MECHANISM OF AUTOIMMUNE RESPONSE IN HUMAN LUPUS

人类狼疮的自身免疫反应机制

基本信息

批准号：
6043194
负责人：
SYAMAL K DATTA
金额：
$ 17.86万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-08-01 至 2000-08-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6043194
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

项目摘要

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（改编自研究者的摘要）：长期目标该项目的目的是确定该专业的基本机制自身免疫性疾病，系统性红斑狼疮（SLE）。分析所表达的受体的结构和抗原特异性选择诱导产生致病性 T 辅助细胞 (TH) SLE 中的自身抗体可能有助于了解其病因人类狼疮的发病机制。第一组具体目标的目标是定义抗原受体介导的致病信号人类狼疮自身抗体诱导 Th 细胞。关键肽核小体抗原中触发狼疮 Th 细胞的自身表位通过从 MHC 分子中洗脱自然加工的肽并通过重叠肽合成。肽的疾病相关性表位将使用 SCID-人狼疮过继体内测定传输系统。对 MHC 和 TCR 接触残基进行精细定位后肽自身表位，改变的肽配体将被设计用于阻断来自狼疮患者的致病性自身抗体诱导 Th 细胞。这第二组具体目标的目的是确定选择Th和之间的同源相互作用中的共刺激信号狼疮 B 细胞可导致致病性自身抗体的产生。 CD40配体分子（CD40L）在提供第二信号中的作用通过狼疮 B 细胞上的 CD40 产生致病性自身抗体将被研究。 T细胞中CD40L超表达的机制，以及更出乎意料的是，狼疮患者的 B 细胞中将进行研究。关于 CD40L 基因表达调控的拟议研究可能揭示狼疮的内在缺陷对于理解狼疮的基本缺陷非常重要 T 细胞和 B 细胞过度活跃在这种疾病中的机制，将是也具有诊断和预后价值。