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）：对细菌刺激物如脂多糖（例如，S.鼠伤寒沙门氏菌）主要基于来自取自未受刺激小鼠的脾细胞的体外刺激的数据。然而，我们最近在体内小鼠模型中用LPS刺激的发现表明，这种体外数据中的大部分不适合于对体内必然发生的先天性反应进行建模。类似地，我们的发现提出了关于如何将来自体内模型（B细胞转基因、TLR缺陷、寄生虫感染等）的数据关联起来的问题。正常（基因完整）动物的LPS反应。具体而言，我们发现，大部分的LPS刺激的浆细胞反应在体内产生的B-1a（CD 5 + B-1）细胞，其中大部分只迁移到脾后，LPS注射。此外，我们发现体内对LPS的立即反应是由驻留在脾中的B-1a细胞产生的，并且令人惊讶地在1-2天内分化成浆细胞而不经历细胞分裂。这种浆细胞分化的初始波占总体体内反应的相对小的比例，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）分裂的迁移B-1a细胞产生。然而，早期反应者的快速反应能力，可以比作原始免疫记忆，可能是使用先天免疫系统“填补差距”直到适应性免疫系统接管的关键。本文提出的研究旨在提供参与对入侵病原体（包括但不限于LPS）的先天性抗体应答的B细胞和机制的清晰视图。迄今为止，我们的研究结果表明，我们可以有效地与微小的功能性B细胞亚群，介导这些反应（0.1-3%的脾细胞从未刺激或LPS刺激的小鼠，分别）。因此，我们现在建议进一步确定区分居民B-1反应的细胞，解剖和分子机制，从那些移民B-1细胞，并确定在何种程度上其他B细胞区室和受体相互作用有助于先天性反应。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的全面和信息模型提供基础，这些天然抗体反应必须迅速产生，以最大限度地减少入侵病原体造成的损害。公共卫生相关性：这里提出的研究旨在提供一个清晰的视图的B细胞和机制，参与先天抗体反应入侵病原体。迄今为止，我们的研究结果表明，我们可以有效地与微小的功能性B细胞亚群介导这些反应。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的全面和信息模型提供基础，这些天然抗体反应必须迅速产生，以尽量减少入侵病原体造成的损害。

项目成果

Distinct B-cell lineage commitment distinguishes adult bone marrow hematopoietic stem cells

• DOI: 10.1073/pnas.1121632109
• 发表时间: 2012-04-03
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Ghosn, Eliver Eid Bou;Yamamoto, Ryo;Herzenberg, Leonore A.
• 通讯作者: Herzenberg, Leonore A.

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