ROLE OF T CELLS IN MURINE SLE

SLE SCOR项目2的目标是研究其机制 由此引发并传播狼疮自身免疫反应， 肾脏和唾液腺的免疫病理学。该研究将使用，作为一个 模型狼疮自身抗原（Ag），小鼠Ro 60。核心假设是： 系统性自身免疫性疾病，如SLE，可由单个关键的 T细胞对外源性或不相关的免疫应答的强烈和持续的事件 自身肽，其模拟靶自身T细胞肽。之表示支持 通过以下观察。通过共享关键残基序 与自身肽一起，外源T细胞肽诱导自身免疫应答 和疾病一旦被触发，辅助性T细胞反应迅速 随后是自身抗体（autoAb）反应，其多样化， 远距离表位多样化的自身抗体反应，这取决于 内源性Ag的存在，可以通过Ro 60特异性过继转移 T细胞系，并引起SLE样肾脏免疫病理学改变。而且 新生儿期最易诱导自身抗体应答， 表位扩散该项目有三个具体目标：第一个目标将 研究介导自身抗体产生的T细胞应答的性质， 导致肾脏和唾液腺病变。小鼠Ro 60特异性T细胞 将制备细胞克隆，它们的同源Ro 60肽，它们的表型和 过继转移自身抗体和疾病的能力。的基因 将克隆编码Ro 60 T细胞受体（TCR）的基因， 产生TCR转基因小鼠。将对转基因小鼠进行研究， 自发性自身抗体和病理学。为了进一步增强和剖析 为了检测自身免疫应答，将如下操作小鼠：1）非自身免疫应答。 通过使小鼠RAG或TCR-V α 缺陷，2）用佐剂刺激，3）使B细胞缺陷， 4)输注重组小鼠Ro 60或凋亡细胞核，和5） 研究正常小鼠对有限数量的转基因T细胞的反应， 细胞第二个目的将研究新生小鼠对Ro 60的反应 T细胞表位。我们将充分表征新生儿Th 2-显性T细胞 细胞自身免疫反应和记忆自我抗原;并确定这是否 将通过表位扩散导致Ro 60自身抗体应答， 免疫病理学第三个目标是研究分子生物学的作用机制， SLE中的拟态为了解决自身B细胞激活是否是 启动事件，我们将用嵌合肽免疫小鼠， 天然Ro 60 B细胞表位和外源T细胞肽，并研究T细胞 Ro 60、自身抗体多样化和疾病的反应。最后，模仿在 通过共享关键残基基序Ro 60 T细胞表位将被 研究了

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.