Immune Complex Stimulation of TNFalpha

描述(申请人提供)：系统性红斑狼疮(SLE)是一种自身免疫性/炎症性疾病，已发现多种易感基因。与系统性红斑狼疮相关的基因分为四类：[1]抗原提呈，[2]免疫复合体清除，[3]抗体产生失调，[4]T细胞功能失调。在低补体的SLE患者中，FcGammaR在免疫复合物的摄取中起主导作用。这些受体广泛表达在造血细胞上，除了作为清除它们的受体外，还介导对免疫球蛋白和免疫球蛋白复合体的炎症反应。炎症反应包括吞噬、抗体依赖的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转导的信号和抑制性受体转导的信号之间的平衡。我们的初步数据表明，巨噬细胞对免疫复合体的反应高度依赖于成熟状态和环境。我们假设与结合减少相关的FcGammaR基因多态导致免疫复合体清除受损，特别是在伴有活动性疾病和低补体血症的SLE患者中。这些循环免疫复合体沉积在末端器官中，并激发炎症反应。反应的确切性质关键取决于反应细胞的先前经验或暴露、成熟状态和环境。这种对环境信号的敏感性可能是调节摄取和感染反应的系统所必需的，在该系统中，炎症反应是不可取的，而在感染反应中，炎症反应是可取的。为了研究FcGammaR在SLE中的作用，我们将确定FcGammaR基因多态性在SLE易感性中的作用。在特定的目标2中，我们将定义在免疫复合体应答中重要的信号通路以及与TNFpha基因对免疫复合体应答相关的转录因子。在第三个目标中，我们将确定染色质在调节对免疫复合体的反应中的作用。

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.