Anti-Sm B Cell Regulation

抗 Sm B 细胞调节

• 批准号: 6836463
• 负责人: Stephen H Clarke
• 金额: $ 28.98万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-15 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6836463
• 关键词: Anti; Sm; Cell; Regulation

EXCEED THE SPACE PROVIDED. The long-range goal of this work is to determine how B cell tolerance to self-antigens in systemic lupus erythematosus (SLE) is lost. The focus will be the response to the nuclear antigen Smith (Sm), which is unique to human and mouse SLE. We have shown that in non-autoimmune mice some anti-Sin B cells are regulated by negative selection (anergy, developmental arrest, central deletion), while others are positively selected into the marginal zone and B- 1 subsets and are functional. This coexistence of negatively and positively selected B cells is unusual and suggests a possible model for the anti-Sm response. The hypothesis to be tested is that one or few positively selected anti-Sm B cells are activated initially, and that the antibody they produce activates additional anti-Sm B cells, including those that are negatively selected. In Aim 1 we will determine which mechanism(s) of anti-Sm B cell regulation are defective in autoimmune MRL and lpr mice by generating a series Ig H and L chain transgenic mice regulated by different mechanism. These mice will be followed for anti-Sin B cell activation to identify the mechanism(s) activated. In Aim 2 we will determine whether the repertoire of anti-Sm B cells involved in the response expands during its course to include a larger repertoire of B cell clones. Whether anti-Sm antibodies generated early in the response can activate other anti-Sin B cells will also be determined. In Aim 3 we will examine the anti-Sm response in human SLE. We can detect anti-Sm B cells in the peripheral blood of SLE patients and find that they express unusually high CD19 levels, although non-Sm binding na'fve cells have unusually low CD19 levels. We will test the hypothesis that the anti-Sm response in human SLE is antigen-driven and that intra-clonal diversity and affinity maturation are additive through successive periods of active disease. In addition, we will test the hypothesis that the unusual pattern of CD 19 expression affects tolerance and activation. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。这项工作的长期目标是确定系统性红斑狼疮 (SLE) 中 B 细胞对自身抗原的耐受性如何丧失。重点是对核抗原 Smith (Sm) 的反应，这是人类和小鼠 SLE 所特有的。我们已经证明，在非自身免疫小鼠中，一些抗 Sin B 细胞受到负选择（无反应、发育停滞、中央​​缺失）的调节，而其他细胞则被正选择进入边缘区和 B-1 亚群并具有功能。阴性和阳性选择的 B 细胞的这种共存是不寻常的，这表明抗 Sm 反应的可能模型。要测试的假设是，一个或几个正选的抗 Sm B 细胞最初被激活，并且它们产生的抗体会激活其他抗 Sm B 细胞，包括那些负选的细胞。在目标 1 中，我们将通过产生一系列受不同机制调节的 Ig H 和 L 链转基因小鼠来确定自身免疫 MRL 和 lpr 小鼠中哪些抗 Sm B 细胞调节机制有缺陷。将跟踪这些小鼠进行抗 Sin B 细胞激活，以确定激活的机制。在目标 2 中，我们将确定参与反应的抗 Sm B 细胞库是否会在反应过程中扩展以包含更大的 B 细胞克隆库。反应早期产生的抗 Sm 抗体是否可以激活其他抗 Sin B 细胞也将被确定。在目标 3 中，我们将检查人类 SLE 中的抗 Sm 反应。我们可以检测 SLE 患者外周血中的抗 Sm B 细胞，发现它们表达异常高的 CD19 水平，尽管非 Sm 结合的 na'fve 细胞的 CD19 水平异常低。我们将检验以下假设：人类 SLE 中的抗 Sm 反应是抗原驱动的，并且克隆内多样性和亲和力成熟是在连续的活动性疾病时期中累加的。此外，我们将测试 CD 19 表达的异常模式影响耐受性和激活的假设。表演网站==========================================章节结束===============================================