Pathogenic role of the complement system in murine lupus

描述（由申请人提供）：有相当多的间接证据和现在的直接证据表明补体系统参与狼疮肾炎的发病机制。本申请中提出的工作将在人系统性红斑狼疮的精确MRL/lpr小鼠模型中检查补体系统在肾脏疾病中的作用。为了实现这一目标，基因靶向小鼠将用于育种策略，使MRL/lpr小鼠获得特定补体蛋白的缺陷。将研究过敏毒素C3a和C5a的受体，它们存在于循环白细胞和肾小球和肾小管细胞中，可能参与炎症细胞向肾脏的募集以及随着时间的推移而发生的进行性纤维化；CR3，一种多种造血细胞上的受体，在免疫复合物中与iC3b结合，导致其被肝巨噬细胞加工和肾脏炎症细胞积聚；因子H是一种多功能的c3b结合蛋白，作为补体调节剂存在于血浆中，作为免疫粘附受体存在于血小板和内在肾细胞中，其功能尚不确定。除了通过测量蛋白尿和肾小球滤过来检查肾脏表型外，还将研究其他补体依赖性表型变化，包括免疫复合物处理、炎症基因表达、信号级联的评估以及促纤维化基因和蛋白质积累。为了确定与这些补体缺陷引起的表型变化有关的特定细胞，将在敲除型和野生型动物之间进行肾脏和骨髓细胞移植。由于使用敲除动物固有的某些局限性，平行研究将使用这些补体蛋白的特定抑制剂进行。这些研究将最终确定补体系统在狼疮肾炎中的作用，包括相关的补体蛋白/受体是什么，这些受体在哪些细胞上是活跃的，并确定它们与致病级联的特定分支的关系。了解像狼疮肾炎这样复杂疾病的发病机制，为设计基本原理治疗提供了可能。在这个应用中研究的补体系统的每个部位的特定操作现在是可能的，如果在实验动物的工作支持，可以在临床环境中应用。

DESCRIPTION (provided by applicant): There is considerable circumstantial and now direct evidence that the complement system is involved in the pathogenesis of lupus nephritis. The work proposed in this application will examine the role of the complement system in renal disease occurring in the accurate MRL/lpr mouse model of human systemic lupus erythematosus. To accomplish this, gene targeted mice will be used in a breeding strategy so that MRL/lpr mice acquire deficiencies of particular complement proteins. Studied will be receptors for the anaphylatoxins, C3a and C5a, which are present on circulating leukocytes and renal glomerular and tubular cells, and likely to be involved in inflammatory cell recruitment to the kidney as well as the progressive fibrosis occurring over time; CR3, a receptor on a variety of cells of hematopoeitic lineage which binds iC3b in immune complexes, leading to their processing by hepatic macrophages and inflammatory cell accumulation in kidney; and, factor H, a versatile C3b-binding protein present in plasma as a complement regulator, on platelets as the immune adherence receptor and in intrinsic renal cells, where its function is undetermined. In addition to examining renal phenotype through the measurement of albuminuria and glomerular filtration, additional complement dependent phenotypic changes that will be studied include immune complex handling, inflammatory gene expression, assessment of signaling cascades, and pro-fibrotic gene and protein accumulation. To determine the particular cell(s) involved in phenotypic changes brought about by these complement deficiencies, transplantation of kidney and bone marrow cells will be performed between knockout and wild-type animals. Because of certain limitations inherent in using knockout animals, parallel studies will be performed using specific inhibitors of these complement proteins. These studies will allow conclusive determination of the role of the complement system in lupus nephritis, including what the relevant complement protein/receptors are, on which cells these are active, and pinpointing their involvement to a particular limb of the pathogenic cascade. Understanding the pathogenesis of a complex disease like lupus nephritis offers the potential to design rationale therapy. Specific manipulation of the complement system at each of the sites studied in this application is now possible and can be applied in a clinical setting if supported by work in the experimental animal.