TRANSGENIC MODEL FOR B CELL TOLERANCE AND AUTOIMMUNITY

描述(改编自调查者摘要)：系统性狼疮 红斑狼疮(SLE)是一种复杂的疾病，具有一系列的临床特征。 被认为是免疫功能失调的结果的表现 系统。系统性红斑狼疮的显著血清学特征是 抗DNA抗体。虽然这些抗体在诊断上很有用， 无论是它们的病因，还是它们在自身免疫病理中的确切作用 安全。调查者的目标是定义细胞和 影响两者自身抗体表达的分子相互作用 健康和自身免疫状态，首先，通过确定健康的动物 调节自身抗体的表达，第二，通过定义 关键病变(S)在这些过程中导致自身免疫。这个 研究人员将使用免疫球蛋白(Ig)转基因(TG)小鼠进行追踪 自身反应性B细胞的命运。因为抗DNA免疫球蛋白存在于 系统性红斑狼疮在其明显的特异性方面是异质性的 单链(Ss)和双链(Ds)DNA，研究人员将 使用各种抗DNA Ig TGS来概括这些不同 自动指定。具体目标如下：1.确定 抗单链DNA和抗双链DNA Tg B细胞成为一部分时的相对命运 不同的B细胞系，就像自身免疫者的情况一样。 评价不同抗DNA Ig TGS的存在对动力学的影响 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 以及Bcl-2，其表达的变化与该疾病的发生有关 系统性红斑狼疮相关自身抗体。3.识别和比较蜂窝 由自身抗体识别的抗原，研究人员针对这些抗原 有B细胞耐受性的证据和已分离的抗体 来自自身免疫的小鼠。研究细胞凋亡在细胞生成中的作用 通过确定抗核抗体是否来自SLE来靶向SLE的自身抗原 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.