T CELL ANTIGEN RECEPTOR GENES IN AUTOIMMUNITY

自身免疫性疾病的发病机制和分子基础 如系统性红斑狼疮和类风湿性关节炎 仍然不为人所知。这些疾病被认为是由 与耐受性缺陷相关的免疫紊乱 诱导或免疫调节，都受到T细胞的深刻影响 细胞。全身性和器官特异性T细胞依赖性 自身免疫已经在许多病例中得到了确凿的证明 实验系统和一个重要的，也许是关键的角色 特异性自身反应性T细胞克隆型与疾病的关系 进程高度可疑。小鼠自身免疫系统有 为研究T细胞抗原的作用提供了极好的模型 自身免疫中的受体(TCAR)基因在这项研究中，我们将 试图进一步确定TCAR基因在 通过评估生殖系中可能的异常来实现自身免疫 TCAR基因谱系与病前TCAR基因表达 和自发性狼疮/关节炎小鼠的疾病阶段 综合症。包含全部的TCAR cDNA克隆的集合，或 几乎所有的，小鼠的α，β，伽马可变(V)区 序列将被派生出来并最初用于最终分析 这些基因的基因组组成和多态的研究 与疾病相关的具有自身免疫倾向的小鼠。等位基因 生殖系编码的TCAR基因的变异可能会影响 给定菌株的TCAR谱对某些特定基因的反应能力 抗原，也影响其产生自身反应的倾向， 潜在致病性，T细胞克隆型。三、分析了 胸腺选择和表达的TCAR基因谱带 自身免疫小鼠的淋巴器官也将在最初 MRNA水平，以确定V基因使用模式的特征 自身免疫T细胞群，包括克隆性扩增或 唯一或突变的TCAR的缺失和可能的表达 基因。一旦识别出异常表达模式，反 “多型性”(V区特异性)单抗将是 引出并用来在单细胞水平上更准确地定义， 淋巴器官和淋巴细胞的异常克隆型 自身免疫小鼠受累组织的浸润物。反- “多型性”抗体也将在体外和 体内对自身免疫反应和疾病的影响。这些 研究将提供对TCAR曲目的更好理解 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。身份识别 这一中心事件的异常预计将产生重大的 对我们从分子上定义自身免疫性疾病的能力的影响 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.