MECHANISMS OF AUTOANTIBODY PRODUCTION IN SLE

SLE 自身抗体产生机制

• 批准号: 2080018
• 负责人: WESTLEY H REEVES
• 金额: $ 18.44万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2080018
• 关键词: Baculoviridae; T lymphocyte; antibody formation; antigen antibody reaction; antigen presentation; autoantibody; autoantigens; epitope mapping; human subject; laboratory mouse; molecular cloning; monoclonal antibody; systemic lupus erythematosus; tissue /cell culture; vaccinia virus

Antinuclear antibodies are a central feature of SLE and related rheumatic diseases, and are thought to be directly involved in the pathogenesis of these disorders. The antigens recognized by these autoantibodies are generally components of large DNA-protein or RNA-protein particles. It has been shown that Th clones inducing the production of pathogenic anti-DNA antibodies are responsive to DNA-histone complexes, but not to either DNA or histones alone. We have found that autoantibody production and the activation of autoreactive T cells specific for a chromatin protein can be triggered by alterations in its quaternary structure induced by the binding of a viral protein. Thus, the quaternary structure of an autoantigen may be critical for the presentation of epitopes recognized by autoreactive T cells. In view of the importance of quaternary structure in generating autoreactive T cells, it seems worthwhile to characterize the interactions of autoantigenic chromatin proteins with other self and nonself antigens. This competitive renewal application will extend our previous work on the Ku (p70/p80) heterodimer, a nonhistone chromatin antigen recognized by autoantibodies found in the sera of certain patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and overlap syndromes. The basis for autoimmunity to this autoantigen in human disease will also be examined. We hypothesize that the binding of either foreign antigens or autoantibodies to certain functional domains of Ku or other antigens may trigger autoimmunity by enhancing the presentation of cryptic T cell epitopes of self to which tolerance is incomplete. In Specific Aim 1, the domains of Ku mediating p70-p80 dimerization and binding to a 350 kDa protein (p350) with DNA-dependent protein kinase activity will be determined using prokaryotic and eukaryotic expression systems and specific monoclonal antibodies generated previously in our laboratory. Parallel studies will address the question of whether the same domains are involved in interactions with foreign (viral) antigens that might potentially trigger autoimmunity. In Specific Aim 2, the importance of these functional domains as targets of autoantibodies in SLE, SSc and overlap syndrome will be determined. The HLA associations of autoantibodies to individual epitopes of Ku will be determined, and the basis for the association of anti-Ku, anti-Su, and anti-RNA polymerase II autoantibodies in many sera will be explored. Finally, the possibility that autoantibodies of particular specificities can spread autoimmunity from one antigen to another by altering antigen processing will be investigated. Although the latter studies are exploratory in nature, they may provide direct evidence that the binding of certain autoantibodies, like some foreign proteins, can trigger autoimmunity by altering the quaternary structure of an autoantigen.

抗核抗体是系统性红斑狼疮和相关风湿病的核心特征 疾病，并被认为是直接参与的发病机制， 这些紊乱。这些自身抗体识别的抗原是 通常是大的DNA-蛋白质或RNA-蛋白质颗粒的组分。它有 已经表明，诱导病原性抗-DNA产生的Th克隆 抗体对DNA-组蛋白复合物有反应，但对DNA 或单独的组蛋白。我们已经发现，自身抗体的产生和 对染色质蛋白特异性的自身反应性T细胞的活化可以 引发的变化，其四级结构诱导的 病毒蛋白的结合。因此， 自身抗原可能是关键的表位识别的呈递 自身反应性T细胞鉴于四级结构的重要性， 产生自身反应性T细胞，这似乎是值得的特点， 自身抗原染色质蛋白与其他自身和 非自身抗原这种竞争性的续约申请将延长我们的 Ku（p70/p80）异二聚体（一种非组蛋白染色质）的前期工作 在某些病人的血清中发现的自身抗体所识别的抗原 系统性红斑狼疮（SLE）、系统性硬化症（SSc）和 重叠综合征人对该自身抗原产生自身免疫的基础 疾病也将被检查。我们假设， 针对Ku的某些功能结构域的外源抗原或自身抗体，或 其它抗原可通过增强自身免疫的呈递来触发自身免疫。 自身的隐蔽性T细胞表位，其耐受性不完全。在 特异性目的1，Ku介导p70-p80二聚化的结构域， 用DNA依赖性蛋白激酶与350 kDa蛋白（p350）结合 活性将使用原核和真核表达来测定 系统和特异性单克隆抗体产生之前在我们的 实验室平行研究将解决是否相同的问题， 结构域参与与外来（病毒）抗原的相互作用， 可能会引发自身免疫在具体目标2中， 这些功能结构域作为SLE、SSc和 将确定重叠综合征。的HLA协会 将确定针对Ku的单个表位的自身抗体，并且 抗Ku、抗Su和抗RNA聚合酶II相关的基础 将探索许多血清中的自身抗体。最后， 特定的自身抗体可以传播自身免疫 从一种抗原到另一种抗原， 研究了虽然后者的研究是探索性的， 可以提供直接的证据证明某些自身抗体的结合， 像一些外来蛋白质一样，可以通过改变免疫原性来引发自身免疫。 自身抗原的四级结构。