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：专用于对病原体的免疫？ 幼稚CD4T细胞和毛囊生发中心B细胞产生的T辅助细胞随年龄增长 产生高亲和力抗体(Ab)所需的B细胞会受到损害。最新版本 老年人的流感疫苗在诱导这些关键反应方面并不有效。因此，老年人， 尽管已经为生命早期遇到的病原体提供了抗体保护，但它们对新的 病毒株(如流感)和新出现的病原体(如新冠肺炎)。我们注意到了一代 在老年小鼠中发现的异常数量的分泌抗体的B细胞可以活着感染流感，我们发现这是源于 通过刺激最近描述的“年龄相关B细胞”(ABC)。一个由流感引起的ABC人群 (IABC)的产生独立于CD4T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，当帮助可用时，类似GCB的响应可以 被诱导并产生浆细胞。我们还发现ABC在无菌小鼠中的发育支持固有的 与年龄相关的ABC发展的性质。值得注意的是，ABC是主要的幼稚B细胞，对 在衰老的小鼠身上。 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 这两种反应。我们已经开发了转移方法，使我们能够评估IABC或GCB 从ABC或各自产生的抗体中提取，以应对甲型流感病毒，可提供预防 致命病毒，可有效中和或以其他方式清除流感感染。我们还将审查ABC 在老年东道主的背景下具有潜力。如果我们发现老年人ABC在免疫方面做出了很大贡献 否则就会损害年迈的主机，这将证明未来利用ABC提供改进的主要努力是合理的 针对老年人的疫苗和免疫疗法。