The CTLA‐4 gene polymorphisms are associated with CTLA‐4 protein expression levels in multiple sclerosis patients and with susceptibility to disease

Abstract

Summary Cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) is an important molecule in the down‐regulation of T‐cell activation. A study was undertaken to evaluate the association of the CTLA‐4 gene polymorphisms −319C/T, +49A/G, (AT)n, CT60A/G and Jo31G/T with the levels of membrane CTLA‐4 (mCTLA‐4) and cytoplasmic CTLA‐4 (cCTLA‐4) in CD4+ T lymphocytes from patients with multiple sclerosis (MS) and with susceptibility to MS, and the course of the disease. It was found that the Jo31GG and CT60GG genotypes were associated with decreased mean fluorescence intensity (MFI) of total CTLA‐4 (mCTLA‐4 + cCTLA‐4) molecules in CD4+ T cells from both relapsing‐remitting (RR) and secondary progressive (SP) MS patients compared with others. Consequently, possessing the Jo31G allele and/or the CT60G allele were associated with susceptibility to MS. The percentages of cells expressing mCTLA‐4 and cCTLA‐4 in RR patients were higher in carriers of the alleles non‐predisposing to MS (namely CT60A and Jo31T), but the percentages of corresponding cells were unexpectedly significantly lower in SP patients than in RR patients. Increased risk of paresthesia and pyramidal signs as a first manifestation of disease, and earlier transition to the SP form in those patients, was also noted. It is hypothesized that the decreasing frequencies of cells expressing immunosuppressive mCTLA‐4 and cCTLA‐4 in carriers of alleles non‐predisposing to MS (i.e. CT60A and Jo31T) may lead to inadequate down‐regulation of ongoing T‐cell responses in these patients and, as a consequence, earlier progression of disease from the RR form to the SP form.

Influence of CTLA-4/CD28/ICOS gene polymorphisms on the susceptibility to cervical squamous cell carcinoma and stage of differentiation in the Polish population

“…The CT60 polymorphism has been shown to be associated with the mRNA level of soluble CTLA-4 [24]. Our recently published results indicate that this SNP is associated with the levels of membrane (mCTLA-4) and cytoplasmic (cCTLA-4) CTLA-4 in CD4 ϩ T lymphocytes from multiple sclerosis patients [25] and with the variation of serum soluble CTLA-4 level in Graves' disease patients [26]. The functional role of CD28c.17ϩ3TϾC and ICOSc.1554ϩ4GT (8 -15) is not clearly established.…”

“…The literature has demonstrated dysregulated expression and kinetics of the costimulatory molecules CD28 and CTLA-4 on peripheral nonmalignant T cells in malignancies [13][14][15][16]. Abnormal expression and/or dysfunction of these molecules may be caused by polymorphism of the corresponding genes [17][18][19][20][21][22][23][24][25][26]. The polymorphic markers that we chose have been reported to be associated with altered immune responses.…”

Alternative splicing in multiple sclerosis and other autoimmune diseases

“…Yet, reports on the association of CTLA-4 with MS have been inconsistent. [32][33][34][35][36][37][38][39][40][41] However confusing the association of CTLA-4 with MS, it is worth considering this gene as a potential contributor to the disease.…”

Is the Genetic Background of Co-Stimulatory CD28/CTLA-4 Pathway the Risk Factor for Prostate Cancer?

“…This SNP influences the ratio between mRNA for full length and soluble form of CTLA-4. The results from our previous study indicated that this SNP, together with Jo31, is associated with variations in the levels of membrane and cytoplasmic CTLA-4 in CD4+ T lymphocytes in multiple sclerosis patients [54], thus enhancing the activity of T-cells.…”