Bagavant Harini, Fu Shu Man
Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia, Charlottesville, 22908, USA.
Curr Opin Rheumatol. 2005 Sep;17(5):523-8. doi: 10.1097/01.bor.0000169361.23325.1e.
This review summarizes current literature on genetic regulation of different phenotypes in systemic lupus erythematosus in context of end-organ disease. Recent findings conflicting with the current paradigm that loss of tolerance to chromatin is the critical step for end-organ injury are discussed.
Systemic lupus erythematosus is a prototype immune complex disease with circulating autoantibodies to chromatin, histone proteins, Sm/La, and other nuclear and cytoplasmic proteins. Extensive studies have been carried out on the regulation of B-cell and autoantibody production in lupus mice. However, the hypothesis that autoantibodies are primary mediators of organ damage fails to explain the heterogenous presentation in patients. Studies in murine models of systemic lupus erythematosus clearly dissociate genetic control of autoantibody responses to classic lupus antigens and kidney disease. There is increasing evidence to support the role of autoreactive T cells and genetic control of end organ susceptibility. These studies suggest complex interactions between innate and adaptive immunity resulting in end-organ damage. This review focuses on autoimmune responses and renal involvement in spontaneous systemic lupus erythematosus using murine models of lupus nephritis.
Studies in murine models demonstrate complex genetic interactions regulating spontaneous systemic lupus erythematosus. Although detection of serum autoantibodies is considered a hallmark for clinical diagnosis of systemic lupus erythematosus, recent evidence shows that autoantibodies to classic lupus antigens are neither required nor sufficient for end-organ damage. Thus, murine models provide new insights into the pathogenesis of systemic lupus erythematosus.
本综述总结了系统性红斑狼疮不同表型的遗传调控在终末器官疾病背景下的当前文献。讨论了与目前认为对染色质耐受性丧失是终末器官损伤关键步骤的范式相矛盾的最新发现。
系统性红斑狼疮是一种典型的免疫复合物疾病，存在针对染色质、组蛋白、Sm/La以及其他核蛋白和胞浆蛋白的循环自身抗体。对狼疮小鼠中B细胞和自身抗体产生的调控进行了广泛研究。然而，自身抗体是器官损伤主要介质的假说无法解释患者的异质性表现。在系统性红斑狼疮小鼠模型中的研究清楚地将对经典狼疮抗原的自身抗体反应的遗传控制与肾脏疾病区分开来。越来越多的证据支持自身反应性T细胞的作用以及终末器官易感性的遗传控制。这些研究表明先天性免疫和适应性免疫之间存在复杂的相互作用，导致终末器官损伤。本综述使用狼疮性肾炎小鼠模型重点关注自身免疫反应和自发系统性红斑狼疮中的肾脏受累情况。
在小鼠模型中的研究表明，调控自发系统性红斑狼疮存在复杂的遗传相互作用。尽管血清自身抗体的检测被认为是系统性红斑狼疮临床诊断的标志，但最近的证据表明，针对经典狼疮抗原的自身抗体对于终末器官损伤既非必需也不充分。因此，小鼠模型为系统性红斑狼疮的发病机制提供了新的见解。
