ROLE OF TNF ALPHA IN SLE

描述：（改编自研究者摘要）：系统性狼疮 红斑性狼疮（SLE）是一种自身免疫性/炎性疾病，其中多个 易感基因已被鉴定。与SLE有关的基因 分为四类：[1]抗原呈递，[2]免疫复合物清除， [3]抗体产生失调和[4] T细胞功能失调。的 研究者的初步数据表明，TNF-α 启动子多态性与非裔美国人SLE的关系这种启动子多态性 （TNF-α-308 A）与TNF-α产生增加有关， 可能影响T和B细胞凋亡或发育。研究者已 鉴定并纯化了一种巨噬细胞特异性复合物， TNF-α启动子多态性位点。该复合物由64 kDa和 55 kDa蛋白质。研究人员已经部分克隆了一个亚基， 广泛表达并与转录因子Ets-1相关。的 巨噬细胞特异性复合物与多态性启动子序列相互作用 具有比野生型序列更高的亲和力。研究人员假设 复合物对多态性启动子序列的高亲和力 直接介导TNF-α转录的增加， TNF-α参与SLE的发病机制。目前， 有证据支持TNF-α的增加参与了 SLE的发病机制：[1] TNF-α-308A多态性与SLE相关， [2]SLE患者的循环TNF-α水平升高， 疾病活动，[3] SLE患者的骨髓细胞自发产生 高水平的TNF-α和[4]沙利度胺治疗（降低 TNF-α）导致临床改善。系统性红斑狼疮动物模型也支持 TNF-α在SLE发病机制中的作用MRL/lpr小鼠具有高的 循环TNF-α和干扰TNF-α表达改善 在NZB/NZW小鼠中，低剂量的TNF-α加速疾病。的 研究者将独立确认TNF-α-308 A与 非裔美国人和高加索人的SLE。她将研究 巨噬细胞特异性复合物在TNF-α转录中的作用 转染技术，他们将直接测量亲和力的差异， 野生型和多态性靶序列的蛋白质。她将 我还试图克隆编码第二种蛋白质的基因，以确定其作用 在TNF-α的结合相互作用和转录调节中。 这种机制的方法将定义的作用，巨噬细胞特异性 在TNF-α的转录调控中起重要作用。这些研究可能 最终实现针对TNF-α的合理干预。

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.