ROLE OF DNA IN SYSTEMIC LUPUS

DNA 在系统性狼疮中的作用

• 批准号: 3155256
• 负责人: Woodruff Emlen
• 金额: $ 14.69万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3155256
• 关键词: DNA; Kupffer's cell; antibody formation; antibody receptor; antinuclear autoantibody; autoantibody; autoradiography; binding proteins; immunogenetics; laboratory rat; molecular pathology; systemic lupus erythematosus; tissue /cell culture

Systemic Lupus Erythematosus (SLE) is the prototype autoimmune disease, characterized clinically by glomerulonephritis and vasculitis and immunologically by the production of multiple autoantibodies. Of these autoantibodies, antibodies (Abs) to dsDNA correlate strongly with disease activity, and evidence suggests they play a direct role in the pathogenesis of tissue damage. DNA Abs could potentially exert their pathogenic effects in 3 ways: 1.) binding to DNA to form pathogenic immune complexes (IC), 2.) binding directly to tissue antigens, or 3.) directly modifying cell function. The focus of this grant has been to study the formation and clearance of DNA IC; we have studied the clearance of extracellular DNA to investigate how DNA might become available for Ab binding, and we have studied the in vivo behavior of model DNA IC. During these studies, we identified a subset of DNA Abs, the presence of which correlates with SLE disease activity. We now propose: 1.) to characterize this subset of DNA Abs to understand its pathogenicity, 2.) to extend our studies on DNA IC, and 3.) to begin studies on mechanisms by which DNA Abs might be pathogenic other than by the formation of DNA IC. 1.) Ab subsets which bind DNA by monogamous bivalent binding or by cross-linking DNA have been identified. The basis for this difference will be studied by examining the binding specificity and avidity of each Ab type. Clinical associations with each Ab type will be sought. 2) The in vivo behavior of defined IC made with both Ab subsets will be examined (mice); the effect of IC size and Ab/Ag ratio will be studied. Since DNA binds to Clq, we will also study C1 activation of these DNA IC. To examine the possibility that DNA Abs cross-react with tissue antigens, binding of DNA Abs directly to renal tissue will be studied using a renal perfusion model. 3.) The DNA receptor will be isolated from Kupffer cells and characterized. These studies should define parameters which control the clearance of DNA IC, and directly address the question of cross- reactivity of DNA Abs with tissue (renal) antigens. In addition, we will begin to address the broader question of the physiologic role of the DNA receptor.

系统性红斑狼疮 (SLE) 是自身免疫性疾病的原型 疾病，临床特征为肾小球肾炎和 血管炎和免疫学上通过产生多种 自身抗体。 在这些自身抗体中，抗体 (Abs) 双链DNA与疾病活动密切相关，证据 表明它们在组织的发病机制中发挥直接作用 损害。 DNA Abs 可能发挥其致病作用 通过 3 种方式产生作用：1.) 与 DNA 结合形成致病性免疫 复合物 (IC)，2.) 直接结合组织抗原，或 3.) 直接改变细胞功能。 此次资助的重点是 研究DNA IC的形成和清除；我们研究过 清除细胞外 DNA 以研究 DNA 的作用 变得可用于 Ab 结合，并且我们已经研究了体内 模型 DNA IC 的行为。 在这些研究中，我们确定了 DNA 抗体子集，其存在与 SLE 相关 疾病活动。 我们现在建议：1.) 表征这个子集 DNA Abs 以了解其致病性，2.) 扩展我们的研究 DNA IC 的研究，以及 3.) 开始研究机制 哪些 DNA Abs 可能是致病性的，而不是通过形成 DNA IC。 1.) 通过一夫一妻制二价结合结合 DNA 的抗体亚群 或通过交联DNA进行鉴定。 这样做的基础 将通过检查结合特异性来研究差异 每种抗体类型的亲和力。 与每种抗体类型的临床关联 将被寻求。 2) 所定义的 IC 的体内行为 将检查两个 Ab 子集（小鼠）； IC尺寸的影响和 将研究 Ab/Ag 比率。 由于 DNA 与 Clq 结合，我们还将 研究这些 DNA IC 的 C1 激活。 来检验可能性 DNA Abs 与组织抗原发生交叉反应，结合 DNA 将使用肾灌注研究直接作用于肾组织的吸收 模型。 3.) DNA受体将从库普弗细胞中分离出来 并进行了表征。 这些研究应该定义控制参数 DNA IC的清关，直接解决交叉问题 DNA 抗体与组织（肾）抗原的反应性。 此外， 我们将开始解决更广泛的生理问题 DNA受体的作用。