Chemokine regulation in human SLE nephritis

白细胞的渗入在SLE肾损害的发病机制中起着关键作用。在SLE中，白细胞被招募到肾脏以响应免疫复合体(IC)的沉积。然而，目前的概念并不能充分解释IC沉积是如何导致组织中的白细胞渗透的。我们推测，IC与白细胞和肾实质细胞相互作用，激活局部产生的趋化因子，然后负责将炎症细胞招募到肾脏。SLE肾脏损伤的严重程度取决于调节趋化因子生物活性的内源性机制，以及决定IC沉积反应中趋化因子表达强度的遗传因素。目的1验证IC诱导的趋化因子在肾脏的表达是由IC激活的FcGamma受体III型淋巴细胞介导的假设。为此，建立了致病IC与白细胞和肾脏相互作用的细胞培养模型。将在SLE肾炎患者群体中寻找支持这一模型的证据。目的探讨系统性红斑狼疮肾炎时可能激活的内源性保护机制，以减轻趋化因子的生物学活性。这些假定的保护因子包括实质趋化因子受体和抑制性补体成分。用免疫组织化学方法检测SLE肾炎时肾脏趋化因子受体的表达。将研究培养的肾细胞对受体表达的调节。在白细胞和肾细胞的共培养系统中，将评估实质趋化因子受体对趋化因子生物活性的影响。目的3将验证趋化因子基因调控区的多态影响趋化因子对激活刺激的反应的假设。来自健康个体的DNA将被测序，以识别这种多态。调控区域变异体将连接到报告载体中进行功能评估。SLE肾炎人群中功能基因多态性的存在将与肾脏损伤的严重程度相关。最后，在项目4中，将前瞻性跟踪SLE肾炎患者的尿液趋化因子水平，以确定趋化因子的表达是否预测SLE复发的开始或严重程度。该项目有望为系统性红斑狼疮中肾白细胞浸润的发病机制提供新的见解。因此，这些研究将解决计划项目中的问题，即SLE中致病IC的缺陷清除如何导致肾脏损伤。

Infiltrating leukocytes play a key role in the pathogenesis of renal injury in SLE. In SLE, leukocytes are recruited to the kidney in response to immune complex (IC) deposition. Current concepts do not, however adequately explain how IC deposition leads to tissue leukocyte infiltration. We postulate that IC interact with leukocytes and renal parenchymal cells to activate local production of chemokines that are then responsible for recruiting inflammatory cells to the kidney. The severity of renal injury in SLE is dependent on endogenous mechanisms that regulate chemokine bioactivity, and on genetic factors that determine the intensity of chemokine expression in response to IC deposition. Aim 1 will test the hypothesis that IC-induced chemokine expression in the kidney is mediated by Fcgamma-receptor III bearing lymphocytes that have been activated by IC. A cell culture model of pathogenic IC interaction with leukocytes and renal was developed for this evaluation. Evidence to support this model will be sought in the SLE nephritis patient population. Aim 2 will investigate endogenous protective mechanisms that may be activated during SLE nephritis to attenuate the biologic activity of chemokines. These putative protective factors include parenchymal chemokine receptors and inhibitory complement components. Chemokine receptors expressed by the kidney during SLE nephritis will be determined by immunohistochemically. Regulation of receptor expression by cultured renal cells will be investigated. In a co- culture system of leukocytes and renal cells, the effects of parenchymal chemokine receptors on chemokine bioactivity will be assessed. Aim 3 will test the hypothesis that polymorphisms in the regulatory regions of chemokine genes affect the chemokine response to activating stimuli. DNA from healthy individuals will be sequenced to identify such polymorphisms. Regulatory region variants will be ligated into a reporter vector for functional evaluation. The presence of functional polymorphisms in the SLE nephritis population will be correlated to severity of renal injury. Finally, with Project 4, urine chemokine levels in SLE nephritis patients will be followed prospectively to determine whether chemokine expression predicts onset or severity of SLE relapse. This project is expected to offer novel insight into the pathogenesis of renal leukocyte infiltration in SLE. These studies will thus address the Program Project question of how defective clearance of pathogenic IC in SLE results in renal injury.