Anti-Sm B Cell Regulation

这项工作的长期目标是确定系统性狼疮患者的B细胞对自身抗原的耐受性 红斑性狼疮（SLE）的症状消失了。重点将是对核抗原Smith（Sm）的反应， 是人类和小鼠SLE特有的。我们已经证明，在非自身免疫小鼠中，一些抗Sin B细胞是 受负选择（无能，发育停滞，中央缺失），而其他人是积极的 被选入边缘区和B- 1亚群并且是功能性的。这种消极和消极的共存 阳性选择的B细胞是不寻常的，并提出了一个可能的抗Sm反应的模型。的假设 一个或几个阳性选择的抗Sm B细胞最初被激活， 它们产生激活额外的抗Sm B细胞，包括那些被阴性选择的细胞。在目标1中， 将确定抗Sm B细胞调节的哪些机制在自身免疫性MRL和lpr中存在缺陷 通过建立一系列不同机制调控的IG H和L链转基因小鼠。这些小鼠 将跟踪抗Sin B细胞活化，以确定活化机制。在目标2中， 确定参与应答的抗Sm B细胞库是否在其过程中扩增， 包括更大的B细胞克隆库。是否在反应早期产生的抗Sm抗体可以 还将确定激活其它抗Sin B细胞。在目标3中，我们将检查抗Sm反应， 人SLE。我们可以检测SLE患者外周血中抗Sm B细胞，发现它们表达 异常高的CD 19水平，尽管非Sm结合幼稚细胞具有异常低的CD 19水平。我们将 检验人类SLE的抗Sm应答是抗原驱动的，克隆内多样性 和亲和力成熟在连续的活动性疾病期间是累加的。此外，我们将测试 CD 19表达的不寻常模式影响耐受性和活化的假说。

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.