T CELL ANTIGEN RECEPTOR GENES IN AUTOIMMUNITY

自身免疫性疾病的发病机制及分子基础 如系统性红斑狼疮和类风湿性关节炎 仍然未知。 这些疾病被认为是由 与耐受性缺陷有关的免疫紊乱 诱导或免疫调节，两者都受到T 细胞 全身性和器官特异性的T细胞依赖性 自身免疫性已经在许多人中得到了决定性的证明。 实验系统和一个重要的，也许是关键的作用， 特异性自身反应性T细胞克隆型在引发疾病 过程受到高度怀疑。 小鼠自身免疫系统具有 为研究T细胞抗原的作用提供了极好的模型 受体（TCAR）基因在自身免疫中的作用 在这项研究中，我们将 试图进一步确定TCAR基因在 通过评估生殖系可能的异常来评估自身免疫性 TCAR基因库和患病前TCAR基因表达 和患有自发性狼疮/关节炎的小鼠的患病阶段 综合征 TCAR cDNA克隆的集合，其包含所有，或 几乎所有的鼠α，β，γ可变区（V） 序列将被导出并最初用于确定性分析 这些基因的基因组组成和多态性， 与疾病相关的自身免疫倾向小鼠。 等位基因 种系编码的TCAR基因的变异可能会影响 给定菌株的TCAR库对某些特定的免疫应答的能力 抗原，并且还影响其产生自身反应性的倾向， 潜在致病性T细胞克隆型。 分析 胸腺选择和表达的TCAR基因库， 自身免疫小鼠的淋巴器官最初也将在 mRNA水平，以确定V基因使用模式的特点， 自身免疫性T细胞群，包括克隆扩增或 缺失和可能表达独特或突变的TCAR 基因. 一旦识别出异常表达模式， “变异型”（V区特异性）单克隆抗体将是 引出并用于更精确地定义，在单细胞水平， 淋巴器官和淋巴细胞中的异常克隆型 自身免疫小鼠的患病组织的浸润。 反 还将评估“变异型”抗体的体外和体内活性。 对自身免疫反应和疾病的体内影响。 这些 研究将更好地了解TCAR库 胸腺选择过程中的“塑造”及其在胸腺发育中的可能作用 自身反应性T细胞克隆的发展。 鉴定 这一中心事件的异常预计将产生重大影响。 对我们从分子水平定义自身免疫性疾病能力的影响 并制定具体和准确的管理方法。

The pathogenesis and molecular basis of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis remain unknown. These diseases are believed to be caused by immunologic disturbances related to defects in tolerance induction or immunoregulation, both profoundly affected by T cells. The T cell-dependence of both systemic and organ-specific autoimmunity has been demonstrated conclusively in many experimental systems and an important, perhaps pivotal, role for specific autoreactive T cell clonotypes in initiating the disease process is highly suspected. Mouse autoimmune systems have provided excellent models to study the role of T cell antigen receptor (TCAR) genes in autoimmunity. In this study, we will attempt to further define the role of TCAR genes in autoimmunity by assessing possible abnormalities in germline TCAR gene repertoire and TCAR gene expression at prediseased and diseased stages of mice with spontaneous lupus/arthritis syndromes. A collection of TCAR cDNA clones containing all, or nearly all, the murine alpha, beta, gamma variable (V) region sequences will be derived and used initially for definitive analysis of the genomic composition and polymorphisms of these genes in auto-immune-prone mice that correlate with disease. Allelic variations in germline-encoded TCAR genes could affect the ability of a given strain's TCAR repertoire to respond to certain antigens, and also affect its tendency to product autoreactive, potentially pathogenic, T cell clonotypes. Analysis of the thymically-selected and expressed TCAR gene repertoires in lymphoid organs of autoimmune mice will also be, initially at the mRNA level, to identify V gene usage patterns characteristic of autoimmune T cell populations, including clonal expansions or deletions, and possible expression of unique or mutated TCAR genes. Once abnormal expression patterns are identified, anti- "variotypic" (V region-specific) monoclonal antibodies will be elicited and used to more precisely define, at the single-cell level, aberrant clonotypes in lymphoid organs and lymphoid cell infiltrates of afflicted tissues of autoimmune mice. Anti- "variotypic" antibodies will also be assessed for their in vitro and in vivo effects on autoimmune responses and disease. These studies will provide a better understanding of TCAR repertoire "shaping" during thymic selection and its possible role in the development of autoreactive T cell clones. Identification of aberrancies in this central event is expected to have a significant impact on our ability to molecularly define autoimmune diseases and to devise specific and accurate means for their management.