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.
这个项目的广泛的,长期的目标是阐明机制或机制的基础上,
老年人血清免疫力相对缺乏,特别注意人B1-β细胞样细胞,
由此衍生的天然抗体。本申请的具体重点是了解年龄-性别
在休息时和免疫后,针对肺炎链球菌感染的免疫防御的相关失败
治疗传染性肺炎球菌的关键机制在于调理作用
通过血清抗体,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-β细胞,其结合PC并分泌抗β PC抗体。
已知人血清中含有抗PC的抗体,人B1-β细胞能识别
随着年龄的增长,人类B1-β细胞的总数量也在下降,但还不知道发生了什么
与年轻个体相比,老年个体中的PC-β结合B1-β样细胞。
转移实验是可能的,来自老年小鼠B1细胞的血清IgM不能改变转移过程。
肺炎球菌感染的小鼠缺乏抗体,而同样数量的血清IgM,
这与年龄相关的小鼠B1细胞抗CD 4 + T细胞的潜在性质的变化相一致。
作为转录免疫球蛋白的PC抗体在序列上变得更少种系。
年龄相关的人B1-β-CD样细胞总数和小鼠B1细胞抗CD 3 PC抗体库的变化
提示老年人肺炎球菌防御失败的机制。
我们推测老年人对PC/肺炎球菌的血清学免疫相对缺乏,
人类,在肺炎球菌疫苗接种前后,是由于一个或多个:年龄相关的PC-β 2的损失
结合B1-β 1样细胞,B1-β 1样细胞抗-β 1-PC抗体序列/库的侵蚀,以及PC-β 1功能障碍,
结合B1-β 1样细胞/B1-β 1样细胞抗-β 1-PC抗体的功能差。这些特征要么从未
在人B1-β 1样细胞中进行了研究,或从未在抗原特异性人B1-β 1样细胞中进行过检测,
我们将通过以下目标来确定我们假设的有效性,我们将
比较老年与年轻健康献血者,以及老年献血者接种肺炎球菌疫苗前后的情况。
SA 1.通过免疫荧光染色检测B细胞中PC-β 2结合B1-β 2样细胞的水平
SA 2.我们将确定细胞的亚群和PC-RFLP结合,然后进行流式细胞术/细胞分选。
通过单细胞PCR随后测序,
SA 3.我们将评估PC-β 2结合B1-β 2样细胞的功能,以及PC-β 2结合B1-β 2样细胞的特异性。
通过用ELISPOT测定法测定B1-β 1样细胞分泌,
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
这将为提高老年人抗肺炎球菌抗体的免疫防御提供新的方法。
项目成果
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THOMAS L ROTHSTEIN其他文献
THOMAS L ROTHSTEIN的其他文献
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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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9305007 - 财政年份:2016
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