MECHANISM OF AUTOIMMUNE RESPONSE IN HUMAN LUPUS

人类狼疮的自身免疫反应机制

• 批准号: 2748628
• 负责人: SYAMAL K DATTA
• 金额: $ 17.17万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2748628
• 关键词: B lymphocyte; CD40 molecule; MHC class II antigen; SCID mouse; T cell receptor; antibody formation; antigen presentation; antinuclear autoantibody; autoantigens; biological signal transduction; epitope mapping; helper T lymphocyte; human tissue; ligands; systemic lupus erythematosus; tissue /cell culture; tissue mosaicism

DESCRIPTION (Adapted from Investigator's abstract): The long term objective of this project is to define the fundamental mechanism of the major autoimmune disease, Systemic Lupus Erythematosus (SLE). Analysis of the structure and antigenic specificities of the receptors expressed by the select T helper (TH) cells that induce the production of pathogenic autoantibodies in SLE, may lead to an understanding of the etiologic mechanism of lupus in humans. The goal of the first set of specific aims is to define the antigen receptor mediated signal for the pathogenic autoantibody-inducing Th cells of human lupus. Critical peptide autoepitopes in nucleosomal antigens that trigger lupus Th cells will be identified by eluting naturally processed peptides from MHC molecules and by overlapping peptide synthesis. The disease relevance of the peptide epitopes will be determined in vivo using a SCID-human lupus adoptive transfer system. After fine mapping of MHC and TCR contact residues in the peptide autoepitopes, altered peptide ligands will be designed for blocking pathogenic autoantibody-inducing Th cells from lupus patients. The objective of the second set of specific aims is to define the role of costimulatory signals in the cognate interaction between the select Th and B-cells of lupus that leads to the production of pathogenic autoantibodies. The role of the CD40 ligand molecule (CD40L) in providing the second signal via CD40 on lupus B-cells for production of pathogenic autoantibodies will be studied. The mechanism of hyperexpression of CD40L in the T-cells, and more unexpectedly in the B-cells of lupus patients, will be investigated. Proposed studies on the regulation of CD40L gene expression may reveal an intrinsic defect in lupus which will be important in understanding the basic mechanism of T-cell and B-cell hyperactivity in this disease and will be of diagnostic and prognostic value as well.

描述(改编自《调查者摘要》)：长期目标 这一项目的根本机制是明确重大的 自身免疫性疾病系统性红斑狼疮(SLE)。三、分析了 表达的受体的结构和抗原性 选择诱导致病因子产生的辅助性T细胞 系统性红斑狼疮中的自身抗体可能有助于对病因的了解 人类狼疮的发病机制。第一套具体目标的目标是 明确抗原受体介导的致病信号 人狼疮自身抗体诱生的Th细胞。临界多肽 触发狼疮Th细胞的核小体抗原的自身表位将是 通过从MHC分子中洗脱自然处理的多肽和通过 重叠的多肽合成。多肽与疾病的相关性 将使用SCID-人类狼疮收养者在体内确定表位 转账系统。在对MHC和TCR接触残留物进行精细测绘后 多肽自身表位，改变的多肽配体将被设计为封闭 狼疮患者致病性自身抗体诱导的Th细胞。这个 第二组具体目标的目标是定义 SELECT Th和Th之间同源相互作用中的共刺激信号 导致病理性自身抗体产生的狼疮B细胞。 CD40配体分子(CD40L)在提供第二信号中的作用 通过CD40在狼疮B细胞上产生致病性自身抗体 被研究。CD40L在T细胞中高表达的机制 更出乎意料的是，在狼疮患者的B细胞中，将进行调查。 对CD40L基因表达调控的拟议研究可能揭示 狼疮的内在缺陷，这将是重要的理解基础 T细胞和B细胞功能亢进在本病中的作用机制 也具有诊断和预后价值。