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FDC regulation of self-reactive B cells

FDC 对自身反应 B 细胞的调节

基本信息

批准号：
10308457
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
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-14 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10308457
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

项目摘要

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：自身反应性B细胞的FDC调节摘要：系统性红斑狼疮（狼疮）是一种B细胞疾病，其特征是分泌致病性对核抗原特异的自身抗体或“DAMPS”。该疾病的一个标志是自发形成脾脏和淋巴结中的生发中心（GC）以及致病性长寿记忆B细胞的发育。滤泡树突状细胞（Follicular dendritic cells，FDC）是间质来源的树突状细胞，在维持B细胞结构中起重要作用卵泡对于GC的形成和维持是必需的，因为它们是B细胞抗原的主要来源，生存因素。我们提出FDC在自身反应性B细胞耐受性的调节中起关键作用，它们的分化和致病抗体的分泌。使用狼疮易感小鼠模型，我们发现， FDC通过CD 21摄取核抗原触发内体TLR，促进B细胞耐受性丧失，分化因此，FDC不仅是自身抗原的关键来源，而且是免疫缺陷病毒的重要来源。可以“驱动”自身反应性B细胞分化为自身抗体产生细胞和记忆B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。为了测试这种可能性，在临床前模型中，狼疮小鼠将用针对CD 21的阻断抗体治疗1个月的时间 FDC表达的受体。我们的假设将利用几种新的小鼠模型，如：人-小鼠CD 21嵌合狼疮小鼠，其中FDC表达鼠CD 21，B细胞表达人CD 21。使用这个新系统，我们将测试抗小鼠CD 21疗法在消除CD 21方面的功效。通过FDC保留核抗原和“关闭”TLR信号传导和细胞因子分泌。提出了三个目标：目标1.检验自身反应性B细胞的耐受性受FDC调节的假设目标2.检验自我反应记忆B细胞的维持依赖于FDC的假设目标3.在狼疮小鼠模型中测试阻断CD 21的功效总结：本研究的成功完成不仅将为人类提供有价值的试剂和新的工具，推动该领域向前发展，但它可能导致新的策略和/或阻断疗法的发展，系统性自身免疫，如狼疮。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Clonal Evolution of Autoreactive Germinal Centers.

自动发芽中心的克隆进化。

DOI：
10.1016/j.cell.2017.07.026
发表时间：
2017-08-24
期刊：
Cell
影响因子：
64.5
作者：
Degn SE;van der Poel CE;Firl DJ;Ayoglu B;Al Qureshah FA;Bajic G;Mesin L;Reynaud CA;Weill JC;Utz PJ;Victora GD;Carroll MC
通讯作者：
Carroll MC

Invasion of spontaneous germinal centers by naive B cells is rapid and persistent.

初始 B 细胞对自发生发中心的侵袭是快速且持久的。