FDC regulation of self-reactive B cells

FDC 对自身反应 B 细胞的调节

• 批准号: 10058807
• 负责人: Michael Craig Carroll
• 金额: $ 53.1万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-14 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058807
• 关键词: Antibodies; Antibody-Producing Cells; Antigen-Antibody Complex; Antigens; Architecture; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; B cell differentiation; B-Lymphocytes; Blocking Antibodies; Cells; Chronic; Complement 3d Receptors; Complex; Development; Disease; Effector Cell; Follicular Dendritic Cells; Gene Expression Profile; Human; Individual; Inflammation; Informal Social Control; Interferon Type I; Interferon-alpha; Interferons; Kidney; Lead; Lupus; Maintenance; Memory; Memory B-Lymphocyte; Molecular; Mus; Neurologic Symptoms; Nuclear Antigens; Pathogenicity; Patients; Pattern; Peripheral; Phenotype; Play; Pre-Clinical Model; Proteins; Publishing; Reaction; Reagent; Regulation; Reporter; Role; Self Tolerance; Signal Transduction; Skin; Source; Spleen; Stromal Cells; Structure of germinal center of lymph node; System; Systemic Lupus Erythematosus; Systemic Therapy; TLR7 gene; Techniques; Testing; Tissues; activation-induced cytidine deaminase; autoreactive B cell; autoreactivity; base; cell type; chemokine; cytokine; droplet sequencing; efficacy testing; experimental study; long term memory; lupus prone mice; lymph nodes; mouse model; new therapeutic target; novel; novel strategies; pathogenic autoantibodies; receptor; response; systemic autoimmune disease; systemic autoimmunity; tool; transcriptome; uptake

TITLE: FDC regulation of self-reactive B cells Abstract: Systemic lupus erythematosus (lupus) is a B cell disease characterized by secretion of pathogenic autoantibody specific for nuclear antigens or "DAMPS". A hallmark of the disease is spontaneous formation of germinal centers (GC) in spleen and lymph nodes and development of pathogenic long- lived memory B cells. Follicular dendritic cells (FDC) which are stromal derived and important in maintaining the architecture of B cell follicles are essential to formation and maintenance of GC as they are a major source of B cell antigen and survival factors. We propose FDC play a critical role in the regulation of tolerance of autoreactive B cells and their differentiation and secretion of pathogenic antibodies. Using a lupus-prone mouse model, we found that FDC uptake of nuclear antigens via CD21 triggers endosomal TLR promoting B cell loss of tolerance and differentiation. Thus, FDC are not only a critical source of self-antigen; but they are an important source of signals that can “drive” self-reactive B cells to differentiate into autoantibody producing cells and memory B cells. These findings suggest FDC may be a novel target for therapy in lupus patients. To test this possibility in a pre-clinical model, lupus mice will be treated over a period of 1 month with a blocking antibody to the CD21 receptor expressed by FDC. Our hypothesis will take advantage of several novel murine models such as a human-mouse CD21 chimeric lupus mouse where the FDC express murine CD21 and the B cells express human CD21. Using this novel system, we will test the efficacy of anti-mouse CD21 therapy in the elimination of retention of nuclear antigens by FDC and "turning-off" TLR signaling and cytokine secretion. Three aims are proposed: Aim 1. Test the hypothesis that the tolerance of self-reactive B cells is regulated by FDCs Aim 2. Test the hypothesis that the maintenance of self-reactive memory B cells is FDC-dependent Aim 3. Test the efficacy of blocking CD21 in lupus mouse models Summary: The successful completion of this study will not only provide valuable reagents and novel tools to push the field forward but it could lead to development of novel strategies and/or blocking therapies for systemic autoimmunity such as lupus.

标题：FDC对自身反应性B细胞的调节 摘要： 系统性红斑狼疮(SLUS)是一种以分泌性致病物质为特征的B细胞性疾病 核抗原或“核抗原”的自身抗体。这种疾病的一个特征是自发形成的 脾和淋巴结中的生发中心(GC)和致病的长寿记忆B细胞的发展。 滤泡树突状细胞(FDC)是一种基质来源的细胞，对维持B细胞的结构很重要 卵泡对于GC的形成和维持是必不可少的，因为它们是B细胞抗原和 生存因素。我们认为FDC在自身反应性B细胞的耐受性调节中起关键作用。 它们的分化和致病抗体的分泌。使用易患狼疮的小鼠模型，我们发现 FDC通过CD21摄取核抗原触发内体TLR促进B细胞耐受性丧失和 差异化。因此，FDC不仅是自身抗原的关键来源；而且也是 能“驱动”自身反应性B细胞分化为自身抗体产生细胞和记忆性B细胞的信号 细胞。这些发现表明，FDC可能是狼疮患者治疗的新靶点。为了测试这一可能性， 作为临床前模型，狼疮小鼠将接受CD21封闭抗体为期1个月的治疗。 FDC表达的受体。我们的假设将利用几种新的小鼠模型，例如 人-鼠CD21嵌合狼疮鼠，FDC表达小鼠CD21，B细胞表达 人类CD21。利用这个新的系统，我们将测试抗鼠CD21疗法在消除 FDC保留核抗原，并“关闭”TLR信号和细胞因子的分泌。 提出了三个目标： 目的1.验证自身反应性B细胞的耐受性受FDCs调节的假设 目的2.检验自我反应性记忆B细胞的维持依赖于FDC的假设 目的3.检测封闭CD21对狼疮小鼠模型的影响 总结：这项研究的成功完成不仅将提供有价值的试剂和新工具 推动该领域向前发展，但它可能导致开发新的策略和/或阻断疗法 系统性自身免疫性疾病，如狼疮。