Genetic and Familial Influence on EBNA-1 Immune Response in Multiple Sclerosis

Multiple sclerosis (MS) is a complex neuroinflammatory disorder, strongly influenced by both genetic predisposition and environmental factors. Epstein-Barr Virus (EBV) infection, particularly the immune response against the Epstein-Barr nuclear antigen 1 (EBNA-1), is well-established as a significant environmental risk factor in MS. In their 2020 study, Mescheriakova et al. delve into the genetic contribution to EBNA-1 IgG levels by investigating multiplex MS families, unaffected siblings, and unrelated healthy spouses. The study reveals important insights into the genetic factors underlying EBNA-1 immune responses and their relationship to MS susceptibility.

Study Objectives and Hypothesis
The primary objective of the study was to determine whether there is a genetic influence on the humoral immune response to EBNA-1 in families with MS. The authors hypothesized that since patients with MS share genetic risk factors with their unaffected siblings, these siblings might exhibit higher EBNA-1 IgG titers compared to unrelated controls. They aimed to explore this hypothesis by measuring EBNA-1 and varicella zoster virus (VZV) IgG levels in patients, siblings, and healthy spouses, while investigating the role of specific genetic loci, particularly the MS-associated HLA-DRB1*1501 and HLA-A*02 alleles.

Methods: Participants and Serological Testing
The study included 301 patients with MS, 198 unaffected siblings, and 174 unrelated healthy spouses, making it one of the larger studies exploring familial MS and EBV. Serum EBNA-1 and VZV IgG levels were measured using chemiluminescent assays, and genotyping was conducted to assess the role of HLA-DRB11501 and HLA-A02 loci. Notably, EBNA-1 titers were dichotomized as high or low based on the 75th percentile of IgG levels in spouses, allowing for comparison across groups​.

Key Findings: A Genetic Gradient in EBNA-1 IgG Titers
The study found a significant gradient in EBNA-1 IgG titers, with the highest levels observed in patients with MS, intermediate levels in their unaffected siblings, and the lowest levels in unrelated spouses. This gradient suggests a genetic contribution to the immune response against EBNA-1, as siblings of patients with MS, who share genetic risk factors, exhibited higher EBNA-1 IgG titers than spouses​.

The Role of HLA-DRB1*1501
HLA-DRB11501 is the strongest genetic risk factor associated with MS, and its contribution to elevated EBNA-1 IgG titers was confirmed in this study. The study found that both patients with MS and their siblings carrying HLA-DRB11501 had higher EBNA-1 IgG titers compared to those without the allele. Interestingly, even after accounting for HLA-DRB1*1501 carriership, the gradient in EBNA-1 IgG titers remained, particularly in younger patients and siblings, indicating that other genetic factors may also play a role​.

No Association with HLA-A*02
In contrast to HLA-DRB11501, the study did not find any significant association between HLA-A02 and EBNA-1 IgG titers. This is consistent with prior studies that have shown that HLA-A*02 has a protective effect against MS but does not appear to influence the immune response to EBNA-1​.

Age-Related Differences in EBNA-1 Titers
One of the intriguing findings of the study was the age-related difference in EBNA-1 IgG titers. Younger patients with MS and their siblings had significantly higher EBNA-1 IgG levels compared to older participants. This could be due to the phenomenon of immunosenescence, where the immune system's ability to mount strong responses diminishes with age. The study suggests that genetic factors, particularly HLA-DRB1*1501, may be crucial for sustaining a strong immune response to EBV in older individuals​.

Implications and Future Directions
The findings from Mescheriakova et al.'s study underscore the importance of genetic factors in shaping the immune response to EBNA-1 in MS. While HLA-DRB1*1501 plays a key role, other genetic contributors remain to be identified. Future research exploring non-HLA MS risk loci and their impact on EBNA-1 IgG titers could further illuminate the complex interplay between genetics and environmental factors in MS. Moreover, the study highlights the need to consider age when investigating immune responses, as younger individuals may exhibit stronger humoral responses compared to their older counterparts.

Conclusion
Mescheriakova et al.'s 2020 study provides compelling evidence that EBNA-1 IgG titers are influenced by genetic factors in MS, with a clear gradient observed between patients, their siblings, and unrelated spouses. The study adds to the growing body of literature highlighting the genetic basis of immune responses in MS, particularly in relation to EBV, one of the most significant environmental risk factors for the disease. Future studies focusing on additional genetic risk loci and the long-term immune response to EBV could offer deeper insights into MS pathogenesis and potential therapeutic targets.

References:
Mescheriakova, J. Y., van Nierop, G. P., van der Eijk, A. A., Kreft, K. L., & Hintzen, R. Q. (2020). EBNA-1 titer gradient in families with multiple sclerosis indicates a genetic contribution. Neurology: Neuroimmunology & Neuroinflammation, 7(6), e872.