ROLE OF T CELLS IN MURINE SLE

SLE SCOR项目2的目标是研究其机制 由此启动和传播狼疮自身免疫反应，导致 肾脏和唾液腺的免疫病理学。这项研究将作为一种 模型狼疮自身抗原(Ag)，小鼠Ro60。核心假设是： 系统性自身免疫性疾病，如系统性红斑狼疮，可由单一枢纽引起 T细胞对外来或无关的强而持久的反应事件 模拟靶向自身T细胞多肽的自体多肽。它被支持 通过以下观察。通过分享一个关键的残基主题 外源T细胞多肽与自身多肽共同诱导自身免疫反应 和疾病。一旦被触发，辅助T细胞的反应就会迅速 然后是自身抗体(AutoAb)反应，该反应多样化 遥远的表位。多样化的自身抗体反应，这取决于 内源性抗原的存在可以通过Ro60特异性的过继转移 T细胞株，并引起狼疮样肾脏免疫病理。此外， 新生儿期最易诱发自身抗体反应 表位扩散。该项目有三个具体目标：第一个目标将 研究调节自身抗体产生的T细胞反应的本质， 导致肾脏和唾液腺的病理改变。小鼠Ro60特异性T细胞 将进行细胞克隆，它们的同源Ro60肽，它们的表型和 能够过继转移自身抗体和定义的疾病。基因 编码Ro60 T细胞受体(TCR)的基因将被克隆并用于 产生TCR转基因小鼠。转基因小鼠将被研究 自发性自身抗体与病理学为了进一步加强和剖析 自身免疫反应时，将对小鼠进行如下操作：1)非 小鼠RAG或TCR-Vα诱导消除转基因T细胞 缺乏，2)用佐剂刺激，3)使B细胞缺乏， 4)输注重组小鼠Ro60或凋亡细胞核；5) 有限数量转基因T细胞对正常小鼠免疫应答的研究 细胞。第二个目标是研究新生小鼠对Ro60的反应 T细胞表位。我们将全面描述新生儿Th2占优势的T细胞 细胞对自身抗原的自身免疫反应和记忆；并确定这是否 会通过表位扩散导致Ro60自身抗体反应，肾脏 免疫病理学。第三个目标是研究分子机制。 系统性红斑狼疮的拟态。为了解决自身B细胞激活是否是 启动事件，我们将用包含以下内容的嵌合肽免疫小鼠 原生Ro60B细胞表位和外源T细胞多肽，并对T细胞进行研究 对Ro60的反应、自身抗体的多样化和疾病。最后，模仿 通过共享关键残基基序的Ro60T细胞表位将是 调查过了。

The goal of the Project 2 of the SLE SCOR is to investigate the mechanism whereby the lupus autoimmune response is initiated and propagated, leading to renal and salivary gland immunopathology. The study will use, as a model lupus autoantigen (Ag), mouse Ro60. The central hypothesis is: systemic autoimmune disease like SLE can result from the single pivotal event of a strong and persistent T cell response to a foreign or unrelated self peptide that mimics the target self T cell peptide. It is supported by the following observations. Through sharing of a critical residue motif with self peptide, a foreign T cell peptide induces autoimmune response and disease. Once triggered, the helper T cell response is rapidly followed by an autoantibody (autoAb) response that is diversified to distant epitopes. The diversified autoAb response, which depends on the presence of endogenous Ag, can be adoptively transferred by Ro60 specific T cell line, and cause SLE-like renal immunopathology. Moreover, the neonatal period is most susceptible to induction of autoAb response and epitope spreading. The project has three Specific Aims: The first Aim will study the nature of T cell response that mediates autoAb production, resulting in renal and salivary gland pathology. Mouse Ro60 specific T cell clones will be made, their cognate Ro60 peptide, their phenotype and ability to adoptively transfer autoAb and disease defined. The genes encoding the Ro60 T cell receptor (TCR) will be cloned and used to generate TCR transgenic mice. The transgenic mice will be studied for spontaneous autoAb and pathology. To further enhance and dissect the autoimmune response, the mice will be manipulated, as follows: 1) non- transgenic T cell elimination by rendering the mice RAG or TCR-V alpha deficient, 2) to stimulate with adjuvant, 3) to be made B cell deficient, 4) infusion of recombinant mouse Ro60 or apoptotic cell nuclei, and 5) study the responses of normal mice given a finite number of transgenic T cells. The second Aim will study the response of neonatal mice to the Ro60 T cell epitope. We will fully characterize the neonatal Th2-dominant T cell autoimmune response and memory to self Ag; and determine whether this will lead to Ro60 autoAb response through epitope spreading, and renal immunopathology. The third Aim will study the mechanisms of molecular mimicry in SLE. To address whether self B cell activation is the initiating event, we will immunize mice with chimeric peptides containing native Ro60 B cell epitope and foreign T cell peptide, and study T cell response to Ro60, autoAb diversification and disease. Finally, mimicry at the Ro60 T cell epitope through sharing of critical residue motif will be investigated.