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

项目摘要/摘要 肺炎链球菌是肺炎的最常见原因，在超过20年的时间内导致个人死亡 尽管疫苗由来已久，但65岁的人比5-49岁的人高8倍 适用于这个年龄段(1983年批准)。在小鼠和人类系统中，都有更高的发病率和 男性对肺炎球菌感染的易感性；然而，造成这种差异的因素 雄性和雌性之间的差异是未知的。因此，这项研究的长期目标是获得更大的 在性别背景下理解衰老的免疫系统，这将使新的 肺炎链球菌感染的预防和/或治疗策略。具体地说，这项提议的目标是 确定雌激素是否对特定的B细胞亚群B1a细胞有影响，B1a细胞提供必要的 通过产生天然抗体保护肺炎链球菌，从而使其存活。 抗体通过结合病原体和防止宿主细胞感染来防御感染。 在没有感染或故意免疫的情况下，存在天然抗体。B1a的独特能力 对肺炎链球菌提供保护的细胞归因于它们产生天然抗体，这种抗体 具有独特的结构特征，源于B1a细胞的胎儿发育。除了胎儿 在发育过程中，成人骨髓中的B1细胞前体细胞也可以对B1a细胞库做出贡献；然而， 胎儿B1a细胞来源的天然抗体在这些成人B1a细胞来源的天然抗体中丢失 抗体。我们已经证明来自老年雄性小鼠的自然血清IgM不能提供保护 抗肺炎链球菌感染。出乎意料的是，我们的初步结果显示了天然抗体的差异 取自老年男性和女性B1a细胞，在男性B1a细胞经历的与年龄相关的变化中 抗体似乎不会出现在女性身上。然而，我们不知道性别在衰老过程中所起的作用 随着时间的推移影响B1a细胞，导致在老年男性中产生无效的B1a细胞来源的天然抗体。 我们假设雌激素会影响天然抗体库，这些抗体库能够对S。 老年人肺炎。检验这一假设，并确定雌激素等与性有关的因素是否会影响 B1a细胞随年龄增长保持保护性天然IgM的能力，我们将实现以下目标：1) 雌激素在肺炎链球菌天然免疫球蛋白产生中的作用 老年男性和女性，2)决定雌激素在B1a细胞发育和选择中的作用 以及3)研究性别和雌激素暴露对人类B1细胞数量和 年轻、中年和老年捐赠者的曲目。这个项目将确定雌激素对 随着年龄的增长，B1a细胞对肺炎链球菌感染提供即时保护的能力。这 进一步了解老年免疫系统与性行为的关系可能会提出新的预防措施。 和/或老年男性和女性人群中肺炎链球菌感染的治疗策略。

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.