CTLA4 gene polymorphisms and soluble CTLA4 protein in Behcet’s disease

Abstract

Cytotoxic T lymphocyte antigen 4 (CTLA4; CD152) is a costimulatory molecule expressed on activated T cells that plays a key inhibitory role during T lymphocyte activation. The gene encoding for CTLA4 has been suggested as a candidate for conferring susceptibility to autoinflammatory diseases. We investigated the polymorphisms of the CTLA4 gene [promoter region (21722 T/C, 21661 A/G and 2318 C/T) and exon 1 (149 G/A)] and the differences of serum soluble sCTLA4 levels in 285 patients with Behcet's disease (BD) and 287 controls. The frequency of the CTLA4 21661 GG genotype was significantly higher in BD patients than in controls [P ¼ 0.019, odds ratio (OR) ¼ 5.2, 95% confidence interval (CI) ¼ 1. 13-23.86]. Also, the genotype frequency for CTLA4 21722 TC was significantly higher (P ¼ 0.014, OR ¼ 1.8, 95% CI ¼ 1.13-2.99), while CTLA4 21722 CC was significantly lower (P ¼ 0.018, OR ¼ 0.4, 95% CI ¼ 0.20 -0.87) in BD patients with ocular lesions compared with patients without this symptom. Serum sCTLA4 levels in BD patients were significantly lower, especially in BD patients with the CTLA4 149 G allele, than those in healthy controls (P < 0.05). Although our understanding of the role of the CTLA4 gene and its protein product in BD is incomplete, these results suggest that single nucleotide polymorphisms of the promoter and exon regions in the CTLA4 gene are candidates that predispose to BD and that sCTLA4 may be related to the immunological abnormalities and disease expressions associated with BD.

The Role of CTLA-4 Exon-1 49 A/G Polymorphism and Soluble CTLA-4 Protein Level in Egyptian Patients with Behçet's Disease

“…Meanwhile, our results disagree with the meta-analysis study of Lee and Song et al [21] and Zhang et al [22] as well as with multiple previous studies conducted on different ethnic populations like Chinese [23], Korean [24], and UK and Middle East populations [25]. This inconsistency may be due to the racial/ethnic differences in allele frequencies, population differences, environmental factors (microbial loading), and limited number of study participants or due to the wide differences of the clinical manifestations in BD patients.…”

“…In the present study, there were significantly decreased sCTLA-4 concentrations in BD patients in comparison to the controls being in concordance with Park et al [24] who found that the mean serum sCTLA-4 concentration in BD patients was significantly lower than that in controls, concluding that decreased level of sCTLA-4 might result in enhanced activation and proliferation of T cells, which could lead to the development of chronic inflammatory diseases like BD [24]. However, this result is partially contradictory to that of Sim et al [27] who reported a reduced expression of CTLA-4 in CD4+ T cells in patients with active Behçet's disease, with no difference in the production of sCTLA-4, leading to subsequent increase in Th1 cell proliferation and a tendency to the development of Behçet's disease.…”

“…This is in accordance with results of Sallakci et al [3] but in opposition to the results found in other previous studies [19, 20, 24, 25], where there was no significant association between the studied polymorphism and clinical manifestations of BD. We thought that discrepancy between our results and those of Gunesacar et al [20] may be due to negative results of A allele and A/A genotype which they reported while being elevated in our group of patients.…”

CTLA4 −1661A/G and 3′UTR long repeat polymorphisms are associated with ulcerative colitis and influence CTLA4 mRNA and protein expression

“…Our data have shown lower levels of flCTLA4 and sCTLA4 mRNA in biopsies of inflamed colonic tissue obtained from UC patients. Our findings are similar with those of several recent reports, which showed that the flCTLA4 protein and sCTLA4 mRNA levels were decreased in myasthenia gravis patients, 29,41 and sCTLA4 protein levels were decreased in individuals with diabetes, Behcet's disease and abdominal aortic aneurysm; [42][43][44] however, Wong et al 45 have shown increased levels of the sCTLA4 protein in systemic lupus erythematosus. Possible mechanisms producing different levels of sCTLA4 levels in autoimmune diseases could be: (1) stimulation of T lymphocytes results in significantly decreased expression of sCTLA4, 15 (2) there are cell types other than T cells expressing CTLA4, for example, skeletal muscle cells and granulocytes, 46,47 which also may express sCTLA4 and secrete into serum, (3) protein levels are affected not only by mRNA levels; and (4) differential sCTLA4 levels may correlate with different CTLA4 genotypes, disease types and immunological states.…”

CTLA-4 +49 A/G, -318 C/T, -1661 A/G, CT60 A/G Gene Polymorphisms in Patients with Pemphigus in Turkey

“…Yousefipour et al (20) detected that this polymorphism was associated with susceptibility to multiple sclerosis in Iranian population. Park et al (21) found this polymorphism to be significantly higher in patients with Behçet's disease compared to healthy controls.…”