The intricate role of complement component C4 in human systemic lupus erythematosus.
The intricate role of complement component C4 in human systemic lupus erythematosus.
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补体成分 C4 在人类系统性红斑狼疮中的复杂作用。
DOI：
10.1159/000075689
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Yu,CYung
中科院分区：
文献类型：
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作者：
Yang,Yan;Chung,ErwinK;Zhou,Bi;Lhotta,Karl;Hebert,LeeA;Birmingham,DanielJ;Rovin,BradH;Yu,CYung
大约50年前，人们观察到，血清补体活性低或补体C4蛋白浓度低与系统性红斑狼疮(SLE)的疾病活动是一致的。补体成分C4a和C4b的完全缺乏，尽管在人类群体中很少见，但在不同的人类白细胞抗原单倍型和种族背景下，是SLE或狼疮样疾病最强烈的遗传风险因素之一。然而，C4a(C4AQ0)或C4b(C4BQ0)杂合性或部分缺失是否是SLE的易感因素一直是一个非常有争议的话题。在这篇综述中，我们批判性地分析了过去关于人类SLE中C4a或C4b缺乏的流行病学研究。超过35项不同研究的累积结果显示，来自几乎所有被调查的民族或种族的40%-60%的SLE患者存在C4a杂合和纯合缺陷，包括北欧和中欧人、盎格鲁-撒克逊人、美国高加索人、非裔美国人、亚裔中国人、韩国人和日本人。此外，法国系统性红斑狼疮患者和对照人群的C4AQ0频率相对较低，但患者和对照人群之间的差异具有统计学意义。不同民族SLE患者发生C4AQ0的相对危险度在2.3~5.3之间。在高加索人和非洲人SLE患者中，C4AQ0的两个主要原因是(1)在主要组织相容性复合体中存在带有单个短C4b基因的单S RCCX(RP-C4-CyP21-Tnx)模块；(2)突变C4a基因外显子29的第1213密码子序列中插入了2个碱基。东方系统性红斑狼疮患者C4AQ0基因外显子29缺失或罕见单S结构和2-碱基插入。C4AQ0与多种人类白细胞抗原单倍型和人种间的高度相关性，以及导致SLE患者C4a蛋白缺乏的不同机制的存在，提示C4a蛋白的缺乏或低表达水平本身是SLE疾病易感性的主要危险因素。另一方面，西班牙人、墨西哥人、澳大利亚原住民SLE
It was observed about 50 years ago that low serum complement activity or low protein concentrations of complement C4 concurred with disease activities of systemic lupus erythematosus (SLE). Complete deficiencies of complement components C4A and C4B, albeit rare in human populations, are among the strongest genetic risk factors for SLE or lupus-like disease, across HLA haplotypes and racial backgrounds. However, whether heterozygous or partial deficiency of C4A (C4AQ0) or C4B (C4BQ0) is a predisposing factor for SLE has been a highly controversial topic. In this review we critically analyzed past epidemiologic studies on deficiency of C4A or C4B in human SLE. Cumulative results from more than 35 different studies revealed that heterozygous and homozygous deficiencies of C4A were present in 40–60% of SLE patients from almost all ethnic groups or races investigated, which included northern and central Europeans, Anglo-Saxons, Caucasians in the US, African Americans, Asian Chinese, Koreans and Japanese. In addition, French SLE and control populations had relatively low frequencies of C4AQ0, but the difference between the patient and control groups was statistically significant. The relative risk of C4AQ0 in SLE varied between 2.3 and 5.3 among different ethnic groups. In Caucasian and African SLE patients, the two major causes for C4AQ0 are (1) the presence of a mono-S RCCX (RP-C4-CYP21-TNX) module with a single, short C4B gene in the major histocompatibility complex; and (2) a 2-bp insertion into the sequence for codon 1213 at exon 29 of the mutant C4A gene. Both mono-S structures and 2-bp insertion in exon 29 are absent or extremely rare in the C4AQ0 of Oriental SLE patients. The highly significant association of C4AQ0 with SLE across multiple HLA haplotypes and ethnic groups, and the presence of different mechanisms leading to a C4A protein deficiency among SLE patients suggested that deficiency or low expression level of C4A protein is a primary risk factor for SLE disease susceptibility per se. On the other hand, Spanish, Mexican, Australian Aborigine SLE