CTLA-4 gene expression is influenced by promoter and exon 1 polymorphisms

• Published in: Genes and immunity Vol. 2; no. 3; pp. 145 - 152
• Main Authors: Ligers, A, Teleshova, N, Masterman, T, Huang, W X, Hillert, J
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.05.2001
• Subjects: Abatacept; Adenine; Analysis of Variance; Antigens; Antigens, CD; Antigens, Differentiation - biosynthesis; Antigens, Differentiation - genetics; Autoimmune diseases; CD3 antigen; CD4 antigen; CD8 antigen; Cell surface; CTLA-4 Antigen; CTLA-4 protein; CTLA4 gene; Disease; exon 1; Exons; Flow cytometry; Gene Expression; Genotype; Genotyping; Haplotypes; Homeostasis; Humans; Immunoconjugates; Immunosuppressive Agents; Leukocytes (mononuclear); Lymphocytes; Lymphocytes T; Medicin och hälsovetenskap; Multiple sclerosis; Multiple Sclerosis - genetics; Myasthenia; Myasthenia gravis; Myasthenia Gravis - genetics; Neuromuscular junctions; Patients; Peripheral blood mononuclear cells; Polymorphism, Genetic; Promoter Regions, Genetic; Protein expression; Proteins; Risk assessment; Thymine; Sweden
• ISSN: 1466-4879; 1476-5470
• DOI: 10.1038/sj.gene.6363752

CTLA-4, expressed mainly on activated T cells, helps maintain, through its inhibitory function, immune-system homeostasis. Polymorphisms in the CTLA-4 gene (CTLA4) are known to be important in several autoimmune diseases, including multiple sclerosis (MS). Here, we have performed genotyping for CTLA4 polymorphisms, and investigated expression by peripheral blood mononuclear cells of CTLA-4 mRNA and protein, in patients with MS and myasthenia gravis and in healthy controls. Expression levels for mRNA and protein were similar in the patient and control groups; however, there was a clear relationship between genotype and CTLA-4 expression. Specifically, individuals carrying thymine at position -318 of the CTLA4 promoter (T(-318)) and homozygous for adenine at position 49 in exon 1 showed significantly increased expression both of cell-surface CTLA-4 after cellular stimulation and of CTLA-4 mRNA in non-stimulated cells. The association was seen most clearly for unsorted CD3(+) cells and was absent in the CD8(+) subset. The T(-318) allele has been shown to be negatively associated with susceptibility to MS in an earlier study by our group. Thus, we propose that the susceptibility-influencing role of CTLA4 in MS may be related to genotypically conditioned promoter function, whereby high gene expression may decrease the risk of disease.