PATHOGENIC ANTI-DNA AUTOANTIAB-REGULATION IN HUMAN LUPUS

描述：（改编自申请人摘要） 术语目标是定义原型系统的基本机制 自身免疫性疾病，系统性红斑狼疮（SLE）。 神学的 SLE的发病机制仍不清楚，因为触发SLE的主要抗原 这种疾病中的致病性自身免疫反应是未知的。 尽管 为了克服这一障碍，研究人员克隆了选定的T辅助细胞， 诱导抗DNA自身抗体的致病性变化的产生 在SLE中。 通过对表达的受体的结构和特异性的分析， 这些特殊的T细胞和产生病原性自身抗体的B细胞 这些疾病的代表，以及他们的研究， 调节可能有助于了解狼疮的病因机制 在人类身上。 本申请的具体目标包括：（1）致病性 T细胞：（a）确定受体（TcR）的V区序列 由致病性抗DNA自身抗体诱导T细胞表达， 狼疮患者检测任何克隆限制/复发使用或任何 它们连接区（CDR 3）序列中的特殊特征， 为它们的抗原特异性提供了线索 (b)确定 这些狼疮T辅助细胞的特异性， 使用合成肽， 和自体B细胞克隆。 (c)确定体内致病性 这些自身免疫性T辅助细胞克隆与免疫缺陷 SCID小鼠。 (2)致病性B细胞：（a）克隆人狼疮B细胞， 产生IgG类和阳离子的病原性抗DNA自身抗体 消费标准. 确定这些自身抗体的体内致病相关性 以及它们在人类狼疮性肾炎中的代表性。 (b)定义 阳离子电荷结构基础、抗原特异性、独特型 病原性抗DNA抗体间的交叉反应和克隆关系 自身抗体 (c)定义导致SLE的内在B细胞缺陷 热休克蛋白的过度产生。 这些研究将有助于 我们要设计特定的治疗方法， 导致系统性自身免疫疾病

DESCRIPTION: (Adapted from Applicant's Abstract) The investigator's long term goal is to define the fundamental mechanism of the prototypic systemic autoimmune disease, Systemic Lupus Erythematosus (SLE). Theetiological mechanism of SLE remains elusive because the primary antigen that triggers the pathogenic autoimmune response in this disease is unknown. In spite of this obstacle, the investigators have cloned the select T-helper cells that induce the production of the pathogenic variety of anti-DNA autoanitbodies in SLE. Analysis of the structure and specificities of the receptors expressed by these particular T-cells and the pathogenic autoantibody producing B-cells that are representative of the disease, as well as studies of their regulation may lead to an understanding of the etiologic mechanism of lupus in humans. The specific goals of this application involve: (1) PATHOGENIC T-CELLS: (a) Determine the V region sequences of the receptors (TcRs) expressed by the pathogenic anti-DNA autoantibody-inducing T-cells from lupus patients to detect any clonal restriction/recurrent usage or any special featuure in their junctional region (CDR3) sequences that would provide clues for their antigenic specificities. (b) Determine the specificities of these lupus T-helper cells that preferentially interact with pathogenic autoantibody- producing B-cells, using synthetic peptides and autologous B-cell clones. (c) Determine the in vivo pathogenic relevance of theseautoimmune T-helper cell clones using immunodeficient SCID mice. (2) PATHOGENIC B-CELLS: (a) Clone human lupus B-cells that produce pathogenic anti-DNA autoantibodies of IgG class and cationic charge. Determine the in vivo pathogenic relevance of such autoantibodies and their representation in human lupus nephritis. (b) Define the structural basis of cationic charge, antigenic specificities, idiotypic cross-reactions and clonalrelationships among the pathogenic anti- DNA autoantibodies. (c) Define the intrinsic B-cell defect in SLE that leads to an excessive production of heat shock proteins. These studies will help us todesign specific therapies that would intervene in the basic steps leading to systemic autoimmune disease.