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宣称全球约有400万人的生命 每年，将这些感染在全球死亡原因清单上。肺炎链球菌是 肺炎最常见的原因导致65岁以上八倍的人死亡 比那些5-49岁的年龄段的年龄段的疫苗长期供应（1983年批准）。 在鼠类和人类系统中，肺炎球菌感染的事件和易感性更大。 在男性中；然而，导致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上下文中更了解对免疫系统的了解 性。具体而言，该提议的目的是确定性别和/或解剖位置是否影响 B细胞B1细胞的特定子集，该细胞提供了必不可少的保护，因此可从S. 通过生产天然抗体，肺炎感染。 抗体通过结合病原体和预防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单元的独特能力 提供针对肺炎链球菌的保护归因于其自然抗体的产生，这些抗体具有 其胎儿发育产生的独特结构特征。胎儿衍生的B1细胞维持其 通过自我更新过程的种群，该过程与B细胞子集不同，B2细胞由B2细胞产生 造血干细胞。因此，自我更新对于维持天然抗体至关重要 防止感染的保护性，尽管对性别如何影响B1细胞的自我更新为老年知之甚少。 我们已经证明了老年雄性小鼠的天然抗体并未提供针对S的保护。 肺炎感染，而老年雌性的天然抗体保持其保护能力。 我们假设通过自我更新来维持B1细胞在衰老过程中受到性的影响。我们 假设雌性B1细胞保持生产力更高的B1自我更新，从而使 对性和年龄感染感染的敏感性。为了检验该假设，我们将执行以下目的：1）阐明 通过A 独特的转基因记者系列与自我更新的检查以确定功能 性别，年龄和细胞周期活动对保护抗体的产生的结果，2）确定如何 维持人类的自我更新可能会反映鼠系统并影响自然的产生 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 随后对衰老过程中天然抗体产生的影响。对 性别背景下的免疫系统可能会暗示肺炎链球菌的新预防和/或治疗策略 男性和女性衰老的感染。