Complement in Human Lupus: Deficiencies, Profiles and Complications

项目总结/摘要 虽然发病率很低，但在一种早期成分中完全缺乏的人， 补体系统的经典途径几乎总是导致系统性红斑狼疮的发作 (SLE)不分种族、性别和HLA背景。有趣的是，33 - 50%的白色SLE患者 补体C4基因拷贝数低，特别是C4 A。大多数SLE患者还获得了 由于免疫复合物驱动的激活和消耗而导致的补体表型缺陷。的 遗传缺陷与SLE的相关性提示补体可预防SLE。然而 由于补体激活导致的获得性缺陷与SLE和LN的相关性表明， 补体也是SLE疾病活动的重要驱动因素。为了充分理解补体在 SLE的发病机制和进展，必须破译遗传和表型的确切细节， 在补体系统中发挥作用。这项提案的调查人员有很长的研究历史， 补体基因和蛋白在SLE中的作用。利用最新的技术进步，我们建议 全面研究补体系统在遗传易感性和调节 人类SLE和LN的疾病特征和并发症。具体目的：（1）研究遗传学 SLE患者和欧洲、非洲和东亚血统的健康对照者补体C4水平的差异。 SLE危险因素的频率和效应大小在种族间差异很大。康贝特人将以 基因拷贝数的变化，总C4，C4 A和C4 B，长C4和短C4，并检查他们的作用， 在三个不同的SLE患者中，在与HLA-DRB 1变异体连锁不平衡的背景下， 种族组，在成人发病和儿童发病患者;（2）调查基因型差异如何影响 补体调节补体表型谱和SLE疾病特征。我们将调查 补体遗传变异与其血清蛋白水平的相关性， 激活产品与血液和心血管疾病，以及它们与I型干扰素的相互作用 刺激基因表达。将选择一组SLE患者进行所有补体的深入分析。 通过外显子组测序的基因;和（3）表征在周期期间变化的补体表型 导致从LN疾病静止到疾病发作和疾病缓解。纵向表型 测量将包括补体蛋白（激活剂，调节剂，受体），激活片段， 血液循环和尿液中的补体自身抗体。变化之间的时间关系 将分析补体表型和LN发作/缓解，并分析遗传变异的影响。 将建立这些关系补充。这一建议将产生重要的知识， 补体系统的变体有助于SLE的遗传易感性和疾病进展， LN.这将有助于准确诊断和有效治疗这种女性占主导地位的慢性疾病。

Project Summary/Abstract Although rare in prevalence, humans with a complete deficiency in one of the early components for the classical pathway of the complement system almost always lead to an onset of systemic lupus erythematosus (SLE), regardless of race, sex and HLA backgrounds. Intriguingly, between 33 and 50% of White SLE patients have low gene copy number of complement C4, specifically C4A. Most SLE patients also have acquired phenotypic deficiencies of complement due to immune complex-driven activation and consumption. The association of genetic deficiencies with SLE suggests that complement protects against SLE. Yet, the association of acquired deficiencies, due to complement activation, with SLE and LN, suggests that complement is also an important driver of SLE disease activity. To fully understand the role of complement in SLE pathogenesis and progression, it is imperative to decipher the exact details of genetic and phenotypic diversities in the complement system. Investigators of this proposal have a long history of research on complement genes and proteins in SLE. Leveraging on recent technological advances, we propose to investigate comprehensively the roles of the complement system on genetic predisposition and modulation of disease profiles and complications in human SLE and LN. The Specific Aims are: (1) To investigate the genetic diversities of complement C4 in SLE and healthy controls of European, African and East-Asian ancestries. The frequencies and effect sizes of SLE risk factors vary substantially among races. We will determine the gene copy number variations of total C4, C4A and C4B, long C4 and short C4 and examine their roles on genetic susceptibility to SLE in the context of linkage disequilibrium with HLA-DRB1 variants in three different racial groups, in adult onset and childhood onset patients; (2) To investigate how genotypic diversities of complement modulate complement phenotypic profiles and SLE disease features. We will investigate the correlations between complement genetic variants and their serum protein levels, relationships of processed activation products with hematologic and cardiovascular diseases, plus their interactions with type I interferon stimulated gene expression. A group of SLE patients will be selected for in-depth analyses for all complement genes through exome sequencing; and (3) To characterize changing complement phenotypes during periods leading from LN disease quiescence to disease flare, and to disease remission. Longitudinal phenotype measurements will include complement proteins (activators, regulators, receptors), activation fragments, and complement autoantibodies in the circulation and in the urine. The temporal relationship between changing complement phenotypes and LN flare onset/remission will be analyzed, and the influences of genetic variation in complement on these relationships will be established. This proposal will yield important knowledge on how variants of the complement system contribute to genetic predisposition and disease progression of SLE and LN. It will facilitate precision diagnosis and effective therapies of this female dominant chronic disease.