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）：本发明的长期目标是： 本项目旨在明确系统性狼疮自身免疫的基本机制 红斑狼疮（SLE），通过关注疾病相关的T辅助（Th）细胞， 诱导SLE中致病性抗DNA自身抗体的产生。充分 主要肽表位谱，包括天然加工肽 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。共有表位 狼疮的自身免疫性B细胞也将被识别。免疫相关性 影响自身免疫T细胞和B细胞功能的表位将是 研究了肽表位中的T细胞受体（TCR）和MHC接触残基 将被精细地绘制出来，以寻找可能导致 使用致耐受性肽或 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以阻断病原性抗DNA 体外自身抗体产生。核小体肽-HLA-DR四聚体（或 肽-MHC-IG嵌合二聚体）将被制备用于追踪免疫性T细胞， 用于诊断和预后目的的狼疮患者和家庭成员，以及 用于研究肽耐受原的体外作用。的第二部分 该项目将涉及CD 40配体长期高表达的机制 CD 40配体与T细胞免疫应答的诱导和维持 狼疮T细胞信号转导通路的主要成分参与 T细胞活化和无反应性，特别是在CD 40 L的背景下 将定义超表达。丝裂原活化蛋白激酶活性差异在 狼疮T细胞中CD 40 L的高表达和CD 40 L mRNA的稳定性将是一个重要的研究课题。 研究了B7-CD 28和CTLA-4表达和功能的可能异常 正在分析可能导致上述缺陷的狼疮T细胞。 自身免疫性T辅助细胞关键肽表位的鉴定 共刺激分子表达调控缺陷的研究 信号分子正在引导人们了解 疾病和特异性免疫疗法的发展。