title: Overexpression and secretion of the soluble CTLA-4 splice variant in various autoimmune diseases and in cases with overlapping autoimmunity.
abstract: OBJECTIVE
  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 (6.8 ng/mL, p=0.005), SLE (6.34 ng/mL, p=0.007), and OP (8.75 ng/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.
  
  
  CONCLUSIONS
  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.
authors: Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, Kuwait University, Kuwait, Kuwait. s.alfadhli@hsc.edu.kw
authors: Suad
authors: S
authors: AlFadhli
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D001327:Autoimmune Diseases / Q000150:complications* / Q000235:genetics* / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D060908:CTLA-4 Antigen / Q000235:genetics* / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007730:Kuwait; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012326:RNA Splicing; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D020413:3' Untranslated Regions; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human