Complement C4 and HLA class III genes in human SLE

补体蛋白在免疫复合物（IC）的溶解中是必不可少的。致病性IC的循环是肾脏和自身免疫性疾病的致病因素。系统性红斑狼疮（SLE）是一种遗传特征复杂、临床表现多样的多因素疾病。狼疮性肾炎（SLE-N）是一种严重的疾病。具体而言，该建议旨在确定补体成分C4在SLE和SLE-N的疾病病因学中的作用，补体成分C4在每个个体中存在的基因和蛋白质的数量和质量方面具有惊人的变化程度。定量变化包括存在的C4 A和C4 B基因的数量，其可以确定患者和正常人中表达的蛋白质的水平。我们假设C4（C4 A、C4 B或两者）的过表达、C4（C4 A或C4 B或两者）的低表达以及C4 A或C4 B的功能障碍有助于SLE和SLE-N的病因学过程。换句话说，SLE的发病机制可能与C4基因剂量（C4基因的数量）、C4基因类型（长和短C4基因）和C4蛋白功能（C4 A和C4 B同种型和同种异型）有关。C4的过度表达可能通过直接促进导致组织损伤的补体系统的局部活化而加重疾病。CR功能障碍的表达不足将导致IC溶解受损。本实验室已建立了测定RCCX组分（包括补体C4 A和C4 B）定性和定量变化的特定技术。许多新的基因已被发现在MHC III类区域。这些突破使得以下特定目标得以解决：I）确定SLE、SLE-N和正常人中的RCCX模块变异; II）确定SLE-SLE-N和正常人中C4 A和C4 B缺陷的分子基础; IV）研究SLE、SLE-N和正常人中MHC III类基因的分子遗传学。研究人群包括250名患有SLE-N的个体，以及相同数量的具有非肾脏受累的SLE患者、受影响的基于家族的对照和病例匹配的对照。该提案的结果将直接影响SLE和SLE-N治疗（可能治愈）的理念。它可能对SLE和其他风湿性疾病患者的医疗保健产生巨大影响。

Complement proteins are essential in the dissolution of immune complexes (IC). The circulation of pathogenic IC is an etiologic factor for kidney and autoimmune disease. Systemic lupus erythematosus (SLE) is multi-factorial disease with complex genetic trait and diverse clinical manifestations. Lupus nephritis (SLE-N) is a severe form of the disease. Specifically, this proposal seeks to determine the roles of complement component C4, which has an amazing degree of variations in the quantities and qualities of the genes and proteins present in each individual, in the disease etiology of SLE and SLE-N. The quantitative variations include the number of the C4A and C4B genes present that may determine the levels of proteins expressed in patients and in normals. We hypothesize that over-expression of C4 (C4A, C4B or both), under- expression of C4 (C4A or C4B or both), and malfunction of C4A or C4B contribute to the etiological processes of SLE and SLE-N. In other words, the pathogenesis of SLE may be related to the C4 gene dosage (number of C4 genes), C4 gene types (long and short C4 genes), and C4 protein functions (C4A and C4B isotypes and allotypes). Over-expression of C4 may aggravate the disease by directly promoting the local activation of the complement system that causes tissue injuries. Under-expression of malfunction of the CR would lead to impairment in the dissolution of IC. Specific techniques to determine the qualitative and quantitative variations of the RCCX constituents including complement C4A and C4B have been established by our laboratory. Many novel genes have been discovered in the MHC class III region. These breakthroughs allow the following Specific Aims to be addressed: I) To determine the RCCX modular variations in SLE, SLE-N and normals; II) To determine the molecular bases of C4A and C4B deficiencies in SLE-SLE-N and normals; IV) To investigate the molecular genetics of the MHC class III genes in SLE, SLE-N and normals. The study population include 250 individuals with SLE-N, and equal numbers of SLE patients with non- renal involvement, affected family based controls and case matched controls. The results of this proposal will directly influence the philosophy on the treatment (and possibly cure) of SLE and SLE-N. It may have enormous impact on the medicare of the SLE and other rheumatic disease patients.