HLA-DR15 In Multiple Sclerosis

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:

1. In addition to DR15, DR17 is positively associated with susceptibility to MS

2. None of the HLA-DRB1 alleles influences course or outcome in MS

3. Carriers of DR15 are prone to MS development at an earlier age than noncarriers

4. 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

Background
Individuals with high levels of AntiBodies to the Epstein-Barr Virus Nuclear Antigen 1 (EBNA-1) have an increased risk of developing Multiple Sclerosis (MS), but this association could be confounded by genetic susceptibility.

Methods
We conducted a nested case-control study including 148 women with MS (18 with blood collected before disease onset) and 296 age-matched healthy women.

To determine whether the Human Leukocyte Antigen (HLA) DRB1*1501 allele (DR15) and Anti-Epstein-Barr Virus (anti-EBV) AntiBody Titers are independent risk factors for MS.

Results
The association between Anti-EBNA-1 AntiBody Titers and MS risk was not affected by adjustment for DR15 and was similar in DR15-positive and DR15-negative women.

The relative risk of MS among DR15-positive women with elevated (>1:320) Anti-EBNA-1 Titers was ninefold higher than that of DR15-negative women with low (< 1:80) Anti-EBNA-1 Titers.

Conclusions
Anti-Epstein-Barr Virus Nuclear Antigen 1 (Anti-EBNA-1) AntiBody Titers are a risk factor for Multiple Sclerosis (MS), independently from the DR15 allele.

Carriers of the DR15 allele with elevated Anti-EBNA-1 AntiBody Titers may have a markedly increased risk of MS.

The risk for development of Multiple Sclerosis has been associated with Human Leukocyte Antigen-DRB1*1501-DQB1*0602 (HLA-DR15) genotype, low infant sibling exposure, and high Epstein-Barr nuclear antigen IgG levels.

In a population-based case-control study (Tasmania, Australia), we found that the combined effect of HLA-DR15 positivity and low infant sibling exposure on Multiple Sclerosis:

Odds ratio, 7.88; 95% confidence interval, 3.43-18.11 was 3.9-fold greater than expected (test for interaction, p = 0.019).

This interaction was observed irrespective of Epstein-Barr nuclear antigen IgG levels.

This suggests that immune mechanisms involving HLA Class II molecules are susceptible to modulation in early life.

Ann Neurol 2009;66:261-265 ANN NEUROL 2010;67:259-263.