CHEMOKINE REGULATION IN IMMUNE COMPLEX RENAL DISEASE

令人信服的证据表明，趋化因子在肾炎的发生发展中起着关键作用。趋化因子在人类肾脏疾病中的表达调控还知之甚少。这项研究将在免疫损伤的临床相关机制--免疫复合体(IC)介导的肾脏炎症的背景下，检查趋化因子调节的分子、细胞和遗传学方面。在目标1中，将检验IC诱导的趋化因子在肾脏中的表达是由IC激活的FCGamma受体III受体的淋巴细胞介导的假设。将使用致病IC与白细胞和肾实质细胞相互作用的细胞培养模型进行评估。在体内，将在系统性红斑狼疮(SLE)肾炎患者群体中寻找支持该模型的相关因素，系统性红斑狼疮肾炎是一种典型的IC依赖性肾脏损害。由于Fc受体的多态可以改变Fc受体的功能，可以想象Fc受体介导的趋化因子的表达受Fc受体表型的影响。因此，我们将评估Fc受体基因多态性对IC诱导的白细胞趋化因子产生的影响。在目标2中，趋化因子表达的遗传调控的主题将通过检验以下假设来扩展：趋化因子基因调控区的多态影响趋化因子的产生水平，从而影响组织对IC或促炎细胞因子的反应程度。来自正常人群的基因组DNA将被测序，以确定趋化因子基因调控元件的多态。这些调控区域的多态变体将被插入到报告载体中进行功能评估。将在SLE肾炎患者群体中评估功能调节区多态的发生率，并将其与肾脏损伤的严重程度相关联。这些研究有望对引发炎症的分子和细胞机制提供新的见解，并确定IC肾脏疾病的炎症严重程度。这一信息可能会为控制肾脏炎症的干预措施提供新的方向。

Compelling evidence indicates that chemokines play a key role in the development of renal inflammation. The regulation of chemokine expression in human renal disease is poorly understood. This investigation will examine molecular, cellular, and genetic aspects of chemokine regulation in the context of a clinically relevant mechanism of immune injury, immune complex (IC)-mediated renal inflammation. In Aim 1 the hypothesis that IC-induced chemokine expression in the kidney is mediated by FCgamma- receptor III-bearing lymphocytes that have been activated by IC will be tested. A cell culture model of pathogenic IC interaction with leukocytes and renal parenchymal cells will be used for this evaluation. In vivo correlates to support the model will be sought in a patient population with systemic lupus erythematosus (SLE) nephritis, a classical IC-dependent renal lesion. Because polymorphisms of Fc receptors have been described that alter Fc receptor function, it is conceivable that Fc-receptor mediated chemokine expression is influenced by Fc receptor phenotype. Therefore, the effect of Fc receptor polymorphisms on IC-induced leukocyte chemokine production will be assessed. In Aim 2, the theme of genetic regulation of chemokine expression will be expanded by testing the hypothesis that polymorphisms in the regulatory regions of chemokine genes affect the level of chemokine production, and consequently the degree of tissue inflammation in response to IC or pro- inflammatory cytokines. Genomic DNA from a normal population will be sequenced to identify polymorphisms in the regulatory elements of chemokine genes. Polymorphic variants of these regulatory regions will be inserted into reporter vectors for functional evaluation. The prevalence of functional regulatory region polymorphisms will be assessed in the SLE nephritis patient population, and correlated to severity of renal injury. These studies are expected to offer novel insights into the molecular and cellular mechanisms that initiate inflammation and determine the severity of inflammation in IC renal disease. This information will likely suggest new directions for interventions to control renal inflammation.