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

项目总结/摘要 肺炎链球菌是肺炎最常见的原因，导致死亡的个人超过 65岁的人比5-49岁的人多8倍，尽管疫苗长期存在 （1983年批准）。在鼠和人的系统中， 男性对肺炎球菌感染的易感性;然而，导致这种差异的因素 男性和女性之间的差异是未知的。因此，本研究的长期目标是获得更大的 了解性背景下衰老的免疫系统，这将有助于开发新的免疫系统 预防和/或治疗策略的S.肺炎感染。具体而言，该提案的目标是 确定雌激素是否对特定的B细胞亚群，B1 a细胞有影响，B1 a细胞提供必需的 保护和生存S。肺炎感染通过生产天然抗体。 抗体通过结合病原体并防止宿主细胞感染来提供针对感染的防御。 天然抗体在没有感染或有意免疫的情况下存在。B1 a的独特能力 细胞以提供对S.肺炎是由于他们生产的天然抗体， 具有B1 a细胞的胎儿发育所导致的独特结构特征。除了胎儿 在发育过程中，成人骨髓中的B1细胞祖细胞也可以贡献于B1 a细胞库;然而， 胎儿B1 a细胞衍生的天然抗体的特征在这些成人B1 a细胞衍生的天然抗体中丢失。 抗体的我们已经证明来自老年雄性小鼠的天然血清IgM不提供保护作用 对于S.肺炎感染。出乎意料的是，我们的初步结果揭示了天然抗体的差异， 从老化的雄性和雌性B1 a细胞获得，因为雄性B1 a细胞经历的年龄相关变化 抗体似乎不出现在女性。然而，我们不知道性在衰老过程中所扮演的角色， 随着时间的推移影响B1 a细胞，导致老年男性中无效的B1 a细胞衍生的天然抗体。 我们假设雌激素影响能够提供抗链球菌保护的天然抗体库。 老年人肺炎为了验证这一假设，并确定是否与性有关的因素，如雌激素影响 随着年龄的增长，B1 a细胞维持保护性天然IgM的能力，我们将执行以下目标：1） 阐明雌激素在天然IgM产生中的作用，保护抗链球菌。肺炎感染 2）确定雌激素在B1 a细胞发育和选择中的作用， 增加年龄，和3）检查性别和雌激素暴露对人B1细胞数量的影响， 在年轻、中年和老年供体中的保留。这个项目将确定雌激素对 B1 a细胞对S.肺炎感染随着年龄的增长。这 进一步了解老年人的免疫系统在性方面可能会提出新的预防措施。 和/或治疗策略。肺炎感染的男性和女性老年人群。

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.