Overexpression and Secretion of the Soluble CTLA-4 Splice Variant in Various Autoimmune Diseases and in Cases with Overlapping Autoimmunity

摘要

Aim: To explore the potential genetic association of CTLA-4 Exon1 + 49A/G and 3'UTR (AT)_n to susceptibility to systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and overlapping (OP) autoimmunity; affected with more than one autoimmune disease. Expression of two major CTLA-4 isoforms; full length (mCTLA-4) and soluble (sCTLA-4) were explored in all subjects. A total of 680-age/gender/ethnically matched Kuwaitis were recruited and polymerase chain reaction (PCR)-fragment analysis was employed for genotyping both markers. mCTLA-4 and sCTLA-4 mRNA expression were analyzed using quantitative real time-PCR. The enzyme-linked immunosorbent assay (ELISA) was used to screen sCTLA-4 in all subjects' sera. Results: Only two CTLA-4 3'UTR (AT)_n allelotypes; (AT)_(15) and (AT)_6 were detected. The heterozygous (AT)_(15/6) genotype confers protectivity rather than susceptibility to SLE (p = 0.01, odds ratio = 0.43, and confidence interval = 0.21-0.86). No significant association was observed between Exon 1 + 49A/G and any of the tested diseases. A consistently high serum sCTLA-4 level was observed in RA (6.8ng/mL, p = 0.005), SLE (6.34ng/mL, p = 0.007), and OP (8.75ng/mL, p = 0.012) compared to healthy control. A significant increase in the expression of sCTLA-4 mRNA was observed in OP (p = 0.05) and SLE (p = 0.047), while a significant increase in the expression of mCTLA-4 (p = 0.01) was observed only in OP. Conclusion: The present study is the first to report a statistically significant association between OP and serum sCTLA-4. The novelty of our study is the significance of CTLA-4 in the pathogenesis of OP besides SLE and RA.