Polymorphisms in the CD3Z Gene Influence TCRζ Expression in Systemic Lupus Erythematosus Patients and Healthy Controls

• Published in: The Journal of immunology (1950) 2008-01, Vol.180 (2), p.1060-1070
• Main Authors: Gorman, Claire L., Russell, Andrew I., Zhang, Zhuoli, Cunninghame Graham, Deborah, Cope, Andrew P., Vyse, Timothy J.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.180.2.1060

TCRζ (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 TCRζ-chain is down-regulated in many chronic infectious and inflammatory diseases, including systemic lupus erythematosus (SLE). It is unclear whether reduced TCRζ 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 TCRζ protein expression using a FACS-based expression index and documented considerable, but longitudinally stable, variation in TCRζ expression in healthy individuals. The variation in TCRζ 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 TCRζ 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 TCRζ expression has functional consequences manifested by systemic autoimmunity.