Gorman Claire L, Russell Andrew I, Zhang Zhuoli, Cunninghame Graham Deborah, Cope Andrew P, Vyse Timothy J
Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, UK.
J Immunol. 2008 Jan 15;180(2):1060-70. doi: 10.4049/jimmunol.180.2.1060.
TCRzeta (CD247) functions as an amplification module in the TCR signaling cascade and is essential for assembly and surface expression of the TCR/CD3 complex. The TCRzeta-chain is down-regulated in many chronic infectious and inflammatory diseases, including systemic lupus erythematosus (SLE). It is unclear whether reduced TCRzeta expression is a cause or a consequence of chronic inflammatory responses. We have addressed this question by adopting a combined genetic and functional approach. We analyzed TCRzeta protein expression using a FACS-based expression index and documented considerable, but longitudinally stable, variation in TCRzeta expression in healthy individuals. The variation in TCRzeta expression was associated with polymorphisms in the CD3Z 3'-untranslated region (UTR) in SLE patients and healthy controls. Detailed mapping of the 3'-UTR revealed that the minor alleles of two single nucleotide polymorphisms (SNPs) in strong disequilibrium (rs1052230 and rs1052231) were the causal variants associated with low TCRzeta expression (p=0.015). Using allelic imbalance analysis, the minor alleles of these 3'-UTR SNPs were associated with one-third of the level of mRNA compared with the major allele. A family-based association analysis showed that the haplotype carrying the low-expression variants predisposes to SLE (p=0.033). This suggests that a genetically determined reduction in TCRzeta expression has functional consequences manifested by systemic autoimmunity.
TCRζ（CD247）在TCR信号级联反应中作为一个放大模块发挥作用，对于TCR/CD3复合物的组装和表面表达至关重要。TCRζ链在许多慢性感染性和炎症性疾病中表达下调，包括系统性红斑狼疮（SLE）。目前尚不清楚TCRζ表达降低是慢性炎症反应的原因还是结果。我们采用了基因和功能相结合的方法来解决这个问题。我们使用基于流式细胞术的表达指数分析TCRζ蛋白表达，并记录了健康个体中TCRζ表达存在相当大但纵向稳定的差异。TCRζ表达的差异与SLE患者和健康对照者CD3Z 3'非翻译区（UTR）的多态性相关。对3'UTR的详细定位显示，处于强连锁不平衡状态的两个单核苷酸多态性（SNP）（rs1052230和rs1052231）的次要等位基因是与低TCRζ表达相关的因果变异（p=0.015）。使用等位基因不平衡分析，与主要等位基因相比，这些3'UTR SNP的次要等位基因与mRNA水平的三分之一相关。基于家系的关联分析表明，携带低表达变异的单倍型易患SLE（p=0.033）。这表明，基因决定的TCRζ表达降低具有由系统性自身免疫表现出的功能后果。
