A CR1 polymorphism associated with constitutive erythrocyte CR1 levels affects binding to C4b but not C3b
A CR1 polymorphism associated with constitutive erythrocyte CR1 levels affects binding to C4b but not C3b
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DOI：
10.1046/j.1365-2567.2003.01579.x
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发表时间：
2003-04-01
期刊：
影响因子：
6.4
通讯作者：
Nagaraja, HN
中科院分区：
文献类型：
--
作者：
Birmingham, DJ;Chen, W;Nagaraja, HN
红细胞1型补体受体（E-CR 1）介导补体调理免疫复合物（IC）的红细胞结合，并有助于防止循环IC的随机沉积。两个连锁的CR 1多态性发生在结合结构域，在I643 T和Q981 H。在高加索人中，变异等位基因（643 T，981 H）与低组成性E-CR 1表达水平相关。本研究旨在确定这些多态性是否影响配体结合，如果是，则代表自身免疫性IC疾病系统性红斑狼疮（SLE）的风险因素。在比较相对配体结合差异的ELISA中，来自变体残基纯合个体（643 TT/981 HH）的E-CR 1比纯合野生型E-CR 1表现出更大的C4 b结合，但不表现出C3 b结合。单结合结构域CR 1构建体的分析表明，981 H残基赋予这种增强的C4 b结合。白人对照组（0.170，n = 100）和SLE患者组（0.130，n = 150，P = 0.133），非裔美国人对照组（0.169，n = 71）和SLE患者组（0.157，n = 67）的981 H等位基因频率无差异。在一个评估CR 1大小的个体亚组中，从该分析中排除那些表达至少一个B等位基因的个体，揭示了高加索对照中981 H等位基因过度表达的趋势（频率0.231，n = 26）与SLE患者（0.139，n = 83，P = 0.089），但非洲裔美国人对照组（0.188，n = 24）和SLE患者（0.191，n = 34）之间也无差异。这些数据表明，981 H残基通过增强C4 b结合补偿了高加索人中E-CR 1的低组成型表达。这可能有助于预防SLE。
The erythrocyte type one complement receptor (E-CR1) mediates erythrocyte binding of complement-opsonized immune complexes (IC), and helps protect against random deposition of circulating IC. Two linked CR1 polymorphisms occur in binding domains, at I643T and Q981H. In Caucasians, the variant alleles (643T, 981H) are associated with low constitutive E-CR1 expression levels. This study was conducted to determine if these polymorphisms affect ligand binding, and if so, represent risk factors for the autoimmune IC disease, systemic lupus erythematosus (SLE). In an ELISA comparing relative ligand binding differences, E-CR1 from individuals homozygous for the variant residues (643TT/981HH) exhibited greater binding to C4b, but not C3b, than homozygous wild-type E-CR1. Analysis of single-binding domain CR1 constructs demonstrated that the 981H residue imparted this enhanced C4b binding. No differences were observed in the 981H allele frequency between Caucasian controls (0.170, n = 100) and SLE patients (0.130, n = 150, P = 0.133), or between African American controls (0.169, n = 71) and SLE patients (0.157, n = 67). In a subset of individuals assessed for CR1 size, excluding from this analysis those expressing at least one B allele revealed a trend for over-representation of the 981H allele in Caucasian controls (0.231 frequency, n = 26) versus SLE patients (0.139, n = 83, P = 0.089), but again no difference between African American controls (0.188, n = 24) and SLE patients (0.191, n = 34). These data suggest that the 981H residue compensates for low constitutive expression of E-CR1 in Caucasians by enhancing C4b binding. This may contribute protection against SLE.