ROLE OF TNF ALPHA IN SLE

描述：(改编自调查人员摘要)：系统性红斑狼疮 红斑狼疮(SLE)是一种自身免疫/炎症性疾病，其中 易感基因已经确定。与系统性红斑狼疮发病有关的基因 分为四类：[1]抗原提呈，[2]免疫复合体清除， [3]抗体生成失调，[4]T细胞功能失调。这个 研究人员的初步数据表明，肿瘤坏死因子-α与 非裔美国人系统性红斑狼疮患者的启动子多态性。该启动子的多态 (肿瘤坏死因子-α-308a)与肿瘤坏死因子-α的产生增加有关，这可能 可能影响T和B细胞的凋亡或发育。调查员已经 鉴定和纯化一种巨噬细胞特异性复合体，该复合体与 肿瘤坏死因子-α启动子位于多态位点。这个建筑群是由和 55 kDa的蛋白质。研究人员已经部分克隆了一个亚基，即 广泛表达，并与转录因子Ets-1相关。这个 巨噬细胞特异性复合体与多态启动子序列相互作用 比野生型序列具有更高的亲和力。调查者假设 该复合体对多态启动子序列具有较高的亲和力 直接介导了肿瘤坏死因子-α转录的增加，这增加了 肿瘤坏死因子-α参与系统性红斑狼疮的发病。现在有大量的 有证据支持增加的肿瘤坏死因子-α参与了 系统性红斑狼疮发病机制：[1]肿瘤坏死因子-α-308a基因多态性与系统性红斑狼疮相关。 [2]系统性红斑狼疮患者外周血中肿瘤坏死因子-α水平升高，并与 疾病活动性，[3]SLE患者的骨髓细胞自发产生 高水平的肿瘤坏死因子-α和[4]沙利度胺治疗(减少 肿瘤坏死因子-α)可改善临床症状。系统性红斑狼疮的动物模型也支持 肿瘤坏死因子-α在系统性红斑狼疮发病中的作用MRL/LPR小鼠有较高的 循环中的肿瘤坏死因子-α及其对肿瘤坏死因子-α表达的干预作用 疾病，以及低剂量的肿瘤坏死因子-α会加速NZB/NZW小鼠的疾病。这个 研究人员将独立确认肿瘤坏死因子-α-308a与 非裔美国人和高加索人的系统性红斑狼疮。她将研究 巨噬细胞特异性复合体在瞬时转录肿瘤坏死因子-α中的作用 他们将直接测量亲和力的差异 野生型和多态靶标序列的蛋白质。她会的 我还试图克隆编码第二种蛋白质的基因，以确定其作用 在肿瘤坏死因子-α的结合作用和转录调控中起重要作用。 这种机械方法将定义巨噬细胞特异性的作用。 在转录调控中的复杂的肿瘤坏死因子-α。这些研究可能 最终实现针对肿瘤坏死因子-α的理性干预。

DESCRIPTION: (Adapted from the Investigator's abstract): Systemic lupus erythematosus (SLE) is an autoimmune/inflammatory disorder in which multiple susceptibility genes have been identified. The genes implicated in SLE fall into four categories: [1] antigen presentation, [2] immune complex clearance, [3] dysregulated antibody production, and [4] dysregulated T cell function. The investigator's preliminary data demonstrate an association of a TNF-alpha promoter polymorphism with SLE in African Americans. This promoter polymorphism (TNF-alpha-308A) is associated with increased TNF-alpha production that could potentially affect T and B cell apoptosis or development. The investigator has identified and purified a macrophage-specific complex that interacts with the TNF-alpha promoter at the polymorphic site. This complex consists of 64 kDa and 55 kDa proteins. The investigator has partially cloned one subunit, which is ubiquitously expressed and is related to the transcription factor Ets-1. The macrophage-specific complex interacts with the polymorphic promoter sequence with higher affinity than the wild-type sequence. The investigator hypothesizes that the complex's higher affinity for the polymorphic promoter sequence directly mediates increased transcription of TNF-alpha and that this increased TNF-alpha participates in the pathogenesis of SLE. There is now substantial evidence to support the idea that increased TNF-alpha is involved in the pathogenesis of SLE: [1] TNF-alpha-308A polymorphism is associated with SLE, [2] SLE patients have increased circulating TNF-alpha and levels correlate with disease activity, [3] bone marrow cells from SLE patients spontaneously produce high levels of TNF-alpha, and [4] thalidomide treatment (which decreases TNF-alpha) results in clinical improvement. Animal models of SLE also support a role for TNF-alpha in the etiopathogenesis of SLE. MRL/lpr mice have high circulating TNF-alpha and interference with TNF-alpha expression ameliorates disease, and low doses of TNF-alpha accelerate disease in NZB/NZW mice. The investigator will independently confirm the association of TNF-alpha-308A with SLE in African Americans and Caucasians. She will examine the role of the macrophage-specific complex in the transcription of TNF-alpha by transient transfection techniques and they will directly measure differences in affinity of the protein for the wild type and polymorphic target sequences. She will also attempt to clone the gene encoding the second protein to identify its role in the binding interaction and the transcriptional regulation of TNF-alpha. This mechanistic approach will define the role of the macrophage-specific complex in the transcriptional regulation of TNF-alpha. These studies may ultimately enable rational interventions directed at TNF-alpha.