CD40 LIGAND IN SYSTEMIC LUPUS ERYTHEMATOSUS

系统性红斑狼疮(SLE)代表了系统性红斑狼疮的原型 自身免疫性疾病，人体免疫系统不能调节的疾病 对染色质和其他自身特征良好的免疫反应性 抗原。辅助性T细胞(Th)，中枢免疫调节细胞 正常的免疫系统，调节高丙种球蛋白血症和 导致系统性红斑狼疮组织损伤的自身抗体的形成。CD40配体 肿瘤坏死因子基因家族成员(C40L)介导Th细胞信号 驱动B细胞活化和分化的物质。几个新的 淋巴细胞表面CD40L表达调控的观察 来自SLE患者的代表着重要的初步数据 建议的研究：1)CD40L的基线表达在 活动期系统性红斑狼疮患者CD40L表达延长 PMA和离子霉素治疗SLE T淋巴细胞的研究 绕过TCR信号事件；3)可溶性CD40L在SLE和 在患者的血清样本中很容易检测到。 拟议的实验将研究潜在的机制和 脑内CD40L表达调控改变的功能后果 SLE。要追寻的假设是，在SLE中，调节受损 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。CD40L既是一种标志物，也是 这种异常T细胞的介体有帮助。该项目的具体目标 包括： 1.研究CD40L在人T细胞中的表达调控。我们 将研究诱导CD40L mRNA所需的T细胞刺激 和蛋白质表达，这是介导诱导的生化途径 CD40L的表达、对可溶性CD40L产生的调节以及对CD40L的影响 细胞表面细胞因子和可溶性CD40L的表达。 研究CD40L在系统性红斑狼疮中的表达规律。我们会 表征SLE T细胞的基线激活状态，研究 共刺激分子和细胞因子在CD40L诱导中的作用 在系统性红斑狼疮中的表达，研究转录和转录后 CD40L在系统性红斑狼疮中的表达及对CD40L的切割和清除 SLE患者细胞表面CD40L的表达 三、细胞表面和可溶性功能特性研究 CD40L在系统性红斑狼疮中的表达。我们将描述T细胞的功能特性 系统性红斑狼疮中CD40L亚群的表达及其功能效应研究 可溶性CD40L在靶细胞群上的表达。 这些研究应该阐明疾病的发病机制，并确定新的 系统性红斑狼疮的治疗靶点。

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.