Human B1-like Cells and Pneumococcal Defense in the Elderly
人类 B1 样细胞和老年人的肺炎球菌防御
基本信息
- 批准号:10330573
- 负责人:
- 金额:$ 37.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-02-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdoptive TransferAgeAgingAntibodiesAntibody RepertoireAntigensAttentionB-LymphocytesBacteriaBindingBiological AssayCell CountCell SeparationCell physiologyCell secretionCellsCharacteristicsCloningCommunicable DiseasesDiagnosisElderlyEnzyme-Linked Immunosorbent AssayFailureFlow CytometryFunctional disorderFutureHumanImmuneImmune System DiseasesImmunityImmunizationImmunoglobulin MImmunoglobulinsIndividualInfectionMS4A1 geneModelingMorbidity - disease rateMusNatureOrganismPerformancePersonsPhosphorylcholinePneumococcal InfectionsPneumococcal vaccinePopulationProcessReportingRestRoleSerologySerumSeverity of illnessSpecificityStainsStreptococcus pneumoniaeSystemTimeVaccinationVaccinesWorkage relatedenzyme linked immunospot assayexperimental studyimmune functionimprovedin vivomicrobialmortalitynatural antibodiesnovel therapeutic intervention
项目摘要
The broad, long term objective of this project is to elucidate the mechanism or mechanisms underlying the
relative deficiency of serological immunity in the elderly, with particular attention to human B1-like cells and
natural antibodies derived therefrom. The specific focus of the present application is to understand the age-
related failure of immune defense against infection with S. pneumoniae, both at rest and after immunization
with pneumococcal vaccine. A key mechanism for disposing of infectious pneumococci lies in opsonization
by serum antibody, and a principal target for opsonizing antibody is phosphorylcholine (PC). Thus, we will
study B cells, particularly B1-like cells, that bind PC and secrete anti-PC antibodies.
It is known that human serum contains antibodies against PC, that human B1-like cells recognize
PC, and that the total population of human B1-like cells declines with age. But it is not known what happens
to PC-binding B1-like cells in older individuals as compared to younger individuals. In mice, where adoptive
transfer experiments are possible, serum IgM derived from B1 cells of older mice fails to alter the course of
pneumococcal infection in mice lacking antibody, whereas an equal amount of serum IgM from younger
mice is effective. This coincides with an age-related change in the underlying nature of mouse B1 cell anti-
PC antibodies as transcribed immunoglobulin becomes less germline in sequence. These reports regarding
age-related changes in total human B1-like cell number and in mouse B1 cell anti-PC antibody repertoire
suggest mechanisms for the failure of pneumococcal defense in older people.
We hypothesize that the relative deficiency of serological immunity against PC/pneumococci in older
humans, before and after pneumococcal vaccination, is due to one or more of: age-related loss of PC-
binding B1-like cells, erosion of B1-like cell anti-PC antibody sequence/repertoire, and dysfunction of PC-
binding B1-like cells/poor function of B1-like cell anti-PC antibodies. These characteristics have either never
been studied in human B1-like cells or never been examined in antigen-specific human B1-like cells with
respect to age. We will determine the validity of our hypotheses through the following aims in which we will
compare older vs younger healthy donors, and older donors before and after pneumococcal vaccination.
SA1. We will evaluate the level of PC-binding B1-like cells, by immunofluorescent staining for B cell
subpopulations and PC-binding, followed by flow cytometry/cell sorting. SA2. We will determine the
sequence/repertoire of PC-binding B1-like cell antibodies by single cell PCR followed by sequencing,
cloning, and ELISA for specificity. SA3. We will evaluate the function of PC-binding B1-like cells and the
antibodies they produce, by determining B1-like cell secretion with ELISPOT assays and determining anti-
pneumococcal function with opsonophagocytic assays. This work will provide completely new information
that will suggest new ways to improve anti-pneumococcal antibody immune defense in the elderly.
该项目的广泛、长期目标是阐明潜在的机制或机制
老年人血清学免疫相对缺乏,特别关注人类 B1 样细胞和
由此衍生的天然抗体。 本应用程序的具体重点是了解年龄
休息时和免疫后抵抗肺炎链球菌感染的相关免疫防御失败
接种肺炎球菌疫苗。 处理传染性肺炎球菌的关键机制在于调理作用
血清抗体,调理抗体的主要靶标是磷酸胆碱 (PC)。 因此,我们将
研究 B 细胞,特别是 B1 样细胞,它们结合 PC 并分泌抗 PC 抗体。
众所周知,人类血清含有针对 PC 的抗体,人类 B1 样细胞可识别该抗体
PC,并且人类 B1 样细胞的总数随着年龄的增长而减少。 但不知道会发生什么
与年轻个体相比,老年人体内的 PC 结合 B1 样细胞。 在小鼠中,收养的
转移实验是可能的,来自老年小鼠 B1 细胞的血清 IgM 未能改变转移过程
缺乏抗体的小鼠的肺炎球菌感染,而年轻小鼠的血清 IgM 等量
老鼠是有效的。 这与小鼠 B1 细胞抗
PC 抗体作为转录的免疫球蛋白,按顺序变得较少种系。 这些报告涉及
人类 B1 样细胞总数和小鼠 B1 细胞抗 PC 抗体库与年龄相关的变化
提出老年人肺炎球菌防御失败的机制。
我们假设老年人对 PC/肺炎球菌的血清学免疫相对缺乏
人类在接种肺炎球菌疫苗之前和之后,是由于以下一种或多种原因造成的:与年龄相关的 PC-丧失
结合 B1 样细胞、B1 样细胞抗 PC 抗体序列/库的侵蚀以及 PC- 的功能障碍
结合 B1 样细胞/B1 样细胞抗 PC 抗体功能较差。 这些特征从来没有
已在人类 B1 样细胞中进行过研究,或从未在抗原特异性人类 B1 样细胞中进行过检查
尊重年龄。 我们将通过以下目标来确定我们假设的有效性
比较老年与年轻健康捐赠者以及老年捐赠者在肺炎球菌疫苗接种之前和之后的情况。
SA1。 我们将通过 B 细胞的免疫荧光染色来评估 PC 结合 B1 样细胞的水平
亚群和 PC 结合,然后进行流式细胞术/细胞分选。 SA2。 我们将确定
通过单细胞 PCR 和测序得到 PC 结合 B1 样细胞抗体的序列/库,
克隆和 ELISA 以确定特异性。 SA3。 我们将评估 PC 结合 B1 样细胞的功能以及
通过使用 ELISPOT 测定法测定 B1 样细胞的分泌,并测定抗
肺炎球菌功能与调理吞噬试验。 这项工作将提供全新的信息
这将为改善老年人的抗肺炎球菌抗体免疫防御提出新的方法。
项目成果
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THOMAS L ROTHSTEIN其他文献
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{{ truncateString('THOMAS L ROTHSTEIN', 18)}}的其他基金
Human B1-like Cells and Pneumococcal Defense in the Elderly
人类 B1 样细胞和老年人的肺炎球菌防御
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