New perspective on innate antibodies in mice

小鼠先天抗体的新视角

• 批准号: 8033790
• 负责人: Leonore A. Herzenberg
• 金额: $ 38.76万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8033790
• 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）：目前对脂多糖（例如，此处使用的来自鼠伤寒沙门氏菌的LPS）等细菌刺激的先天免疫反应的概念主要基于对取自未刺激小鼠的脾细胞进行体外刺激的数据。然而，我们最近在体内小鼠模型中进行 LPS 刺激的发现表明，大部分体外数据不适合模拟先天反应，而先天反应必然发生在体内。同样，我们的研究结果提出了如何将体内模型（B 细胞转基因、TLR 缺陷、寄生虫感染等）的数据与正常（基因完整）动物的 LPS 反应联系起来的问题。具体来说，我们发现体内大部分 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 后迁移到脾脏中。此外，我们发现体内对 LPS 的立即反应是由驻留在脾脏中的 B-1a 细胞产生的，并且令人惊讶地在 1-2 天内分化为浆细胞，而无需进行细胞分裂。浆细胞分化的初始波占体内总体反应的相对较小比例，其在第 3 天达到峰值，并且主要由在分化为浆细胞之前（或同时）分裂的移民 B-1a 细胞产生。然而，早期反应者的快速反应能力（可比作原始免疫记忆）可能是利用先天免疫系统“填补空白”直至适应性免疫系统接管的能力的关键。这里提出的研究旨在提供对 B 细胞和参与对入侵病原体（包括但不限于 LPS）的先天抗体反应的机制的清晰认识。我们迄今为止的研究结果表明，我们可以有效地利用介导这些反应的微小功能性 B 细胞亚群（分别来自未刺激或 LPS 刺激小鼠的脾细胞的 0.1-3%）。因此，我们现在建议进一步定义区分驻留 B-1 反应与移民 B-1 细胞反应的细胞、解剖和分子机制，并确定其他 B 细胞区室和受体相互作用对先天反应的贡献程度。总之，这些研究将为开发涉及天然抗体反应的复杂先天免疫机制提供全面且信息丰富的模型，必须快速产生天然抗体反应，以最大程度地减少入侵病原体造成的损害。公共健康相关性：此处提出的研究旨在提供对参与对入侵病原体的先天抗体反应的 B 细胞和机制的清晰认识。我们迄今为止的研究结果表明，我们可以有效地利用介导这些反应的微小功能性 B 细胞亚群。这些研究将为开发涉及天然抗体反应的复杂先天免疫机制提供全面且信息丰富的模型，必须快速产生天然抗体反应，以最大程度地减少入侵病原体造成的损害。

项目成果

Layered evolution in the immune system: a view from history.

• DOI: 10.1111/nyas.12795
• 发表时间: 2015-12
• 期刊: Annals of the New York Academy of Sciences
• 影响因子: 5.2
• 作者: Herzenberg LA