Anti-Sm B Cell Regulation

描述(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是如何丧失的。重点将放在对人类和小鼠系统性红斑狼疮特有的核抗原Smith(Sm)的反应上。在非自身免疫小鼠中，一些抗Sm B细胞受到负选择(无能、发育停滞、中心缺失)的调节，而另一些抗Sm B细胞则被阳性选择进入边缘地带和B-1亚群并具有功能。这种阴性和阳性选择的B细胞的共存是不寻常的，这表明了一种可能的抗Sm反应模式。需要检验的假设是，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额外的抗Sm B细胞，包括那些被阴性选择的抗Sm B细胞。目的1通过建立一系列不同调节机制的Ig H和L链转基因小鼠，确定在自身免疫的MRL和LPR小鼠中，哪一种抗Sm B细胞调节机制(S)存在缺陷。这些小鼠将被跟踪进行抗Sm B细胞的激活，以确定激活的机制(S)。在目标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大到包括更大的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。在目标3中，我们将检测人类系统性红斑狼疮的抗Sm反应。我们可以在SLE患者的外周血中检测到抗Sm B细胞，发现它们表达异常高的CD19水平，尽管非Sm结合的幼稚细胞的CD19水平异常低。我们将检验这一假设，即人类SLE中的抗Sm反应是由抗原驱动的，并且克隆内多样性和亲和力成熟在疾病活动的连续时期是相加的。此外，我们还将检验CD19异常表达模式影响耐受和激活的假设。

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.