MECHANISM OF AUTOIMMUNE RESPONSE IN HUMAN LUPUS

人类狼疮的自身免疫反应机制

• 批准号: 6191313
• 负责人: SYAMAL K DATTA
• 金额: $ 28.52万
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6191313
• 关键词: B lymphocyte; CD40 molecule; MHC class II antigen; T cell receptor; antibody formation; antigen presentation; antinuclear autoantibody; autoantigens; biological signal transduction; clinical research; helper T lymphocyte; human subject; ligands; systemic lupus erythematosus; tissue /cell culture

DESCRIPTION (Adapted from the Applicant's Abstract): The long-term goal of this project is to define basic mechanisms of autoimmunity in Systemic Lupus Erythematosus (SLE), by focusing on disease-relevant T helper (Th) cells that induce the production of pathogenic anti-DNA autoantibodies in SLE. The full spectrum of major peptide epitopes, including naturally processed peptide epitopes, for the pathogenic autoantibody-inducing Th cells of human lupus that recognize nucleosomes in a promiscuous manner will be defined. Shared epitopes for autoimmune B-cells of lupus will also be identified. Immunologic relevance of the epitopes in influencing autoimmune T- and B-cell functions will be studied. T-cell receptor (TCR) and MHC-contact residues in the peptide epitopes will be finely mapped for finding consensus motifs that could lead to autoantigen -specific therapy of lupus in humans using tolerogenic peptides or altered peptide ligands. Altered peptide ligands that are partial agonists or antagonists will be designed and studied for blocking pathogenic anti-DNA autoantibody production in vitro. Nucleosomal peptide-HLA-DR tetramers (or peptide-MHC-Ig chimeric dimers) will be made to track autoimmune T-cells in lupus patients and family members for diagnostic and prognostic purposes, and for studying the effects of peptide tolerogens in vitro. The second part of the project will deal with mechanisms of prolonged hyper-expression of CD40 ligand (CD40L) and resistance to anergy induction and maintenance in T-cells of human lupus. Major components of T-cell signal transduction pathways involved in T-cell activation, and anergy, particularly in the context of CD40L hyper-expression will be defined. The role of differential MAPK activity in CD40L hyper-expression and stability of CD40L mRNA in lupus T-cells will be studied. Possible anomalies in B7-CD28, and CTLA-4 expression and function in lupus T-cells that could lead to the above mentioned defects being analyzed. Identification of critical peptide epitopes for the autoimmune T helper cells of lupus and studies on regulatory defects in expression of co-stimulatory signaling molecules are leading towards an understanding of basic mechanisms of the disease and development of specific immunotherapy.

描述(改编自申请人的摘要)：该项目的长期目标 项目是确定系统性红斑狼疮自身免疫的基本机制 红斑狼疮(SLE)，通过关注与疾病相关的T辅助细胞(Th)， 诱导SLE患者产生致病性抗DNA自身抗体。完整的 主要多肽表位谱，包括天然加工多肽 人类狼疮致病自身抗体诱导的Th细胞的表位 将定义以混杂方式识别核小体。共享表位 对于自身免疫，狼疮的B细胞也将被识别。免疫学相关性 在影响自身免疫T和B细胞功能的表位中， 学习。多肽表位中的T细胞受体(TCR)和MHC接触残基 将被精细地绘制，以找到可能导致 人类狼疮自身抗原特异性治疗的耐受性多肽或 改变的多肽配体。作为部分激动剂的改变的多肽配体或 将设计和研究拮抗剂来阻断病原性抗DNA 体外产生自身抗体。核小体肽-人类白细胞抗原-DR四聚体(或 多肽-MHC-Ig嵌合二聚体)将用于跟踪自身免疫的T细胞 用于诊断和预后目的的狼疮患者及其家庭成员，以及 用于研究多肽耐受剂的体外作用。第二部分： 该项目将研究CD40配体持续高表达的机制 CD40L与人T细胞对无能诱导和维持的抵抗力 狼疮。T细胞信号转导通路的主要组成部分 T细胞激活和无能，特别是在CD40L的背景下 将定义超级表达式。差异MAPK活性在细胞周期调控中的作用 CD40L在狼疮T细胞中的高表达和稳定性 学习。B7-CD28和CTLA-4的表达和功能可能异常 分析可能导致上述缺陷的狼疮T细胞。 自身免疫辅助性T细胞关键表位的鉴定 狼疮的发病机制及共刺激基因表达调控缺陷的研究 信号分子正在引导我们理解 疾病和特异性免疫治疗的发展。