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循环是肾脏和自身免疫性疾病的病因。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）是该病的一种严重形式。具体而言，本提案旨在确定补体成分C4在SLE和SLE- n疾病病因学中的作用，C4在每个个体中存在的基因和蛋白质的数量和质量上存在惊人程度的差异。定量变化包括存在的C4A和C4B基因的数量，这可能决定了患者和正常人的蛋白质表达水平。我们假设C4的过表达（C4A、C4B或两者都有）、C4的过表达（C4A或C4B或两者都有）以及C4A或C4B的功能障碍与SLE和SLE- n的病因过程有关。也就是说，SLE的发病机制可能与C4基因剂量（C4基因数量）、C4基因类型（长、短C4基因）、C4蛋白功能（C4A和C4B同型和同种异型）有关。C4的过度表达可能通过直接促进补体系统的局部激活而导致组织损伤，从而加重疾病。CR功能障碍的表达不足会导致IC的溶解受损。我们的实验室已经建立了确定RCCX成分（包括补体C4A和C4B）定性和定量变化的特定技术。在MHC III类区域发现了许多新的基因。这些突破使以下具体目标得以实现：1)确定SLE、SLE- n和正常患者的RCCX模块变化；II)确定SLE-SLE-N和正常人中C4A和C4B缺失的分子碱基；IV)探讨SLE、SLE- n和正常人MHC III类基因的分子遗传学。研究人群包括250例SLE- n患者、同等数量的非肾脏受累SLE患者、受影响家庭对照和病例匹配对照。该提案的结果将直接影响SLE和SLE- n的治疗（甚至可能治愈）理念。它可能对SLE和其他风湿病患者的医疗保险产生巨大的影响。

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.