MECHANISMS OF AUTOANTIBODY PRODUCTION IN SLE

抗核抗体是系统性红斑狼疮及相关风湿病的主要特征 疾病，并被认为直接参与了 这些障碍。这些自身抗体识别的抗原是 通常是大的DNA-蛋白质或RNA-蛋白质颗粒的组成部分。它有 已证明Th克隆可诱导产生致病的抗DNA 抗体对DNA-组蛋白复合体有反应，但对任一种DNA都没有反应 或者单独使用组蛋白。我们发现，自身抗体的产生和 对染色质蛋白特异的自身反应性T细胞的激活 由其四元结构的变化触发，由 病毒蛋白的结合。因此，一个四元结构的 自身抗原可能对呈现被识别的表位至关重要 自身反应性T细胞。鉴于四元结构在中国的重要性 产生自体反应性T细胞，似乎值得对 自身抗原性染色质蛋白与自身和他人的相互作用 非自身抗原。这一竞争性续订申请将延长我们的 关于非组蛋白染色质Ku(p70/p80)异二聚体的研究 某些患者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。人类对这种自身抗原产生自身免疫的基础 疾病也将被检查。我们假设任何一个的约束 针对Ku或Ku的某些功能结构域的外来抗原或自身抗体 其他抗原可通过增强抗原提呈而触发自身免疫。 自身的隐秘T细胞表位，对其耐受性不完全。在……里面 特异靶1，Ku介导p70-p80二聚化的结构域和 DNA依赖蛋白激酶与350 kDa蛋白(P350)的结合 活性将通过原核和真核表达来确定。 系统和以前在我们的 实验室。平行的研究将解决这样一个问题，即 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力。在具体目标2中，重要性 在SLE、SSC和SSC中作为自身抗体靶点的这些功能域 将确定重叠综合征。人类白细胞抗原的关联性 将确定针对Ku个别表位的自身抗体，并 抗KU、抗SU和抗RNA聚合酶II相互作用的基础 许多血清中的自身抗体将被研究。最后，有可能 具有特定特异性的自身抗体可以传播自身免疫 通过改变抗原处理从一种抗原转移到另一种 调查过了。尽管后一项研究本质上是探索性的，但它们 可能提供直接证据表明某些自身抗体的结合， 就像一些外来蛋白质一样，可以通过改变 自身抗原的四级结构。

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.