B Cell Tolerance in Lupus

狼疮中的 B 细胞耐受性

• 批准号: 8063816
• 负责人: DWIGHT H KONO
• 金额: $ 25.64万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-20 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063816
• 关键词: Address; Affinity; Amplifiers; Animal Model; Antibodies; Antigen Receptors; Antigen-Antibody Complex; Antigens; Antinuclear Antibodies; Area; Ascaridil; Autoantibodies; Autoantigens; Autoimmune Process; Autoimmune Responses; B-Lymphocytes; Binding; Biological Models; Cells; Characteristics; Collaborations; DNA; DNA Binding; Disease; Event; Generations; Immune; Immunoglobulin Class Switching; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; Immunoglobulins; Injury; Investigation; Lupus; Mature B-Lymphocyte; Mediating; Modeling; Mus; Nature; Nuclear; Nucleic Acid Binding; Nucleic Acids; Participant; Pathogenesis; Play; Process; Production; Reaction; Receptors, Antigen, B-Cell; Research Personnel; Role; Structure of germinal center of lymph node; Surface; System; Systemic Lupus Erythematosus; Tissues; Toll-like receptors; Transgenic Model; Transgenic Organisms; activation-induced cytidine deaminase; antigen binding; autoreactivity; improved; insight; novel; novel strategies; receptor

DESCRIPTION (provided by applicant): There is abundant evidence that autoantibodies (autoAbs) are generated through somatic hypermutation and that tolerance of B cells that acquire self-reactivity through this process is impaired in systemic lupus erythematosus (SLE). Although recent studies have provided considerable insights into the participants and cellular dynamics in germinal center (GC) reactions where somatic hypermutation (SHM) takes place, there has been little progress in understanding the mechanisms for maintaining tolerance of newly generated self- reactive B cells, largely because of the absence of an appropriate model. We, in collaboration with other investigators, have recently used a novel 32a-macroself antigen (Ag) transgenic (Tg) system to show that Fas- deficient mice are defective in censoring B cells that have acquired autoreactivity to a surface-bound Ag. This model, however, utilizes an artificial Ag with characteristics that differ substantially from the purported autoAgs in SLE. To address these limitations, we have formulated a new B cell receptor Tg model that will allow replacement of an innocuous antigen-receptor with a DNA-binding receptor in B cells undergoing class switch recombination (CSR)/SHM, and seek to develop this model and use it to investigate post-SHM tolerance mechanisms in normal and autoimmune mice. To accomplish this, three aims are proposed that will: 1) generate the FLEx-autoAb model system, 2) characterize tolerance of post-CSR/SHM B cells in non- autoimmune mice, and 3) characterize tolerance of post-CSR/SHM in lupus-prone B6-Faslpr mice. This novel approach has the potential for significantly improving our ability to study tolerance of B cells that acquire autoreactivity in the periphery, to generate new and important insights into this process, and to substantially advance this area of investigation, which is highly relevant to SLE and other autoAb-mediated diseases. PUBLIC HEALTH RELEVANCE: Defective tolerance of B cells to self is considered to be one of the major causes of systemic lupus erythematosus (SLE) responsible for the production of harmful autoantibodies; yet many aspects of this process remain poorly understood particularly tolerance mechanisms that keep in check B cells that acquire self-reactivity during somatic hypermutation. Currently none of the existing animal models are able to directly study mature B cells that acquire autoreactivity to self-antigens commonly targeted in SLE. To address this issue, we proposed to generate a new and more relevant model, called FLEx-autoAb, using a novel approach.

描述（由申请人提供）：有大量证据表明，自身抗体 (autoAbs) 是通过体细胞超突变产生的，并且通过该过程获得自身反应性的 B 细胞的耐受性在系统性红斑狼疮 (SLE) 中受损。尽管最近的研究对发生体细胞超突变 (SHM) 的生发中心 (GC) 反应的参与者和细胞动力学提供了相当多的见解，但在理解新生成的自身反应性 B 细胞维持耐受性的机制方面进展甚微，这主要是因为缺乏合适的模型。我们与其他研究人员合作，最近使用了一种新型 32a-宏自抗原 (Ag) 转基因 (Tg) 系统来证明 Fas 缺陷小鼠在审查 B 细胞方面存在缺陷，这些 B 细胞已获得对表面结合 Ag 的自身反应性。然而，该模型使用的人工抗原与 SLE 中所谓的自身抗原有很大不同。为了解决这些局限性，我们制定了一种新的 B 细胞受体 Tg 模型，该模型将允许在经历类别转换重组 (CSR)/SHM 的 B 细胞中用 DNA 结合受体取代无害的抗原受体，并寻求开发该模型并用它来研究正常和自身免疫小鼠的 SHM 后耐受机制。为了实现这一目标，提出了三个目标：1) 生成 FLEx-autoAb 模型系统，2) 表征非自身免疫小鼠中 CSR/SHM 后 B 细胞的耐受性，3) 表征易患狼疮的 B6-Faslpr 小鼠中 CSR/SHM 后的耐受性。这种新方法有可能显着提高我们研究在外周获得自身反应性的 B 细胞耐受性的能力，从而对该过程产生新的重要见解，并大大推进这一与 SLE 和其他自身抗体介导的疾病高度相关的研究领域。 公众健康相关性：B 细胞对自身的耐受性缺陷被认为是系统性红斑狼疮 (SLE) 的主要原因之一，该病会产生有害的自身抗体；然而，这一过程的许多方面仍然知之甚少，特别是耐受机制，它可以控制在体细胞超突变期间获得自我反应性的 B 细胞。目前，现有的动物模型都无法直接研究成熟 B 细胞，这些细胞对 SLE 中常见的自身抗原具有自身反应性。为了解决这个问题，我们建议使用一种新颖的方法生成一个新的、更相关的模型，称为 FLEx-autoAb。