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

B1 B 细胞自我更新和天然抗体产生的性别特异性调节

• 批准号: 10751901
• 负责人: Sarah E Webster
• 金额: $ 6.91万
• 依托单位: WESTERN MICHIGAN UNIV SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751901
• 关键词: Adult; Age; Aging; Anatomy; Antibodies; Antibody Formation; Apoptotic; Autoimmune Diseases; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; Bacteria; Binding; Blood Vessels; Bone Marrow; CD86 gene; Cause of Death; Cell Aging; Cell Cycle; Cell Maintenance; Cells; Cessation of life; Characteristics; DNA Nucleotidylexotransferase; Data; Development; Disease; Encapsulated; Enzymes; Female; Fetal Development; Frequencies; Generations; Genes; Goals; Greater sac of peritoneum; Hematopoietic stem cells; Homeostasis; Human; IL2RA gene; Immune; Immune response; Immune system; Immunization; Immunoglobulin A; Immunoglobulin Genes; Immunoglobulin M; Incidence; Individual; Infection; Infection prevention; Life; Location; Lower Respiratory Tract Infection; Lymphocyte; Maintenance; Mediating; Mus; Natural Immunity; Neonatal; Persons; Phenotype; Play; Pneumococcal Infections; Pneumonia; Population; Predisposition; Prevention strategy; Process; Production; Productivity; Recording of previous events; Regulation; Reporter Genes; Role; Serum; Sex Differences; Source; Spleen; Streptococcus pneumoniae; Structure; System; Testing; Time; Transgenic Organisms; Vaccines; Vulnerable Populations; Work; age effect; age group; age related; aged; aging population; expression cloning; fetal; fighting; human old age (65+); male; microbial; natural antibodies; pathogen; response; self-renewal; sex; stem; stem cell function; stem cell niche; treatment strategy

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.

项目摘要/摘要 肺炎等下呼吸道感染夺走了全球约400万人的生命 每年，使这些感染在全球死因清单上排名第四。肺炎链球菌是 肺炎的最常见原因导致65岁以上人群死亡的频率是65岁以上人群的8倍 比5-49岁的人更多，尽管这一年龄段的疫苗由来已久(1983年批准)。 在小鼠和人类系统中，肺炎球菌感染的发生率和易感性都更高。 在男性中；然而，造成男性和女性之间这种差异的因素尚不清楚。 因此，这项研究的长期目标是在此背景下更好地了解免疫系统 性爱。具体地说，这项建议的目标是确定性别和/或解剖位置是否会影响 一种特殊的B细胞亚群，即B1细胞，它提供必要的保护，因此可以在S。 肺炎通过产生天然抗体而感染。 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。B1细胞的独特能力 对肺炎链球菌的保护作用归因于它们产生天然抗体，这种抗体具有 胎儿发育所产生的独特结构特征。胎儿来源的B1细胞维持其 通过自我更新过程进行种群，这与B细胞子集B2细胞不同，B细胞从 造血干细胞。因此，自我更新对于维持天然抗体是必不可少的。 防止感染，尽管人们对性行为如何影响B1细胞进入老年的自我更新知之甚少。 我们已经证明，来自老年雄性小鼠的天然抗体不能提供对S. 肺炎杆菌感染，而老年女性的天然抗体保持其保护能力。 我们假设，在衰老过程中，B1细胞通过自我更新的维持受到性别的影响。我们 假设雌性B1细胞保持更多的B1自我更新，允许在 感染的易感性随着性别和年龄的增加而增加。为了验证这一假设，我们将实现以下目的：1)阐明 通过检测细胞周期的维持来调节B1细胞的性别发育差异 独特的转基因报告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)如何决定 人类自我更新的维持可能反映了小鼠的系统，并影响自然 抗体。该项目将确定性别如何影响B1细胞自我更新的维持和 随后在衰老过程中对天然抗体的产生产生影响。这进一步加深了对 免疫系统与性别的关系可能会为肺炎链球菌的预防和/或治疗策略提供新的建议 在男性和女性老龄化人口中都有感染。