-cell B cell receptor sequencing revealed that long- lived murine Plasmodium-specific MBCs consisted of three populations: somatically hypermutated, classically defined IgG+ (IgG+), a previously unrecognized population of somatically hypermutated IgM+ (IgMhighIgDlow) MBCs and an unmutated IgD+ (IgMlowIgDhigh) MBC population. Surprisingly, Plasmodium-specific IgM+ antibody dominated the early response to a secondary infection. Further analyses revealed that upon rechallenge, IgM+ MBCs rapidly form two antibody-secreting populations: T cell-independent plasma cells and T-dependent IgM+ and IgG+ plasmablasts. IgM+ MBCs are therefore rapid, plastic, first responders to Plasmodium rechallenge and should be targeted by vaccine strategies. We are now poised to further characterize these and other Plasmodium-specific B cell populations to determine their unique contributions to protection against malaria in both humans and relevant murine models. The central hypothesis of this application is that the development of functionally heterogeneous yet synergistic populations of memory B cells will be required for vaccine-mediated protection to Plasmodium. The goals of this proposal are to identify the molecular and cellular mechanisms that lead to the formation of these distinct MBC subsets and to determine how these cells contribute to protection against malaria in mice and humans. This innovative approach could provide the information required to develop the first effective vaccine against malaria.

记忆B细胞和长寿命的浆细胞负责产生中和 可以有效消除病原体的抗体。了解这些细胞在 因此，对感染的反应以及如何通过疫苗接种诱导和维持它们 对于消除全球健康负担的疾病至关重要。由疟原虫引起的疟疾 SPP是全球重大的健康负担，迫切需要疫苗。五十多年前 结果表明，人类免疫血清的转移可以中和疟原虫在 感染的血液阶段。然而，关于疟原虫特异性B细胞知之甚少 由于研究低频抗原特异性B的困难而产生这些抗体 细胞。另外，尚不了解最近描述的异质种群 记忆B细胞（MBC）子集由蛋白质免疫形式或功能诱导 感染。为了阐明疟疾感染期间不同MBC子集的功能作用，四聚体 生成了鉴定人类和小鼠中疟原虫特异性MBC的生成。 多参数流细胞术和单细胞B细胞受体测序表明长期 生命的鼠质质量特异性MBC由三个人群组成： 超重，经典定义的IgG+（IgG+），以前未被认可的人群 体外高水不见的IgM+（Igmhighigdlow）MBC和未分泌的IgD+（Igmlowigdhigh）MBC 人口。令人惊讶的是，疟原虫特异性IgM+抗体主导了对A的早期反应 继发感染。进一步的分析表明，在获得后，IgM+ MBC迅速形成 两个分泌抗体的种群：T细胞独立的浆细胞和T依赖性IgM+和 IgG+浆膜。因此，IgM+ MBC是快速的，塑料的，第一反应者疟原虫 补给，应由疫苗策略对准。我们现在准备进一步 表征这些和其他疟原虫特异性B细胞群来确定它们的独特 在人类和相关的鼠模型中保护疟疾的贡献。这 该应用的中心假设是功能异质的发展 疫苗介导的保护需要的记忆B细胞的协同种群将需要 疟原虫。该建议的目标是确定分子和细胞机制 这导致形成这些独特的MBC子集并确定这些细胞如何 有助于保护小鼠和人类疟疾的保护。这种创新的方法可以 提供开发首次针对疟疾的有效疫苗所需的信息。