Immune Complex Stimulation of TNFalpha

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种自身免疫/炎症性疾病，已发现多种易感基因。与SLE相关的基因分为四类：[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。在补体不足的SLE患者中，FcgammaR在免疫复合物的摄取中起主导作用。这些受体在造血细胞上广泛表达，除了作为清除IgG和IgG免疫复合物的受体外，还介导对IgG和IgG免疫复合物的炎症反应。炎症反应包括吞噬作用、抗体依赖细胞介导的细胞毒性、细胞因子的释放和活性氧中间体的释放。FcgammaR反应的调节依赖于激活受体和抑制受体所传递的信号之间的平衡。我们的初步数据表明，巨噬细胞对免疫复合物的反应高度依赖于成熟状态和环境。我们假设FcgammaR多态性与结合减少相关，导致免疫复合物清除受损，特别是在活动性疾病和低补体血症的SLE患者中。这些循环免疫复合物沉积在终末器官并引发炎症反应。反应的确切性质主要取决于先前的经验或反应细胞的暴露、成熟状态和环境。这种对环境线索的敏感性可能是一个系统所需要的，这个系统既可以介导摄取，在摄取中不需要炎症反应，也可以介导感染反应，在摄取中需要炎症反应。为了研究FcgammaR在SLE中的作用，我们将确定FcgammaR多态性在SLE易感性中的作用。在特定目标2中，我们将定义免疫复合物反应中重要的信号通路和与TNFalpha基因对免疫复合物反应相关的转录因子。在第三个目标中，我们将定义染色质在免疫复合物反应调节中的作用。

DESCRIPTION (provided by applicant): 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. FcgammaR plays a dominant role in the uptake of immune complexes in SLE patients who are hypocomplementemic. These receptors are widely expressed on hematopoietic cells and mediate inflammatory responses to IgG and IgG-immune complexes in addition to acting as receptors for their clearance. Inflammatory responses include phagocytosis, antibody-dependent cell-mediated cytotoxicity, release of cytokines, and release of reactive oxygen intermediates. Regulation of FcgammaR responses depends upon the balance achieved by signals transduced by activating receptors and signals transduced by inhibitory receptors. Our preliminary data suggest that macrophage responses to immune complexes are highly dependent on maturational status and milieu. We hypothesize that FcgammaR polymorphisms associated with decreased binding result in impaired clearance of immune complexes, particularly in SLE patients with active disease and hypocomplementemia. These circulating immune complexes deposit in end organs and incite an inflammatory response. The precise nature of the response depends critically on the prior experience or exposures of the responding cells, maturational status, and milieu. This sensitivity to environmental cues is probably required by a system that mediates both uptake, in which an inflammatory response is undesirable, and response to infection, in which an inflammatory response is desirable. To investigate the role of FcgammaR in SLE, we will determine the role of FcgammaR polymorphisms in the susceptibility to SLE. In specific aim 2, we will define the signaling pathways important in the responses to immune complexes and transcription factors relevant for the response of the TNFalpha gene to immune complexes. In the third aim, we will define the role of chromatin in the regulation of responses to immune complexes.