CHEMOKINE REGULATION IN IMMUNE COMPLEX RENAL DISEASE

令人信服的证据表明，趋化因子在肾脏炎症的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尚不清楚。本研究将在免疫损伤、免疫复合物（IC）介导的肾脏炎症的临床相关机制的背景下，研究趋化因子调控的分子、细胞和遗传方面。在Aim 1中，我们将检验IC诱导的肾脏趋化因子表达是由被IC激活的携带FCgamma-受体iii的淋巴细胞介导的。将使用致病性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。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体内相关性，这是一种经典的ic依赖性肾脏病变。由于Fc受体的多态性已经被描述为改变Fc受体的功能，因此可以想象Fc受体介导的趋化因子表达受到Fc受体表型的影响。因此，Fc受体多态性对ic诱导的白细胞趋化因子产生的影响将被评估。在Aim 2中，将通过测试趋化因子基因调控区域的多态性影响趋化因子产生水平的假设来扩展趋化因子表达的遗传调控主题，从而影响组织炎症对IC或促炎细胞因子的反应程度。将对正常人群的基因组DNA进行测序，以确定趋化因子基因调控元件的多态性。这些调控区域的多态变异将被插入报告载体中进行功能评估。功能调控区多态性的流行程度将在SLE肾炎患者人群中进行评估，并与肾损伤的严重程度相关。这些研究有望为IC肾病中引发炎症和确定炎症严重程度的分子和细胞机制提供新的见解。这一信息可能为控制肾脏炎症的干预提供新的方向。

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.