ROLE OF TNF ALPHA IN SLE

点击翻译按钮获取中文摘要

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.