TRANSGENIC MODEL FOR B CELL TOLERANCE AND AUTOIMMUNITY

描述（改编自研究者摘要）：系统性狼疮 红斑性狼疮（SLE）是一种复杂的疾病， 被认为是免疫功能失调的结果的表现 系统 SLE的突出血清学特征是存在 抗DNA抗体 虽然这些抗体在诊断上是有用的， 它们的病因和它们在自身免疫病理学中的确切作用都不清楚， 清楚 研究者的目标是确定细胞和 分子相互作用影响自身抗体的表达， 健康和自身免疫状态，首先，通过确定健康动物 调节自身抗体的表达，第二，通过定义 这些过程中的关键病变导致自身免疫。 的 研究者将使用免疫球蛋白（IG）转基因（tg）小鼠来跟踪 自身反应性B细胞的命运。 因为抗DNA免疫球蛋白存在于 SLE的表观特异性是异质的， 单链（ss）与双链（ds）DNA，研究人员将 使用各种抗DNA IG tgs来概括这些不同的 自体特异性 具体目标如下：1. 确定 当抗ssDNA和抗dsDNA tg B细胞是一部分时， 在自身免疫性个体中也是如此。 评价不同抗DNA IG tgs的存在如何影响动力学 自身抗体的表达，并影响肾脏病理的严重程度， MRL-lpr/lpr小鼠。 2. 研究细胞死亡的两个调节因子Fas的作用 和Bcl-2，其表达的改变与 SLE相关的自身抗体 3. 识别和比较细胞 被自身抗体识别的抗原， 有B细胞耐受性的证据， 自体免疫小鼠的 研究细胞凋亡在产生 通过确定抗核抗体是否来自 MRL-lpr/lpr小鼠与暴露在凋亡细胞上的抗原结合。

DESCRIPTION (Adapted from the Investigator's abstract): Systemic lupus erythematosus (SLE) is a complex disease that has a spectrum of clinical manifestations thought to be the consequence of a dysfunctional immune system. The prominent serological feature of SLE is the presence of anti-DNA antibodies. While these antibodies are useful diagnostically, neither their etiology nor their precise role in the autoimmune pathology is clear. The investigator's objectives are to define the cellular and molecular interactions that influence autoantibody expression in both healthy and autoimmune states, first, by determining how healthy animals regulate the expression of autoantibodies, and second, by defining the critical lesion(s) in these processes that lead to autoimmunity. The investigators will use immunoglobulin (Ig) transgenic (tg) mice to follow the fate of autoreactive B cells. Because anti-DNA Igs that are present in SLE are heterogeneous in terms of their apparent specificity for single-stranded (ss) versus double-stranded (ds) DNA, the investigators will use a variety of anti-DNA Ig tgs to recapitulate these different autospecificities. Specific aims are as follows: 1. Determine the relative fates of anti-ssDNA and anti-dsDNA tg B cells when they are a part of a diverse B-cell repertoire as is the case in autoimmune individuals. Evaluate how the presence of different anti-DNA Ig tgs affects the kinetics of autoantibody expression and influences the severity of renal pathology in MRL-lpr/lpr mice. 2. Examine the role of two regulators of cell death, Fas and Bcl-2, whose altered expression has been associated with the occurrence of SLE-associated autoantibodies. 3. Identify and compare cellular antigens that are recognized by autoantibodies for which the investigators have evidence of B cell tolerance and by antibodies which have been isolated from autoimmune mice. Examine the role that apoptosis plays in generating autoantigens targeted in SLE by determining if anti-nuclear antibodies from MRL-lpr/lpr mice bind to antigens exposed on apoptotic cells.