FEASIBILITY STUDY--I KAPPA B EXPRESSION IN SYSTEMIC LUPUS ERYTHEMATOSUS T CELLS

核因子-kappaB是一种转录因子，它似乎从根本上 参与某些特定基因的适当调控表达 细胞因子，IL-2受体，以及MHC I和II类蛋白 在细胞激活和免疫反应中起作用。IkappaB是一种 与核因子-kappaB结合从而阻断其DNA的抑制蛋白 结合活性，从而提供潜在的反馈抑制环 来下调细胞的激活。系统性红斑狼疮(SLE) 一种典型的全身性自身免疫性疾病，其特征是 淋巴细胞过度活跃和存在过多的其他 细胞免疫异常。这些缺陷在某种程度上是暂时的 经常影响受核因子-kappaB调节的受体/细胞因子。因此， IkappaB表达的缺陷(S)可以解释一些免疫 系统性红斑狼疮中已描述的异常(例如，IL-1的升高 2R在T、B细胞上的表达)。因此，我们的假设是， 系统性红斑狼疮患者IkappaB反馈机制异常。我们已经获得了 初步数据显示，IkappaB的 SLE患者T细胞表达与正常对照比较。 目标1中的实验将表征IkappaB和NF-1的表达。 系统性红斑狼疮患者外周血T细胞亚群中的kappaB 和正常对照组，有或没有受体/配体诱导 体外激活。AIM 2的研究将确定T细胞IkappaB 在SLE疾病活动的不同阶段的表达，第一 系统性红斑狼疮患者的程度亲属、疾病和临床 非系统性红斑狼疮的情况。目标3的重点是量化IkappaB 并测定IkappaB蛋白周转率。 这一项目有望进一步加深我们对发病机制的理解。 并可能为新的治疗方法奠定基础 这种紊乱。

NF-kappaB is a transcription factor that appears to be fundamentally involved in the appropriate regulated expression of genes for certain cytokines, the IL-2 receptor, and MHC class I and II proteins that function in cell activation and the immune response. IkappaB is an inhibitor protein that binds to NF-kappaB, thereby blocking its DNA binding activity and thus providing a potential feedback inhibition loop to down-regulate cell activation. Systemic lupus erythematosus (SLE), a prototype systemic autoimmune disease, is characterized by hyperactivity of lymphocytes and the presence of a plethora of other cellular immune abnormalities. These defects are somewhat transient and often affect receptors/cytokines that are regulated by NF-kappaB. Hence, a defect(s) in the expression of IkappaB could explain some of the immune abnormalities that have been described in SLE (e.g., the increase in IL- 2R expression on T and B cells). Our hypothesis, therefore, is that the IkappaB feedback mechanism is aberrant in SLE. We have obtained preliminary data that demonstrate a marked decrease in IkappaB's expression in T cells from SLE patients as compared to normal controls. Experiments in Aim 1 will characterize the expression of IkappaB and NF- kappaB in peripheral blood T cell subpopulations from patients with SLE and normal control subjects, with and without receptor/ligand-induced activation in vitro. Studies in Aim 2 will determine T cell IkappaB expression during different phases of SLE disease activity, in first degree relatives of patients with SLE, and in diseases and clinical situations other than SLE. Emphasis in Aim 3 is on quantitating IkappaB mRNA in T cells and on determining the rate of IkappaB protein turn over. This project is expected to further our understanding of the pathogenesis of SLE and may establish a foundation for new therapeutic approaches in this disorder.