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？

• 批准号: 10218497
• 负责人: SUSAN L SWAIN
• 金额: $ 25.13万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 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/10218497
• 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

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：年龄相关 B 细胞：专门用于对病原体的免疫？ 随着年龄的增长，幼稚 CD4 T 细胞产生滤泡辅助 T 细胞，滤泡产生生发中心 B 细胞 产生高亲和力抗体 (Ab) 所需的 B 细胞受到损害。最新 老年人的流感疫苗不能有效诱导这些关键反应。因此，老年人， 尽管已经受到针对生命早期遇到的病原体的抗体的保护，但仍然非常容易受到新的病原体的影响 病毒株（例如流感）和新出现的病原体（例如 COVID-19）。我们注意到一代 老年小鼠体内分泌抗体的 B 细胞数量异常，可抵抗活流感病毒感染，我们发现这种现象源自 通过刺激最近描述的“年龄相关 B 细胞”(ABC)。一组流感诱发的 ABC (iABC) 的产生独立于 CD4 T 细胞的帮助，但严格依赖于病原体的刺激 相关的“危险”信号。最近我们发现，当可以获得帮助时，类似 GCB 的响应可以代替 被诱导并产生浆细胞。我们还发现 ABC 在无菌小鼠中发育，支持内在的 与年龄相关的 ABC 发展的本质。值得注意的是，ABC 是主要的初始 B 细胞，能够做出反应 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生成 CD4 帮助所需的信号 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 或各自针对甲​​型流感病毒产生的抗体，可以提供针对 致命病毒，可以有效中和或清除流感感染。我们还将检查 ABC 老年主人的潜力。如果我们发现老年ABC对免疫力有很大贡献 否则会受到损害的老年主机，它将证明未来利用 ABC 来提供改进的重大努力是合理的 老年人的疫苗和免疫疗法。