Anti-Sm B Cell Regulation

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是如何丧失的。重点将是对核抗原Smith（Sm）的反应，这是人类和小鼠SLE所特有的。我们已经表明，在非自身免疫小鼠中，一些抗Sm B细胞受负选择（无反应性，发育停滞，中央缺失）的调节，而其他细胞则被积极选择进入边缘区和B-1亚群，并具有功能。这种阴性和阳性选择的B细胞的共存是不寻常的，并提出了一个可能的抗Sm反应的模型。待检验的假设是，一个或几个阳性选择的抗Sm B细胞最初被激活，并且它们产生的抗体激活额外的抗Sm B细胞，包括那些阴性选择的细胞。目的1：通过建立一系列受不同机制调控的IG H和L链转基因小鼠，确定自身免疫性MRL和lpr小鼠中抗Sm B细胞调控机制的缺陷。将对这些小鼠进行抗Sm B细胞活化随访，以确定活化机制。在目标2中，我们将确定是否参与反应的抗Sm B细胞库在其过程中扩展到包括更大的B细胞克隆库。还将确定在反应早期产生的抗Sm抗体是否可以激活其他抗Sm B细胞。在目标3中，我们将研究抗Sm反应在人类SLE。我们可以检测到SLE患者外周血中抗Sm B细胞，并发现它们表达异常高的CD 19水平，尽管非Sm结合的幼稚细胞具有异常低的CD 19水平。我们将测试的假设，在人类SLE的抗Sm反应是抗原驱动的，通过连续的活动性疾病的时期内的克隆内的多样性和亲和力成熟的添加剂。此外，我们将检验CD 19表达的异常模式影响耐受性和活化的假设。

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.