MECHANISM OF AUTOIMMUNE RESPONSE IN HUMAN LUPUS

人类狼疮的自身免疫反应机制

• 批准号: 6374902
• 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 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6374902
• 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）：本项目的长期目标 该项目旨在定义系统性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 (Th) 细胞， 诱导 SLE 中致病性抗 DNA 自身抗体的产生。完整的 主要肽表位谱，包括天然加工的肽 表位，用于人类狼疮的致病性自身抗体诱导 Th 细胞 将定义以混杂方式识别核小体。共享表位 狼疮自身免疫 B 细胞也将被鉴定。免疫学相关性 影响自身免疫 T 细胞和 B 细胞功能的表位将是 研究过。肽表位中的 T 细胞受体 (TCR) 和 MHC 接触残基 将被精细地映射以寻找可能导致的共识主题 使用耐受原性肽或药物对人类狼疮进行自身抗原特异性治疗 改变的肽配体。改变的肽配体是部分激动剂或 将设计和研究拮抗剂来阻断致病性抗 DNA 体外产生自身抗体。核小体肽-HLA-DR四聚体（或 肽-MHC-Ig嵌合二聚体）将被用来追踪自身免疫T细胞 狼疮患者和家庭成员用于诊断和预后目的，以及 用于研究肽耐受原的体外作用。第二部分 项目将研究 CD40 配体长期超表达的机制 (CD40L) 以及对人类 T 细胞无能诱导和维持的抵抗 狼疮。 T细胞信号转导途径的主要组成部分 T 细胞激活和无反应性，特别是在 CD40L 的情况下 超表达将被定义。差异 MAPK 活性的作用 狼疮 T 细胞中 CD40L 的超表达和 CD40L mRNA 的稳定性将受到影响 研究过。 B7-CD28 和 CTLA-4 表达和功能可能存在异常 正在分析可能导致上述缺陷的狼疮 T 细胞。 自身免疫 T 辅助细胞关键肽表位的鉴定 狼疮的发病机制及共刺激表达调控缺陷的研究 信号分子正在引导人们了解基本机制 疾病和特异性免疫疗法的发展。