TRANSGENIC MODEL FOR B-CELL TOLERANCE AND AUTOIMMUNITY

本研究的目的是探讨儿童语言的发展和表达， B细胞对疾病相关自身抗原DNA具有特异性， 非自身免疫和自身免疫小鼠。 我们开发了一种转基因（TG） 使用多组TG的模型系统：仅Vh 3 H9重链TG， 当与内源性轻链配对时，其产生 抗DNA和非DNA结合抗体; Vh 3 H9重链TG配对 与Vkappa 8轻链TG结合，产生基本上单特异性的 抗单链（ss）DNA库;和Vh 3 H9重链TG 与VEGFda 1或VEGFda 2轻链TG配对，两者均 当与Vh 3 H9重链配对时，结合ss和双链 （ds）DNA，但具有不同的亲和力。 对DNA的耐受性表现在 在这些TG中有不同的方式。 在Vh 3 H9/Vkappa 8 TG中，抗ssDNA B 细胞主宰着所有的功能，但它们在功能上是沉默的，它们是 宽容。 我们将研究是什么细胞基础，防止抗- DNA表达在这些小鼠中。 Vh 3 H9 TG扩展了模型， B细胞耐受性在正常小鼠中作用机制不同， 具有抗dsDNA特异性的B细胞：抗dsDNA B细胞缺失或 已显著下调其表面免疫球蛋白（IG）。 的 抗dsDNA B细胞在正常与自身免疫动物中的命运将 被研究。 我们有证据表明，Vh 3 H9/Vkappa 8 TG表达 在自身免疫遗传背景下。 不清楚的是 变化导致他们的表达。 的范围和克隆性， TG抗DNA表达将直接解决 自身免疫 我们想知道为什么对DNA的耐受性以不同的方式表现出来。 抗DNA抗体的特异性和亲合力 影响B细胞的调节方式将使用 TG重链和轻链TG的各种组合。 抗dna 从这些TG产生的抗体在以下方面是异质的 它们识别的DNA的形式， 结构相关的分子，以及它们对DNA的亲和力。 我们 能够确定这些参数中哪些是重要的 决定正常小鼠体内B细胞的命运。 某些类型的抗DNA的表达 病理学是有争议的。 没有任何迹象表明，蚂蚁- DNA抗体存在于正常动物中， 导致自身免疫动物的疾病 的电位范围 可以由TG表达的抗DNA抗体可以提供抗DNA抗体的免疫原性。 有机会将特定抗DNA的表达 抗体与疾病 这项研究的最终目标是 能够治愈自身免疫。 通过使用富裕的人口 抗DNA抗原提呈细胞（APC），我们可以了解的性质， 体内抗原，并最终设计方法来干扰 抗DNA/自身相互作用。

The goal of this study is to examine the development and expression of B cells specific for a disease-associated self-antigen, DNA, in nonautoimmune and autoimmune mice. We have developed a transgenic (TG) model system using multiple sets of TGs: the Vh3H9 heavy chain-only TG, which when paired with endogenous light chains generates a spectrum of anti-DNA and non-Dna binding antibodies; the Vh3H9 heavy chain TG mated to a Vkappa8 light chain TG resulting in an essentially monospecific anti-single strand (ss)DNA repertoire; and the Vh3H9 heavy chain TG mated to either a Vlambda1 or a Vlambda2 light chain TG, both of which when paired with the Vh3H9 heavy chain bind ss and double strand (ds)DNA, but with different affinity. Tolerance to DNA is manifested in different ways in these TGs. In the Vh3H9/Vkappa8 TGs the anti-ssDNA B cells dominate the repertoire yet they are functionally silent, they are tolerized. We will investigate what the cellular basis preventing anti- DNA expression is in these mice. The Vh3H9 TGs extend the model to show that different mechanism of B cell tolerance operate in normal mice on B cells with anti-dsDNA specificity: anti-dsDNA B cells are deleted or have drastically down regulated their surface immunoglobulin (Ig). The fate of the anti-dsDNA B cells in normal versus autoimmune animals will be studied. We have evidence that the Vh3H9/Vkappa8 TGs are expressed when in an autoimmune genetic background. What is not clear is what changes lead to their expression. The extent and the clonality of the TG anti-DNA expression will directly address the etiology of autoimmunity. We want to know why tolerance to DNA is manifested in different ways. How the detailed specificity and avidity of the anti-DNA antibodies influence the way a B cell is regulated will be addressed using the various combinations of TG heavy and light chain TGs. The anti-DNA antibodies generated from these TGs are heterogeneous with respect to the form of DNA they recognize, the extent of reactivity with structurally related molecules, and the avidity they have for DNA. We are in a position to determine which of these parameters are significant in determining the fate of a B cell in normal mice. The direct relationship between expression of certain kinds of anti-DNAs and pathology is controversial. It is not at all established which ant- DNA antibodies are present in normal animals and which are present and contribute to disease in autoimmune animals. The potential range of anti-DNA antibodies that can be expressed by the TGs may provide an opportunity to correlate the expression of particular anti-DNA antibodies with disease. The ultimate goal of this research is to be able to cure autoimmunity. Through the use of the enriched population of anti-DNA antigen presenting cells (APC) we may learn the nature of the in vivo antigen and eventually design methods to interfere with the anti-DNA/self interaction.