The Generation and Maintenance of Human Memory B Cells

人类记忆 B 细胞的生成和维持

• 批准号: 7732602
• 负责人: susan pierce
• 金额: $ 90.82万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7732602
• 关键词: Address; Adjuvant; Agonist; Antibodies; Antigens; Area; B-Cell Activation; B-Lymphocytes; Blood Circulation; Blood specimen; Bone Marrow; Cells; Clinical; Collaborations; Complement component C1s; Contracts; DNA; Data; Dendritic Cells; Development; Dose; Enrollment; Exposure to; Generations; Goals; Human; Humoral Immunities; Immune response; Immune system; Immunity; Immunization; Immunoglobulin G; Immunologic Memory; Individual; Infection; Kinetics; Knowledge; Left; Life; Ligands; Maintenance; Malaria; Malaria Vaccines; Memory; Memory B-Lymphocyte; Merozoite Surface Protein 1; Molecular; Numbers; Pattern recognition receptor; Peripheral Blood Mononuclear Cell; Plasma Cells; Plasmodium falciparum; Play; Process; Proliferating; Property; Research Design; Role; Sampling; Serum; System; Time; Tissues; Toxin; Vaccination; Vaccine Antigen; Vaccines; aluminum sulfate; apical membrane; base; day; experience; interest; microbial; neutralizing antibody; novel vaccines; pathogen; peripheral blood; response; trafficking; vaccine development; volunteer

The adaptive immune system encodes the ability to remember an initial encounter with an antigen and to respond to that antigen upon re-exposure in a rapid and robust fashion for the life time of the individual. This phenomenon of immunological memory is a fundamental property of the adaptive immune system and is the basis for all vaccine development. For most vaccines, neutralizing antibodies plays a critical role in protective immune responses, and thus the mechanisms that underlie the generation and maintenance of humoral memory are of considerable interest. Long-term humoral immunity is encoded in memory B cells (MBC) and long-lived plasma cells (LLPC) which are generated as a part of the primary immune response. LLPC are terminally differentiated cells that reside in the bone marrow and are responsible for the long-term maintenance of serum Ab levels which play a key role in the initial control of pathogens and their toxins upon reinfection. MBC are capable of mounting an antigen-induced response by proliferating and differentiating into plasma cells (PC) resulting in rapid, high titer secondary Ab responses upon re-exposure to pathogens. MBC may provide protection even in individuals with insufficient neutralizing Ab titers. Despite the central role of MBC in combating infections, our understanding of the cellular and molecular mechanisms that underlie the generation and maintenance of B cell memory is incomplete. Efforts to develop new vaccines would benefit from a more detailed knowledge of these processes, particularly vaccines against a pathogen such as Plasmodium falciparum in malaria which appear to subvert immunological memory. This project represented a collaborative effort between Dr. Pierce and Dr. Louis Miller and his colleagues in the Malaria Vaccine Development Branch (MVDB). Over the last year we have focused our efforts on gaining an understanding of the generation, maintenance and activation of B cell memory in nave individuals in response to vaccination. Of particular interest in this process is the role of TLR9, a pattern recognition receptor that initiates innate immune responses. TLR9 detects microbial DNA with hypomethylated CpG motifs and in humans is preferentially expressed by plasmacytoid dendritic cells (PDC) and B cells. TLR9 ligands have been indirectly implicated in the maintenance of B cell memory although at present the role of TLR9 in the generation of B cell memory has not been addressed. We have taken advantage of recent advances in the identification of antigen-specific human memory B cells in peripheral blood to describe the generation and maintenance of malaria-specific memory B cells in the U.S. in response to vaccines currently under development in the MVDB. Over the last year, in collaboration with the MVDB, we described the acquisition of antigen-specific memory B cells in the peripheral blood of volunteers enrolled in two trials of the malaria vaccines, one composed of P. falciparum apical membrane antigen 1 (AMA1) and one of merozoite surface protein 1 (MSP1), both on alum either alone or in combination with the TLR9 agonist, CpG. Volunteers received three doses of the vaccine 28 days apart and peripheral blood samples were collected 3, 7, 14 and 28 days after each vaccination and up to 200 days following the third and last vaccination. The longitudinal design of this study permitted a detailed characterization of the kinetics of MBC generation and maintenance in response to primary and secondary vaccination. The capacity for a detailed characterization was most apparent in the analysis of the AMA1-C1 vaccine trial in which PBMC samples were collected at several time points after each vaccination. We found that the acquisition of memory B cells is a dynamic process in which the antigen-specific memory B cell pool rapidly expands and then contracts following vaccination. In individuals who received CpG-containing vaccines, antigen-specific memory B cells appeared more rapidly, in greater numbers, and persisted for longer. The percentage of vaccine-specific memory B cells present at the time of re-immunization predicted antigen-specific antibody levels 14 days later and at steady state, there was a positive correlation between antigen-specific memory B cells and antibody levels. We also observed an antigen-independent decrease in the total IgG+ memory B cell pool in circulation 3 days after each vaccination, possibly the result of adjuvant-induced trafficking of memory B cells into tissues. Consistent with this possibility we observed a large increase in the total number of plasma cells in circulation, suggesting that memory B cells induced to leave the circulation gave rise to plasma cells. These are the first data describing the naive human memory B cell response to vaccination and will serve as a baseline for similar analyses in malaria endemic areas.

适应性免疫系统对记忆初次接触抗原的能力进行编码，并在个体的一生中以一种快速而强大的方式对该抗原再次接触作出反应。这种免疫记忆现象是适应性免疫系统的基本特性，也是所有疫苗开发的基础。对于大多数疫苗来说，中和抗体在保护性免疫反应中起着关键作用，因此，体液记忆产生和维持的机制引起了相当大的兴趣。长期体液免疫是在记忆B细胞（MBC）和长寿命浆细胞（LLPC）中编码的，它们作为初级免疫反应的一部分产生。LLPC是一种终末分化细胞，存在于骨髓中，负责血清Ab水平的长期维持，在再次感染时病原体及其毒素的初始控制中起关键作用。MBC能够通过增殖和分化成浆细胞（PC），在再次暴露于病原体时产生快速、高滴度的二次Ab反应，从而产生抗原诱导的反应。即使在中和性抗体滴度不足的个体中，MBC也可以提供保护。尽管MBC在对抗感染中发挥着核心作用，但我们对B细胞记忆产生和维持的细胞和分子机制的理解尚不完整。开发新疫苗的努力将受益于对这些过程的更详细的了解，特别是针对一种病原体（如疟疾中的恶性疟原虫）的疫苗，这种病原体似乎会破坏免疫记忆。该项目是皮尔斯博士与疟疾疫苗开发处的路易斯·米勒博士及其同事的合作成果。在过去的一年里，我们一直致力于了解接种疫苗后普通个体B细胞记忆的产生、维持和激活。在这一过程中，TLR9的作用尤其令人感兴趣，TLR9是一种启动先天免疫反应的模式识别受体。TLR9检测具有低甲基化CpG基序的微生物DNA，并且在人类中优先由浆细胞样树突状细胞（PDC）和B细胞表达。TLR9配体间接参与B细胞记忆的维持，尽管目前TLR9在B细胞记忆产生中的作用尚未得到解决。