CTLA-4 Gene A/G～(49) Polymorphism Associated With SLE And RA And Expression Of Soluble CTLA-4 In Patients With SLE And With RA

OBJECTIVE: Systemic lupus erytheraatosus (SLE) and rheumatoid arthritis(RA) are common autoimmune diseases. Genetic susceptibilities to SLE and to RA are conferred not only by various genes within the major histocompatibility complex (MHC) region, but also by several other non-MHC linked genes. The costimulatory interactions of the B7 family molecules CD80 and CD86 on antigen-presenting cells with their T-cell counter-receptors CTLA-4 modulate T lymphocyte-mediated immune responses in a reciprocal manner. CTLA-4 , as a negatively signalling molecule , is involved in establishing and maintaining of peripheral T cell tolerance, which controls T cell activation and reactivity. Its attenuating action helps to prevent an inappropriate initiation of T cell responses to self antigens and to terminate ongoing T cell responses. CTLA-4 gene polymorphism was associated with several kinds of human autoimmune diseases, suggesting that CTLA-4 gene is probably a general susceptibility gene to SLE and RA. The present study was conducted in Chinese to determine whether there is any association of the CTLA-4 gene polymorphism with the development of SLE and RA.We investigated the soluble (s) forms of the T-cell costimulatory molecules CTLA-4 in plasma of patients with systemic lupus erythematosus (SLE) and withrheumatoid arthritis(RA), autoimmune diseases arising from T-lymphocyte dysregulation.METHODS:Using the nested polymerase chain reaction—restriction fragment length polymorphism method with Bbv I digestion, we assessed an exon 1 transition dimorphism (49 A/G) of the CTLA-4 gene in 38 SLE patients and 50 RA patients and in 60 healthy controls.Concentration of sCTLA-4 in plasma of 38 patients with SLE and 50 patients with RA were measured by a sensitive enzyme-linked immunosorbent assay.RESULTS:The distribution of CTLA-4 exon 1 GG-genotypes in the SLE patients and in RA patients were significantly different from that in the controls (chi 2 = 6. 17, p < 0. 01;chi 2 = 8. 78, p < 0. 01), respectively. The distribution of CTLA-4 exon 1 AA-genotypes in the SLE patients and in RA patients were not significantly different from that in the controls(X2=l. 31, P>0. 05;X2=2. 69, P>0.05). The distribution of CTLA-4 exon 1 AG-genotypes in the SLE patients and in RA patients were not significantly different from that in the controls(X2=2. 54, P>0. 05;X2=l. 40, P>0. 05).The frequencies of G49allele in exon 1 CTLA-4 gene in the SLE patients and in RA patients were significantly different from that in the controls (chi 2 = 6.89, p < 0. 01;chi 2 = 8.73, p < 0.01), respectively. The frequencies of G^allele in exon 1 CTLA-4 gene in the SLE patients and in RA patients were higher than the controls.There were no difference of The frequencies of G'9 allele in exon 1 CTLA-4 gene between SLE patients and RA patients.The concentrations of sCTLA-4 in plasma of SLE patients were significantly higher than that in control subjects, 19.61 ± 10.64ng/ml vs 5.08 + 3.89 (P<0.01), respectively. Plasma sCTLA-4 concentration in SLE patients correlated significantly with SLEDAI score (r = 0. 60, P<0.01). however, Theconcentrations of sCTLA-4 in plasma of RA patients were similar with concentrations in control subjects, 6.29 ± 5. Olng/ml vs 5.08 ± 3.89 (P>0.05) , respectively.ConclusionThere were statistically significant differences in CTLA-4 exon 1 (+49) polymorphisms between SLE patients and RA patients with normal controls.The concentrations of sCTLA-4 were high in patients with SLE and related to SLEDAI. Its concentrations in patients with RA were similar with that in control subjects. Plasma sCTLA concentration could potentially serve as a surrogate marker of SLE disease activity, The aberrant production of soluble T-cell costimulatory molecules maybe important in the immunopathogenesis of SLE.