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 细胞和长寿命浆细胞负责产生中和作用 可以有效消除病原体的抗体。了解这些细胞的功能 因此，对感染的反应以及如何通过疫苗接种来诱导和维持这些反应 对于消除造成全球健康负担的疾病至关重要。疟疾，由疟原虫引起 spp 是全球主要的健康负担，迫切需要疫苗。五十多年前的它 结果表明，转移人免疫血清可以中和疟原虫寄生虫 感染的血液阶段。然而，人们对疟原虫特异性 B 细胞知之甚少。 由于研究低频抗原特异性 B 的困难，产生这些抗体 细胞。此外，目前尚不清楚最近如何描述异质群体 由蛋白质免疫诱导的记忆 B 细胞 (MBC) 亚群响应于形式或功能 感染。为了阐明疟疾感染期间不同 MBC 亚群的功能作用，四聚体 产生的结果可以识别人类和小鼠体内的疟原虫特异性 MBC。 多参数流式细胞术和单细胞 B 细胞受体测序表明，长 活的小鼠疟原虫特异性 MBC 由三个群体组成： 超突变，经典定义的 IgG+ (IgG+)，以前未被识别的群体 体细胞超突变 IgM+ (IgMhighIgDlow) MBC 和未突变 IgD+ (IgMlowIgDhigh) MBC 人口。令人惊讶的是，疟原虫特异性 IgM+ 抗体主导了对疟原虫的早期反应。 继发感染。进一步的分析表明，再次攻击后，IgM+ MBC 会迅速形成 两种抗体分泌群体：T 细胞非依赖性浆细胞和 T 依赖性 IgM+ 和 IgG+浆母细胞。因此，IgM+ MBC 是疟原虫的快速、可塑性第一反应者 重新挑战并应成为疫苗策略的目标。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，以确定其独特的 对人类和相关小鼠模型预防疟疾的贡献。这 该应用程序的中心假设是功能异构的开发 疫苗介导的保护需要记忆 B 细胞的协同群体 疟原虫。该提案的目标是确定分子和细胞机制 导致这些不同 MBC 子集的形成并确定这些细胞如何 有助于预防小鼠和人类的疟疾。这种创新方法可以 提供开发第一种有效的疟疾疫苗所需的信息。