B Cell Tolerance in Lupus

描述（由申请人提供）：有大量证据表明，自身抗体（autoAbs）是通过体细胞超突变（SHM）产生的，在系统性红斑狼疮（SLE）中，通过这一过程获得自身反应性的B细胞的耐受性受损。尽管最近的研究对生发中心（GC）反应（SHM发生的地方）的参与者和细胞动力学提供了相当多的见解，但在了解维持新产生的自反应性B细胞耐受性的机制方面进展甚微，主要是因为缺乏适当的模型。我们与其他研究人员合作，最近使用了一种新型的¿2a-巨自身抗原（Ag）转基因（Tg）系统，表明fas缺陷小鼠在审查对表面结合Ag获得自身反应性的B细胞方面存在缺陷。然而，该模型使用了一种人造Ag，其特征与SLE中声称的自体Ag有很大不同。为了解决这些限制，我们开发了一种新的B细胞受体Tg模型，称为FLEx-autoAb，它将允许在B细胞中有条件地用dna结合受体替代无害抗原受体，并寻求使用该模型来研究正常小鼠和自身免疫性小鼠shm后耐受机制。为实现这一目标，提出了两个目标。Specific aim 1将使用FLEx-autoAb系统来研究自身免疫性B6-Faslpr小鼠外周自身反应性B细胞的耐受性，特别关注生发中心B细胞的耐受性。特异性目标2将使用这个新系统研究四种全身自身免疫模型中外周B细胞的耐受性。该项目有可能发现与SLE和其他可能的自身抗体介导的疾病相关的新的调节机制，这些机制控制B细胞在周围获得自身反应性。

DESCRIPTION (provided by applicant): There is abundant evidence that autoantibodies (autoAbs) are generated through somatic hypermutation (SHM) and that tolerance of B cells that acquire self-reactivity through this process is impaired in systemic lupus erythematosus (SLE). Although recent studies have provided considerable insights into the participants and cellular dynamics in germinal center (GC) reactions where SHM takes place, there has been little progress in understanding the mechanisms for maintaining tolerance of newly generated self-reactive B cells, largely because of the absence of an appropriate model. We, in collaboration with other investigators, have recently used a novel ¿2a-macroself antigen (Ag) transgenic (Tg) system to show that Fas-deficient mice are defective in censoring B cells that have acquired autoreactivity to a surface-bound Ag. This model, however, utilizes an artificial Ag with characteristics that differ substantially from the purported autoAgs in SLE. To address these limitations, we have developed a new B cell receptor Tg model, called FLEx-autoAb, that will allow conditional replacement of an innocuous antigen-receptor with a DNA-binding receptor in B cells and seek to use this model to investigate post-SHM tolerance mechanisms in normal and autoimmune mice. To accomplish this, two aims are proposed. Specific aim 1 will use the FLEx-autoAb system to study tolerance of B cells that become autoreactive in the periphery in autoimmune B6-Faslpr mice specifically focusing on tolerance of germinal center B cells. Specific aim 2 will use this new system to study tolerance of B cells in the periphery in four models of systemic autoimmunity. This project has the potential for discovering new regulatory mechanisms, relevant to SLE and likely other autoAb-mediated-diseases, that control B cells that acquire autoreactivity in the periphery.