Chemokine regulation in human SLE nephritis

浸润性白细胞在SLE肾损害的发病机制中起关键作用。在SLE中，白细胞响应于免疫复合物（IC）沉积而被募集到肾脏。然而，目前的概念不能充分解释IC沉积如何导致组织白细胞浸润。我们假设IC与白细胞和肾实质细胞相互作用，激活局部产生趋化因子，然后负责招募炎症细胞到肾脏。SLE肾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沉积时趋化因子表达强度的遗传因素。目的1将测试的假设，IC诱导的趋化因子在肾脏中的表达介导的Fc γ-受体III轴承淋巴细胞已被IC激活。为此，开发了致病性IC与白细胞和肾脏相互作用的细胞培养模型。将在SLE肾炎患者人群中寻找支持该模型的证据。目的二是探讨SLE肾炎时趋化因子的生物学活性减弱的内源性保护机制。这些推定的保护因子包括实质趋化因子受体和抑制性补体成分。SLE肾炎期间肾脏表达的趋化因子受体将通过免疫化学法测定。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验证趋化因子基因调控区的多态性影响趋化因子对激活刺激的反应的假说。将对来自健康个体的DNA进行测序以鉴定此类多态性。将调节区变体连接到报告载体中用于功能评价。SLE肾炎人群中功能多态性的存在与肾损伤的严重程度相关。最后，在项目4中，将对SLE肾炎患者的尿趋化因子水平进行前瞻性随访，以确定趋化因子表达是否可预测SLE复发的发生或严重程度。该项目有望提供新的见解肾白细胞浸润的发病机制在系统性红斑狼疮。因此，这些研究将解决计划项目的问题，即SLE中致病性IC的清除缺陷如何导致肾损伤。

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.