FDC regulation of self-reactive B cells

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。使用这种新的系统，我们将测试抗小鼠CD 21治疗在消除 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。

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.