GENETIC AND CLINICAL RISK FACTORS FOR HUMAN SLE NEPHRITIS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。肾炎是人类系统性红斑狼疮的一种常见且严重的表现。长期的免疫抑制通常是必要的。复发很常见。SLE肾炎是免疫复合物（IC）在肾小球积聚的结果。肾脏受累的危险因素，以及复发和严重程度的决定因素，知之甚少。我们推测：1）肾小球IC蓄积的主要机制是IC清除蛋白的遗传和/或获得性缺陷。此外，同时存在2种或2种以上的IC清除蛋白缺陷/缺陷易导致严重肾炎。2)IC通过调节趋化性细胞因子（chemokines）的局部表达介导肾脏炎症。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，CR 1，FcgRIIa和FcgRIIIa）的遗传多态性，以确定哪些是人类SLE肾炎的易感基因。项目3研究了人类SLE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的基因检测将涉及250名SLE肾炎患者（活检证实）、250名从未患过肾炎的SLE患者和250名匹配的正常人。SLE患者的父母和兄弟姐妹也将用于传播不平衡检测（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。将对100例复发性SLE患者（50例有肾脏表现，50例无肾脏表现）进行为期5年的纵向研究。与项目1-3合作，将在随访期间预期的300多例SLE复发之前、期间和之后获得IC清除蛋白、趋化因子和特定临床因素（应激、性激素、感染、紫外线辐射）的系列定量测量。这些变量将与疾病活动和严重程度相关，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。从这一分析应该出现，第一次，一个清晰的画面SLE肾炎的危险因素和它在人类复发。总结：了解人类系统性红斑狼疮肾炎的遗传和临床危险因素的基本概念应该被揭示，从而提供预测系统性红斑狼疮肾炎复发和严重程度的工具，以及其管理策略

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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,FcgRIIa, and FcgRIIIa), 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. 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. Parents 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