Sex Specific Regulation of B1 B Cell Self-Renewal and Natural Antibody Production

项目总结/摘要 肺炎等下呼吸道感染夺去了全球约400万人的生命 使这些感染在全球死亡原因清单上排名第四。肺炎链球菌是 导致65岁以上人群死亡的肺炎最常见原因， 5-49岁的人，尽管长期以来一直有针对这一年龄组的疫苗（1983年批准）。 在小鼠和人类系统中，肺炎球菌感染的发病率和易感性都更高 在男性中，尽管如此，造成男性和女性之间这种差异的因素尚不清楚。 因此，本研究的长期目标是在背景下更好地了解免疫系统 性具体来说，本提案的目标是确定性别和/或解剖位置是否影响 一种特殊的B细胞亚群，B1细胞，它提供必要的保护，因此可以从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细胞的独特能力， 提供对S的保护。肺炎是由于他们生产的天然抗体， 独特的结构特征导致其胎儿发育。胎儿来源的B1细胞维持其 通过自我更新过程，这与B细胞亚群B2细胞不同， 造血干细胞因此，自我更新对于天然抗体的维持至关重要 尽管对性如何影响B1细胞在老年时的自我更新知之甚少，但它对感染有保护作用。 我们已经证明来自老年雄性小鼠的天然抗体不能提供抗S. 而来自老年女性的天然抗体保持其保护能力。 我们假设，通过自我更新的B1细胞的维护是受老化过程中的性别。我们 假设女性B1细胞保持更有成效的B1自我更新，考虑到 感染易感性与性别和年龄有关。为了验证这一假设，我们将执行以下目标：1）阐明 性别特异性发育差异调节B1细胞通过检查细胞周期的维持， 独特的转基因报告细胞系结合自我更新的检测来确定功能 性别、年龄和细胞周期活动对保护性抗体产生的影响，以及2）确定如何 人类自我更新的维持可能反映了鼠类系统，并影响天然 抗体的该项目将确定性别如何影响B1细胞自我更新的维持， 在老化过程中对天然抗体产生的后续影响。这一进一步的理解 免疫系统与性关系可能提示新的预防和/或治疗S.肺炎 男性和女性老年人群中的感染。

PROJECT SUMMARY/ABSTRACT Lower respiratory tract infections such as pneumonia claims the lives of approximately 4 million people worldwide each year, making these infections fourth on the list of global causes of death. 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 are unknown. Therefore, the long-term goal of this study is to gain a greater understanding of the immune system in the context of sex. Specifically, the goal of this proposal is to determine whether sex and/or anatomical location influences a specific subset of B cells, B1 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. B1 cells’ unique ability to provide protection against S. pneumoniae is attributed to their production of natural antibodies, which have unique structural characteristics resulting from their fetal development. Fetal derived B1 cells maintain their population through a self-renewal process, which is unlike the B cell subset, B2 cells, generated from hematopoietic stem cells. Therefore, self-renewal is essential for the maintenance of natural antibodies protective against infection, though little is known about how sex influences self-renewal of B1 cells into old age. We have demonstrated natural antibody from aged male mice does not provide protection against S. pneumoniae infection whereas, natural antibody from aged females maintains its protective capacity. We hypothesize that maintenance of B1 cells through self-renewal is influenced by sex during aging. We postulate that female B1 cells maintain more productive B1 self-renewal allowing for the differences seen in susceptibility to infection with sex and age. To test this hypothesis, we will perform the following aims: 1) elucidate the sex-specific developmental differences regulating B1 cells by examining cell cycle maintenance through a unique transgenic reporter line combined with examination of self-renewal to determine the functional consequence of sex, age, and cell cycle activity on the production of protective antibody and 2) determine how maintenance of self-renewal in humans may mirror the murine system and influence production of natural antibody. This project will determine how sex influences the maintenance of B1 cell self-renewal and the subsequent impact on the production of natural antibodies during aging. This further understanding of the immune system in context to sex will likely suggest new prevention and/or treatment strategies of S. pneumoniae infection in both male and female aging populations.