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Sex Determines Age-related Changes in the Repertoire and Function of Natural Antibodies Protective against Streptococcus pneumoniae with Increasing Age

随着年龄的增长，性别决定了抵抗肺炎链球菌的天然抗体的库和功能与年龄相关的变化

基本信息

批准号：
10688146
负责人：
Nichol Elizabeth Holodick
金额：
$ 37.75万
依托单位：
WESTERN MICHIGAN UNIV SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-21 至 2024-08-31
项目状态：
已结题

项目摘要

Project Summary/Abstract Streptococcus pneumoniae is the most common cause of pneumonia, leading to death in individuals over the age of 65 eight times more frequently than those aged 5-49, despite the long-standing availability of a vaccine for this age group (approved in 1983). In both murine and human systems, there is a greater incidence of, and susceptibility to, pneumococcal infection in males; nevertheless, the factors contributing to this difference between males and females is unknown. Therefore, the long-term goal of this study is to gain a greater understanding of the aging immune system in the context of sex, which will enable development of new preventative and/or treatment strategies of S. pneumoniae infection. Specifically, the goal of this proposal is to determine whether estrogen has an effect on a specific subset of B cells, B1a cells, which provide essential protection and therefore survival from S. pneumoniae infection through production of natural antibodies. Antibodies provide defense against infection by binding the pathogen and preventing infection of host cells. Natural antibodies are present in the absence of infection or intentional immunization. The unique ability of B1a cells to provide protection against S. pneumoniae is attributed to their production of natural antibodies, which have unique structural characteristics resulting from the fetal development of B1a cells. In addition to fetal development, B1 cell progenitors in adult bone marrow can also contribute to the B1a cell pool; however, the characteristics of fetal B1a cell derived natural antibodies are lost in these adult B1a cell derived natural antibodies. We have demonstrated natural serum IgM from aged male mice does not provide protection against S. pneumoniae infection. Unexpectedly, our preliminary results reveal differences in natural antibodies obtained from aged male and female B1a cells, in that age-related changes experienced by male B1a cell antibodies do not seem to occur in females. Yet, we do not know the role sex plays during the aging process to affect B1a cells over time resulting in a non-effective B1a cell derived natural antibody in aged males. We hypothesize estrogen affects the pool of natural antibodies capable of providing protection against S. pneumoniae in the aged. To test this hypothesis and determine if sex-related factors such as estrogen affect the ability of B1a cells to maintain protective natural IgM with age, we will perform the following aims: 1) Elucidate the role of estrogen in the production of natural IgM protective against S. pneumoniae infection in aged males and females, 2) Determine the role of estrogen in the development and selection of B1a cells with increasing age, and 3) Examine the effects of sex and estrogen exposure upon human B1 cell numbers and repertoire in young, middle aged, and aged donors. This project will determine the effect estrogen has on the ability of B1a cells to provide immediate protection from S. pneumoniae infection with increasing age. This further understanding of the aged immune system in the context of sex will likely suggest new prevention and/or treatments strategies of S. pneumoniae infection in both male and female elderly populations.

项目概要/摘要肺炎链球菌是肺炎最常见的原因，在过去一段时间内导致个人死亡尽管疫苗早已存在，但 65 岁年龄段的发病率是 5-49 岁年龄段的八倍针对这个年龄段（1983 年批准）。在小鼠和人类系统中，发生率较高，并且男性对肺炎球菌感染的易感性；尽管如此，造成这种差异的因素男性和女性之间的情况未知。因此，本研究的长远目标是获得更大的了解性别背景下的衰老免疫系统，这将有助于开发新的免疫系统肺炎链球菌感染的预防和/或治疗策略。具体来说，该提案的目标是确定雌激素是否对特定的 B 细胞亚群（B1a 细胞）有影响，该细胞提供必需的通过产生天然抗体来保护并因此免受肺炎链球菌感染的影响。抗体通过结合病原体并防止宿主细胞感染来防御感染。天然抗体在没有感染或有意免疫的情况下存在。 B1a的独特能力细胞提供针对肺炎链球菌的保护归因于它们产生天然抗体，这些抗体具有由 B1a 细胞胎儿发育产生的独特结构特征。除了胎儿发育过程中，成人骨髓中的 B1 细胞祖细胞也可以为 B1a 细胞库做出贡献；然而，胎儿 B1a 细胞衍生的天然抗体的特征在这些成人 B1a 细胞衍生的天然抗体中丢失抗体。我们已经证明来自老年雄性小鼠的天然血清 IgM 不能提供保护对抗肺炎链球菌感染。出乎意料的是，我们的初步结果揭示了天然抗体的差异从老年男性和女性 B1a 细胞中获得，男性 B1a 细胞经历与年龄相关的变化抗体似乎不会出现在女性身上。然而，我们不知道性在衰老过程中所扮演的角色随着时间的推移，B1a 细胞会受到影响，导致老年男性体内 B1a 细胞衍生的天然抗体无效。我们假设雌激素影响能够提供针对金黄色葡萄球菌的保护的天然抗体库。老年人肺炎。为了检验这一假设并确定雌激素等性别相关因素是否会影响随着年龄的增长，B1a 细胞维持保护性天然 IgM 的能力，我们将实现以下目标：1) 阐明雌激素在天然 IgM 的产生中的作用，以预防肺炎链球菌感染老年男性和女性，2) 确定雌激素在 B1a 细胞发育和选择中的作用年龄增长，以及 3) 检查性别和雌激素暴露对人类 B1 细胞数量的影响年轻、中年和老年捐赠者的曲目。该项目将确定雌激素对随着年龄的增长，B1a 细胞提供立即保护免受肺炎链球菌感染的能力。这进一步了解性行为背景下的老年免疫系统可能会提出新的预防措施和/或男性和女性老年人群肺炎链球菌感染的治疗策略。