Immunogenetic studies of multiple sclerosis

Multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS). Several genetic factors are likely to be of importance for MS rather than one factor.

At least two signals are required for T cell activation - an antigen specific mediated by human leukocyte antigens (HLA)/T cell receptor and co-stimulation signal mediated by B7/CD28 and CTLA-4. By using a newly developed PCR-amplification with sequence-specific primers (PCR-SSP) we found that certain polymorphisms in CTLA-4 gene are associated with susceptibility to MS in sporadic patients and MS families.

Several reports have suggested that a number of autoimmune diseases are associated with the CTLA-4 G49 allele. We found that T-318 and A49 alleles are associated with increased expression of cell-surface CTLA-4 after cellular stimulation and increased mRNA levels in non-stimulated cells. These findings confirm earlier demonstrated results that cells homozygous for the A49 allele have a more profound inhibitory effect on the proliferation for T cells, regardless of the presence of an autoimmune disease. In conclusion, findings from our two studies on CTLA-4 support the hypothesis that increased CTLA-4 expression may decrease the risk of MS.

HLA-DR alleles is known to be associated with MS. Exceptions are MS patients in Sardinia and optico-spinal form of MS in Japan. This inconsistency could be explained by additional independent and modifying genetic factors within HLA region. We demonstrated that the association with HLA-DR15 in MS is modulated by the HLA class I alleles A2 which decreases and A3 which increases the risk of MS. These associations are independent of DR1 5 whereas a B7 association with MS is secondary to the DR15 association. In conclusion, interactions between several HLA complex genes influence the risk of MS.

Associations with HLA genes have been demonstrated in a number of autoimmune diseases. In a large set of sporadic MS patients we found that in addition to DR1 5, also DR1 7 is positively associated with MS and that carriers of DR1 5 allele is associated with lower age at onset in MS. None of the HLA-DRB1 alleles influences course or outcome in MS, cerebrospinal fluid or magnetic resonance imaging results. Identical DR15 phenotype frequencies were found for male and female patients, for patients with familial and sporadicMS. In conclusion, results demonstrate that DRB1*15 carriers may have a genetically determined early start of MS but do not support a previous hypothesis that patients with bout-onset and primary chronic progressive disease course have different HLA-DRB1 allele associations.

We analyzed the importance of the HLA-DR locus for MS susceptibility in 542 MS sibling pairs and their families by nonparametric methods. Significant evidence for linkage was obtained in families carrying the associated allele DRB1*15, but surprisingly also in families lacking the DRB1*15 allele. This indicates either the presence of second susceptibility locus within the HLA region, independent from DRB1 *15 or, alternatively, a single primary (non-DRB1) susceptibility locus in disequilibrium with the DRB1*15.

List of scientific papers

I. Ligers A, Xu C, Saarinen S, Hillert J, Olerup O (1999). "The CTLA-4 gene is associated with multiple sclerosis. " J Neuroimmunol 97(1-2): 182-90
https://pubmed.ncbi.nlm.nih.gov/10408973

II. Ligers A, Teleshova N, Masterman T, Huang WX, Hillert J (2001). "CTLA-4 gene expression is influenced by promoter and exon 1 polymorphisms. " Genes Immun 2(3): 145-52
https://pubmed.ncbi.nlm.nih.gov/11426323

III. Fogdell-Hahn A, Ligers A, Gronning M, Hillert J, Olerup O (2000). "Multiple sclerosis: a modifying influence of HLA class I genes in an HLA class II associated autoimmune disease. " Tissue Antigens 55(2): 140-8
https://pubmed.ncbi.nlm.nih.gov/10746785

IV. Masterman T, Ligers A, Olsson T, Andersson M, Olerup O, Hillert J (2000). "HLA-DR15 is associated with lower age at onset in multiple sclerosis" Ann Neurol 48(2): 211-9
https://pubmed.ncbi.nlm.nih.gov/10939572

V. Ligers A, Dyment DA, Willer CJ, Sadovnick AD, Ebers G, Risch N, Hillert J (2001). "Evidence of linkage with hla-dr in drb1*15-negative families with multiple sclerosis. " Am J Hum Genet 69(4): 900-3
https://pubmed.ncbi.nlm.nih.gov/11519010