MECHANISM OF AUTOIMMUNE RESPONSE IN HUMAN LUPUS

描述（改编自研究者摘要）：长期目的 这个项目的主要目的是确定主要的基本机制 自身免疫性疾病，系统性红斑狼疮（SLE）。 分析 表达的受体的结构和抗原特异性 选择T辅助（TH）细胞，诱导病原性 SLE自身抗体，可能导致了解病因 狼疮的发病机制 第一组具体目标的目标是 为了确定病原体的抗原受体介导的信号， 自身抗体诱导的Th细胞的人类狼疮。 关键肽 核小体抗原中触发狼疮Th细胞的自身表位将被 通过从MHC分子中洗脱天然加工的肽和通过 重叠肽合成。 肽的疾病相关性 表位将使用SCID-人狼疮过继免疫测定法在体内确定。 传输系统 在对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。 的 第二组具体目标的目的是确定 共刺激信号之间的同源相互作用选择Th和 狼疮的B细胞，导致产生致病的自身抗体。 CD 40配体分子（CD 40 L）在提供第二信号中的作用 通过狼疮B细胞上的CD 40产生致病性自身抗体， 被研究。 CD 40 L在T细胞中的高表达机制， 更出乎意料的是，在狼疮患者的B细胞中，将进行研究。 对CD 40 L基因表达调控的研究可能揭示了一个新的机制。 狼疮的内在缺陷，这将是重要的，在了解基本的 T细胞和B细胞过度活跃在这种疾病的机制，并将 诊断和预后价值。

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.