A TRANSGENIC MODEL FOR B CELL TOLERANCE AND AUTOIMMUNITY

系统性红斑狼疮（SLE）和狼疮的鼠模型的标志是存在抗双链（ds）DNA Ab。 我们的目标是了解SLE相关的自身抗体在健康个体中是如何调节的，并确定其在自身免疫中表达的机制。 我们采取的方法是使用仅重链Tg（VH 3 H9）开发转基因（Tg）模型，其可以与内源性轻链配对以产生抗DNA和非DNA抗体（Ab）谱。 该模型的优点在于，抗dsDNA B细胞的发育可以在非自身免疫和自身免疫倾向背景中的多种B细胞库的背景下进行跟踪。 该竞争性更新的目的1是比较已知导致SLE相关自身抗体产生的不同基因突变对抗dsDNA B细胞的表型和功能能力的影响。 具体而言，将研究lpr/lpr、gld/gld和林恩-/-小鼠。 此外，还将在SLE的诱导模型中研究dsDNA B细胞的调节。在MRL-lpr/lpr小鼠中使用VH 3 H9 Tg，我们已经鉴定了在自身抗体产生之前抗dsDNA B细胞的发育状态和组织定位的变化。 目的二是了解这些现象背后的机制，特别强调识别的作用，有缺陷的Fas（lpr/lpr）发挥自身抗体的表达。 目的III：研究MRL-lpr/lpr小鼠CD 4 T细胞与抗dsDNA B细胞共定位的性质和意义。 所提出的研究的新颖方面在于，在VH 3 H9 Tg的背景下，我们可以跟踪抗dsDNA B细胞在不同情况下的命运，以开始鉴定导致自身抗体产生的步骤。 了解影响自身抗体产生的参数可能会激发SLE更有针对性的治疗。

A hallmark of systemic lupus erythematosus (SLE), and murine models of lupus, is the presence of anti-double-stranded (ds) DNA Abs. Our goals are to understand how SLE-associated autoantibodies are regulated in healthy individuals and to identify the mechanisms underlying their expression in autoimmunity. The approach we have taken is to develop a transgenic (Tg) model using a heavy chain-only Tg (VH3H9) which can pair with endogenous light chains to generate a spectrum of anti-DNA and non-DNA antibodies (Abs). The advantage of this model is that the development of anti-dsDNA B cells can be tracked in the context of a diverse B cell repertoire in non- autoimmune and autoimmune-prone backgrounds. Aim 1 of this competitive renewal is to compare the effects of distinct genetic mutations that are known to result in the production of SLE-associated autoantibodies on the phenotype and functional capacity of anti-dsDNA B cells. Specifically, lpr/lpr, gld/gld, and lyn-/- mice will be studied. Furthermore, the regulation of dsDNA B cells will also be investigated in induced models of SLE. Using the VH3H9 Tg in MRL-lpr/lpr mice, we have identified changes in the developmental status and tissue localization of anti-dsDNA B cells that precede autoantibody production. Aim II is to understand the mechanisms behind these phenomena, with particular emphasis on identifying the role that defective Fas (lpr/lpr) plays in autoantibody expression. Aim III is to characterize the nature and significance of the CD4 T cells that co-localize with anti-dsDNA B cells in MRL-lpr/lpr mice. The novel aspect of the proposed studies is that, in the context of the VH3H9 Tg, we can follow the fate of anti-dsDNA B cells under diverse circumstances to begin to identify steps that lead to autoantibody production. Knowledge of the parameters that influence the production of autoantibodies may inspire more targeted therapy for SLE.