GENETIC-VIRAL-IMMUNOLOGIC STUDIES IN NEW ZEALAND MICE

我们的长期目标是确定系统性的根本机制。 自身免疫性疾病 (SLE) 和恶性 B 细胞淋巴瘤 在 NZB 和正常 SWR 小鼠品系之间的杂交中自发产生。 系统性红斑狼疮（SLE）的病因机制仍不清楚 难以捉摸，因为触发致病性自身免疫的主要抗原 这种疾病的反应尚不清楚。 尽管有这样的障碍，我们还是 克隆了 SLE 致病性的精选 T 细胞和 B 细胞。 分析 这些受体表达的结构和特异性 代表疾病和研究的特定 T 和 B 细胞 它们的调节可能有助于了解病因机制 狼疮。 该应用程序的主要目标包括： 1) 致病性 B 细胞： (a) 定义阳离子电荷的结构基础， 抗原特异性、独特型交叉反应和克隆关系 致病性抗 DNA 自身抗体。 b) 研究产生致病性的种系 V 基因库 自身抗体，定义由以下物质编码的抗体的天然特异性 这些种系 V 基因并确定体细胞突变的程度 产生致病性自身抗体所需的。 c) 确定易患狼疮的小鼠是否存在内在 B 细胞缺陷 使用转基因的耐受诱导或 Ig 体细胞突变机制 携带自身抗体V基因的小鼠。 2) 致病性T细胞： (a) 确定V区序列 致病性自身抗体诱导 T 细胞表达的受体 (TCR) 检测任何克隆限制/重复使用或任何特殊功能 它们的连接区（CDR3）序列将为它们提供线索 抗原特异性。 b) 确定这些 T 辅助细胞优先的特异性 与产生致病性自身抗体的 B 细胞相互作用，使用 合成肽和 B-B 杂交瘤。 c) 尝试通过以下方式阻断体内致病性自身免疫反应： 使自身免疫 T 辅助细胞无反应。 这些研究将帮助我们设计特定的疗法 干预导致系统性自身免疫性疾病的基本步骤 狼疮，并可能对其他风湿性疾病采取类似的方法 刺激抗原未知。 此外，了解事物的本质 这些 NZB 杂交中的内在 B 细胞异常可能有助于阐明 这些小鼠 B 细胞淋巴瘤发展的机制。

Our long-term goal is to define the fundamental mechanism of the systemic autoimmune disease (SLE) and malignant B cell lymphomas that develop spontaneously in the crosses between NZB and the normal SWR mouse strains. The etiologic mechanism of Systemic lupus erythematosus (SLE) remains elusive because the primary antigen that triggers the pathogenic autoimmune response in this disease is unknown. In spite of this obstacle, we have cloned the select T and B cells that are pathogenic in SLE. Analyses of the structure and specificities of the receptors expressed by these particular T and B cells that are representative of the disease and studies of their regulation may lead to an understanding of the etiologic mechanism of lupus. The major goals of this application involve: 1) Pathogenic B Cells: (a) Define the structural basis of cationic charge, antigenic specificities, idiotypic cross reactions and clonal relationships among pathogenic anti-DNA autoantibodies. b) Study the germline V gene repertoire that generates the pathogenic autoantibodies, define the natural specificities of antibodies encoded by these germ line V genes and determine the degree of somatic mutations required to generate the pathogenic autoantibodies. c) Determine if the lupus-prone mice have an intrinsic B cell defect in tolerance induction or in Ig somatic mutation mechanisms using transgenic mice carrying autoantibody V genes. 2) Pathogenic T Cells: (a) Determine the V region sequences of the receptors (TCRs) expressed by the pathogenic autoantibody-inducing T cells to detect any clonal restriction/recurrent usage or any special feature in their junctional region (CDR3) sequences that would provide clues for their antigenic specificities. b) Determine the specificities of these T helper cells that preferentially interact with the pathogenic autoantibody-producing B cells, using synthetic peptides and B-B hybridomas. c) Attempt to block the pathogenic autoimmune response in vivo by rendering the autoimmune T helper cells anergic. These studies will help us to design specific therapies that could intervene in the basic steps leading to systematic autoimmune disease in lupus and may direct similar approaches for other rheumatic diseases where the inciting antigen is unknown. Furthermore, understanding the nature of the intrinsic B cell abnormally in these NZB crosses could help elucidate the mechanism of B cell lymphoma development in these mice.