Genetic & Clinical Risk for Human SLE Nephritis

肾炎是人类系统性红斑狼疮常见而严重的表现。长期的免疫抑制通常是必要的。复发是很常见的。系统性红斑狼疮肾炎是肾小球内免疫复合体(IC)聚集的结果。肾脏受累的危险因素，以及复发和严重程度的决定因素，人们知之甚少。我们推测：1)肾小球IC积聚的主要机制是IC清除蛋白的遗传和/或获得性缺陷。此外，2个或2个以上的缺陷/缺陷IC清除蛋白同时存在易导致严重的肾炎。2)IC通过调节局部趋化细胞因子(趋化因子)的表达而介导肾脏炎症。3)特定的、可量化的临床事件是SLE肾炎复发的触发因素，并影响疾病的严重程度。这些假设将通过4个相互关联的项目进行检验。项目1和2分析关键IC清除蛋白(C2、C4、CR1、FcGammaRIIa和FcGammaRIIIa)的遗传多态，以确定哪些是人类SLE肾炎的易感基因。项目3研究人类系统性红斑狼疮肾炎中调节趋化因子活性的遗传、分子和细胞机制。项目3研究人类系统性红斑狼疮肾炎中调节趋化因子活性的遗传、分子和细胞机制。项目1、2和3的基因测试将涉及250名SLE肾炎患者(活组织检查证实)，250名从未患过肾炎的SLE患者，以及250名匹配的正常人。患者和SLE患者的兄弟姐妹也将被用于传递不平衡测试(TDT)。项目4是一项细致的前瞻性研究，旨在确定SLE复发与遗传、免疫学和临床参数之间的关系。100名有复发疾病的SLE患者(50名有肾脏表现，50名没有肾脏表现)将在5年内进行纵向研究。与项目1-3合作，将获得IC清除蛋白、趋化因子和特定临床因素(压力、性激素、感染、紫外线辐射)的一系列定量测量，预计在后续的300多个SLE复发之前、期间和之后。这些变量将与疾病活动性和严重性相关，以确定哪些是SLE复发的“触发因素”，哪些是SLE肾脏表现的决定因素。从这一分析中，应该第一次对SLE肾炎及其在人类中复发的危险因素有一个清晰的了解。摘要：应该揭示人类SLE肾炎的遗传和临床危险因素的基本概念，从而为预测SLE肾炎的复发和严重程度提供工具，并提供其处理策略。

Nephritis is a frequent and severe manifestation of human SLE. Long- term immunosuppression is usually necessary. Relapse is common. SLE nephritis is the result of glomerular accumulation of immune complexes (IC). The risk factors for renal involvement, as well as the determinants of relapse and severity, are poorly understood. We postulate that 1) The dominant mechanism for glomerular IC accumulation is genetic and/or acquired defects of IC clearance proteins. Furthermore, the concurrence of 2 or more defective/deficient IC clearance proteins predisposes to severe nephritis. 2) IC mediate renal inflammation by regulating the local expression of chemotactic cytokines (chemokines). 3) Specific, quantifiable clinical events are triggers for SLE nephritis relapse, and influence disease severity. These hypotheses will be tested by 4 interrelated projects. Projects 1 and 2 analyze genetic polymorphisms of key IC clearance proteins (C2, C4, CR1, FcgammaRIIa, and FcgammaRIIIa), to determine which are susceptibility genes for human SLE nephritis. Project 3 examines genetic, molecular, and cellular mechanisms that regulate chemokine activity in human SLE nephritis. Project 3 examines genetic, molecular, and cellular mechanisms that regulate chemokine activity in human SLE nephritis. The genetic testing of Projects 1, 2, and 3 will involve 250 SLE nephritis patients (biopsy proven), 250 SLE patients who have never had nephritis, and 250 matched normals. Patients and siblings of the SLE patients will also be used for transmission disequilibrium testing (TDT). Project 4 is a meticulous, prospective study designed to determine the relationship between SLE relapse and genetic, immunologic, and clinical parameters. One hundred SLE patients with relapsing disease (50 with and 50 without renal manifestations) will be studied longitudinally over 5 years. In collaboration with Projects 1-3, serial quantitative measures of IC clearance proteins, chemokines, and specific clinical factors (stress, sex hormones, infection, UV radiation) will be obtained before, during, and after each of the more than 300 SLE relapses expected during follow-up. These variables will be correlated to disease activity and severity to determine which are "triggers" for SLE relapse, and which are determinants of the renal manifestations of SLE. From this analysis should emerge, for the first time, a clear picture of the risk factors for SLE nephritis and its relapse in humans. Summary: Concepts fundamental to understanding the genetic and clinical risk factors for human SLE nephritis should be revealed, thus providing tools for predicting SLE nephritis relapse and severity, and strategies for its management.