New perspective on innate antibodies in mice

小鼠先天抗体的新视角

• 批准号: 8121876
• 负责人: Leonore A. Herzenberg
• 金额: $ 8.88万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-23 至 2011-08-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121876
• 关键词: Accounting; Animals; Antibodies; Antibody Formation; Antibody Repertoire; Antigens; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; Cell division; Cells; Complex; Data; Development; Employee Strikes; Failure; Francisella tularensis; Frequencies; Goals; Greater sac of peritoneum; Immigrant; Immune response; Immune system; Immunization; Immunoglobulin Class Switching; Immunologic Memory; In Vitro; Individual; Infection; Invaded; Kinetics; Lipopolysaccharides; Mediating; Memory; Memory B-Lymphocyte; Methods; Modeling; Molecular; Mus; Natural Immunity; Parasites; Plasma Cells; Population; Property; Salmonella typhimurium; Serum; Signal Transduction; Specificity; Spleen; Stimulus; Surface; TLR4 gene; Technology; Time; Transgenic Organisms; Work; base; design; in vivo; in vivo Model; insight; migration; mouse model; pathogen; plasma cell differentiation; public health relevance; receptor; response; vaccine development

DESCRIPTION (provided by applicant): Current concepts of innate immune responses to bacterial stimuli such as lipopolysaccharides (e.g., the LPS from S. typhimurium used here) are largely based on data from in vitro stimulation of spleen cells taken from unstimulated mice. However, our recent findings with LPS stimulation in an in vivo mouse model demonstrate that much of this in vitro data is not suitable for modeling innate responses, which occur perforce in vivo. Similarly, our findings raise questions about the how to relate data from in vivo models (B-cell transgenic, TLR- deficient, parasite infection, etc.) to LPS responses in normal (genetically intact) animals. Specifically, we find that the majority of the LPS-stimulated plasma cell response in vivo is produced by B-1a (CD5+ B-1) cells, most of which only migrate into the spleen after LPS injected. Further, we find that the immediate response to LPS in vivo is produced by the B-1a cells that are resident in the spleen and surprisingly differentiate into plasma cells within 1-2 days without undergoing cell division. This initial wave of plasma cell differentiation accounts for a relatively small proportion of the overall in vivo response, which peaks at day 3 and is largely produced by immigrant B-1a cells that divide before (or while) differentiating to plasma cells. However, the rapid response capabilities of the early responders, which can be likened to primitive immunologic memory, may be key to the ability to use the innate immune system to "fill in the gap" until the adaptive immune system can take over. Studies proposed here are designed to provide a clear view of the B cells and mechanisms that participate in innate antibody responses to invading pathogens, including but not restricted to LPS. Our findings to date demonstrate that we can work effectively with the tiny functional B cell subsets that mediate these responses (0.1-3% of spleen cells from unstimulated or LPS-stimulated mice, respectively). Thus, we now propose to further define the cellular, anatomical and molecular mechanisms that distinguish resident B-1 responses from those of immigrant B-1 cells, and to determine the extent to which other B cell compartments and receptor interactions contribute to the innate response. Together, these studies will provide grounds for developing a comprehensive and informative model of the complex innate immunity mechanisms involved in natural antibody responses that must be produced rapidly to minimize damage due to invading pathogens. Public Health Relevance: Studies proposed here are designed to provide a clear view of the B cells and mechanisms that participate in innate antibody responses to invading pathogens. Our findings to date demonstrate that we can work effectively with the tiny functional B cell subsets that mediate these responses. These studies will provide grounds for developing a comprehensive and informative model of the complex innate immunity mechanisms involved in natural antibody responses that must be produced rapidly to minimize damage due to invading pathogens.

描述（由申请人提供）：当前对细菌刺激的先天免疫反应的概念，例如脂多糖（例如，此处使用的Typhimurium S. typhimurium的LPS）主要基于来自未刺激小鼠的体外刺激细胞的数据。但是，我们在体内小鼠模型中使用LPS刺激的最新发现表明，其中大部分体外数据不适合对天生反应进行建模，这些反应发生在体内。同样，我们的发现提出了有关如何将体内模型（B细胞转基因，TLR缺乏，寄生虫感染等）与LPS反应中的正常动物（遗传完整）动物中的LPS反应相关联的问题。具体而言，我们发现体内大多数LPS刺激的浆细胞反应是由B-1A（CD5+ B-1）细胞产生的，其中大多数仅在注射LPS后才迁移到脾脏中。此外，我们发现对LPS在体内的立即反应是由居住在脾脏中的B-1A细胞产生的，并且在1-2天内不受细胞分裂而在1-2天内出人意料地分化为浆细胞。浆细胞分化的初始波浪占整体体内反应的比例相对较小，该反应在第3天达到峰值，并且在很大程度上是由移民B-1A细胞产生的，这些B-1A细胞在与等离子细胞区分开之前（或）分裂。但是，可以比作原始免疫记忆的早期响应者的快速响应能力可能是使用先天免疫系统“填补空白”的能力的关键，直到适应性免疫系统可以接管。此处提出的研究旨在清楚地了解B细胞和参与对入侵病原体的先天抗体反应的机制，包括但不限于LPS。迄今为止，我们的发现表明，我们可以与介导这些反应的微小功能性B细胞子集有效合作（分别来自未刺激或LPS刺激的小鼠的脾细胞的0.1-3％）。因此，我们现在建议进一步定义细胞，解剖学和分子机制，该机制将居民B-1反应与移民B-1细胞的反应区分开，并确定其他B细胞区室和受体相互作用的程度有助于先天反应。总之，这些研究将为建立一个综合且内容丰富的模型，以了解与天然抗体反应有关的复杂先天免疫机制，这些机制必须迅速产生，以最大程度地减少因入侵病原体而造成的损害。公共卫生相关性：此处提出的研究旨在清楚地了解参与入侵病原体的先天抗体反应的B细胞和机制。迄今为止，我们的发现表明，我们可以与介导这些响应的微小功能B细胞子集有效合作。这些研究将为建立一个综合且内容丰富的模型，以了解必须迅速产生的自然抗体反应的复杂先天免疫机制，以最大程度地减少因入侵病原体而造成的损害。