Age-Associated B Cells Specialized for Immunity to Pathogens?

与年龄相关的 B 细胞专门针对病原体具有免疫能力？

基本信息

批准号：
10401919
负责人：
SUSAN L SWAIN
金额：
$ 20.94万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-15 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401919
关键词：
2019-nCoV Affect Age Aging Agonist Antibodies Antibody Affinity Antibody Response Antigens Autoimmunity Automobile Driving B cell differentiation B-Cell Development B-Lymphocyte Subsets B-Lymphocytes Body Weight decreased Bronchoalveolar Lavage CD4 Positive T Lymphocytes COVID-19 Cell Count Cell Lineage Cell physiology Cells Dangerousness Development Elderly Ensure Exposure to Failure Future Generations Genes Germ-Free Goals Helper-Inducer T-Lymphocyte Immune Immune response Immunity Immunoglobulin Class Switching Immunoglobulin-Secreting Cells Immunotherapy In Situ Infection Inflammatory Influenza Influenza A virus Lead Learning Life Lung Lymphocyte Mediating Memory B-Lymphocyte Mus Mutation Nature Pathway interactions Phenotype Plasma Cells Population Recurrence Role Serum Severe Acute Respiratory Syndrome Signal Transduction Spanish flu Spleen Structure of germinal center of lymph node Supporting Cell T-Lymphocyte TLR7 gene Vaccination Vaccine Design Vaccines Virus Virus Diseases adaptive immune response aged antibody transfer antigen challenge base cytokine improved influenza infection influenza virus strain influenza virus vaccine mortality pandemic disease pathogen pathogenic virus programs response stem vaccine strategy

项目摘要

SUMMARY: Age-associated B cells: Specialized for Immunity to Pathogens? With age the generation of T follicular helpers from naive CD4 T cells and germinal center B cells from follicular B cells, that are both needed for the generation of high affinity antibody (Ab), become compromised. Most current vaccines for influenza in the elderly are not effective at inducing these critical responses. Thus, the elderly, though protected by Ab already in place for pathogens encountered earlier in life, are highly susceptible to new strains of virus (e.g. influenza) and newly emerged pathogens (e.g. COVID-19). We noted the generation of an unusual population of antibody-secreting B cells to live influenza infection in aged mice, that we found is derived by stimulation of recently described "age-associated B cells" (ABC). One population of influenza-induced ABC (iABC) are generated independently of CD4 T cell help, but strictly depend on stimulation by pathogen- associated "danger" signals. Recently we found that when help is available, a GCB-like response can instead be induced and produce plasma cells. We also found ABC develop in germ-free mice supporting the intrinsic nature of the age-associated ABC development. Notably, ABC are the predominant naïve B cells that respond in aged mice. Here we will define the signals required from antigen and pathogen-recognition and from CD4 help that generate the two responses. We have developed transfer approaches that allow us to evaluate whether iABC or GCB derived from ABC or the Ab produced by each in response to by influenza A virus, can provide protection against lethal virus and can effectively neutralize or otherwise clear infection with influenza. We will also examine ABC potential in the context of the elderly host. If we find the aged ABC make a strong contribution to immunity in otherwise compromised aged hosts, it will justify future major efforts to harness ABC to provide improved vaccines and immunotherapies for the aged.

摘要：与年龄相关的B细胞：专门针对病原体的免疫力？随着年龄的年龄生成高亲和力抗体（AB）所需的B细胞都会受到损害。最新较早的影响力的疫苗在诱导这些关键反应方面无效。那，老年尽管已经受到AB的保护，但在生活中早期遇到的病原体已经非常容易受到新的影响病毒（例如影响）和新出现的病原体（例如Covid-19）的菌株。我们注意到一代我们发现的抗体分泌B细胞的异常种群在老年小鼠中生到影响的影响，我们发现这是我们发现的通过刺激最近描述的“年龄相关B细胞”（ABC）。一群影响力诱导的ABC （IABC）独立于CD4 T细胞帮助而产生，但严格取决于病原体的刺激相关的“危险”信号。最近我们发现，当有帮助时，类似GCB的响应可以改为被诱导并产生浆细胞。我们还发现了支持固有的无菌小鼠的ABC发育与年龄相关的ABC发展的性质。值得注意的是，ABC是反应的主要幼稚B细胞在老年小鼠中。在这里，我们将定义抗原和病原体识别所需的信号以及产生的CD4帮助这两个回应。我们开发了转移方法，使我们能够评估IABC还是GCB 源自ABC或每个因影响力而产生的AB，可以提供保护致命的病毒，可以有效地中和或以其他方式清除流感感染。我们还将检查ABC 在古老的主机的背景下的潜力。如果我们发现年龄的ABC对免疫有很大的贡献否则，损害老年人的主人将证明未来的重大努力来利用ABC提供改进的老年人的疫苗和免疫疗法。