CD40 LIGAND IN SYSTEMIC LUPUS ERYTHEMATOSUS

系统性红斑狼疮（SLE）是典型的系统性红斑狼疮， 自身免疫性疾病，其中人类免疫系统无法调节 对染色质和其他特征性自身免疫反应性 抗原 辅助性T细胞（Th）是免疫系统中的中枢免疫调节细胞， 正常免疫系统介导高丙种球蛋白血症， 自身抗体形成导致SLE组织损伤。 cd 40配体 （C40 L）是TNF基因家族的成员，介导Th细胞信号 驱动B细胞活化和分化。 几个新 关于淋巴细胞上CD 40 L表达调节的观察 来自SLE患者的重要初步数据， 建议的研究：1）CD 40 L的基线表达增加， 活动期SLE患者; 2）CD 40 L表达延长， 用PMA和离子霉素治疗SLE T淋巴细胞， 绕过TCR信号传导事件; 3）可溶性CD 40 L在SLE中循环， 在患者的血清样品中很容易检测到。 拟议的实验将研究潜在的机制， CD 40 L表达调节改变的功能后果 SLE。 我们的假设是，在SLE中， T细胞活化导致Th细胞功能过度，自身抗体 形成、炎症和疾病。CD 40 L既是一种标志物， 这种异常T细胞的介导帮助。项目的具体目标 为： I. 人T细胞CD 40 L表达调控的研究 我们 将研究诱导CD 40 L mRNA所需的T细胞刺激 和蛋白质表达，介导诱导的生化途径 CD 40 L的表达，可溶性CD 40 L的调节，以及 细胞因子对细胞表面和可溶性CD 40 L表达的影响。 二. 系统性红斑狼疮患者CD 40配体表达调控的研究 我们将 表征SLE T细胞的基线活化状态，研究 共刺激分子和细胞因子对CD 40 L诱导的影响 SLE中的表达，研究转录和转录后 SLE中CD 40 L mRNA的调节，并评估CD 40 L的切割和清除。 细胞表面CD 40 L的表达。 三. 细胞表面和可溶性蛋白功能性质的研究 CD 40 L在SLE中的表达 我们将描述T细胞的功能特性， 表达CD 40 L的亚群，并研究其功能效应 可溶性CD 40 L对靶细胞群的影响。 这些研究应阐明疾病的发病机制，并确定新的 SLE的治疗靶点。

Systemic lupus erythematosus (SLE) represents the prototype systemic autoimmune disease, in which the human immune system fails to regulate immune reactivity to chromatin and other well-characterized self antigens. The T helper (Th) cell, the central immunoregulatory cell in the normal immune system, mediates the hypergammaglobulinemia and autoantibody formation that result in tissue damage in SLE. CD40 ligand (C40L), a member of the TNF gene family, mediates the Th cell signals that drive B cell activation and differentiation. Several new observations regarding the regulation of CD40L expression on lymphocytes from patients with SLE represent the important preliminary data for the proposed studies: 1) Baseline expression of CD40L is increased in patients with active SLE; 2) Expression of CD40L is prolonged following treatment of SLE T lymphocytes with PMA and ionomycin, a stimulus that bypasses TCR signaling events; 3) Soluble CD40L circulates in SLE and is readily detectable in serum samples from patients. The proposed experiments will investigate potential mechanisms and functional consequences of altered regulation of CD40L expression in SLE. The hypothesis to be pursued is that in SLE, impaired regulation of T cell activation results in excessive Th cell function, autoantibody formation, inflammation, and disease. CD40L is both a marker and mediator of this abnormal T cell help. The specific aims of the project are: I. To Study the Regulation of CD40L Expression in Human T Cells. We will investigate the T cell stimuli required for induction of CD40L mRNA and protein expression, the biochemical pathways that mediate induction of CD40L, the regulation of soluble CD40L production, and the effect of cytokines on expression of cell surface and soluble CD40L. II. To Study the Regulation of CD40L Expression in SLE. We will characterize the baseline activation status of SLE T cells, study the effects of costimulatory molecules and cytokines on induction of CD40L expression in SLE, study transcription and post-transcriptional regulation of CD40L mRNA in SLE, and assess cleavage and clearance of cell surface CD40L in SLE. III. To Study the Functional Properties of Cell Surface and Soluble CD40L in SLE. We will characterize the functional properties of T cell subpopulations expressing CD40L in SLE, and study the functional effects of soluble CD40L on target cell populations. These studies should elucidate disease pathogenesis and identify new targets for therapy in SLE.