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.

Multiple sclerosis (MS) is a presumed autoimmune disease of the central nervous system, shown to be associated with the HLA class II haplotype DRB1*15,DQB1*06. Carrying the HLA class II haplotype DRB1*15,DQB1*06 increases the risk of MS by 3.6. By adopting a polymerase chain reaction (PCR)-based typing technique for HLA class I and class II genes, 200 Swedish MS patients and 210 Swedish healthy controls were analysed for their HLA alleles. Additional HLA class I alleles that increase and decrease the genetic susceptibility to MS were identified. The HLA-A*0301 allele increases the risk of MS (odds ratio=2.1) independently of DRB1*15,DQB1*06. HLA-A*0201 decreases the overall risk (odds ratio= 0.52) and the presence of A*0201 reduces the risk of MS for DRB1*15,DQB1*06 carriers from 3.6 to 1.5. Our findings are the first to identify a major modulating effect of HLA class I alleles on the susceptibility to a human autoimmune disease; a phenomenon that has previously only been observed in animal models.

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To date, more than a dozen studies have investigated the role of HLA genes in determining clinical course and disease severity in multiple sclerosis (MS); in each of these studies, however, patient sample size has been small, and no consistent pattern has emerged from the results. For the present study, we determined HLA class II genotypes and catalogued clinical and demographic data for a total of 948 patients, making our data set the largest ever used to investigate HLA genes in MS. Our goals were both to investigate the impact of HLA-DRB1 alleles on clinical course and disease severity in MS and to compare the frequencies of the established susceptibility allele DR15 in various clinicodemographic subgroups of MS patients. We found that, in addition to DR15, DR17 is positively associated with susceptibility to MS; that none of the HLA-DRB1 alleles influences course or outcome in MS; that carriers of DR15 are prone to MS development at an earlier age than noncarriers; and that differences in DR15 positivity rates, after stratification for diagnostic category and examination results, seem to reflect a gradient of phenocopy contamination, with rates increasing in proportion to the degree of clinical or paraclinical verification of the MS diagnosis.