Anti-Sm B Cell Regulation

抗 Sm B 细胞调节

• 批准号: 6766900
• 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/6766900
• 关键词: Anti; Sm; Cell; Regulation

DESCRIPTION (provided by applicant): 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-Sm 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 mechanisms. These mice will be followed for anti-Sm 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-Sm 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 naIve 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.

描述（由申请人提供）：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。重点将是对核抗原史密斯（Sm）的反应，这是人类和小鼠SLE所特有的。我们已经证明，在非自身免疫性小鼠中，一些抗sm B细胞受到负选择（能量、发育阻滞、中枢缺失）的调节，而其他抗sm B细胞则被正选择进入边缘区和B-1亚群，并具有功能。这种阴性和阳性选择的B细胞共存是不寻常的，这提示了一种可能的抗sm反应模型。要验证的假设是，一个或几个阳性选择的抗sm B细胞最初被激活，它们产生的抗体激活了额外的抗sm B细胞，包括那些阴性选择的细胞。在Aim 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，来确定自身免疫性MRL和lpr小鼠的抗sm B细胞调节机制存在哪些缺陷。这些小鼠将被跟踪进行抗sm B细胞激活，以确定激活的机制。在Aim 2中，我们将确定参与反应的抗sm B细胞库是否在其过程中扩展到包括更大的B细胞克隆库。在应答早期产生的抗sm抗体是否能激活其他抗sm B细胞也将被确定。在Aim 3中，我们将研究人类SLE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naIve细胞具有异常低的CD19水平。我们将验证人类SLE的抗sm反应是抗原驱动的假设，并且克隆内多样性和亲和成熟是通过连续的活动性疾病时期增加的。此外，我们将验证cd19异常表达模式影响耐受性和激活的假设。