The Role of MBP Gene Polymorphism in Multiple Sclerosis Relapses

Multiple Sclerosis (MS) is a complex immune-mediated neurodegenerative disease that targets the central nervous system, leading to demyelination and neurological impairment. While its etiology remains elusive, genetic predisposition and environmental factors are known contributors. Myelin basic protein (MBP) is a significant component of the myelin sheath, and its involvement in the immune response has made it a potential target in MS pathogenesis. Recent research has delved into the association between genetic polymorphisms in the MBP gene and MS progression. Specifically, the rs12959006 single nucleotide polymorphism (SNP) within the MBP gene has been linked to disease severity, including relapse frequency, especially in male patients.

Materials and Methods
This study analyzed 291 confirmed MS patients, collecting clinical data from the first five years of their disease. MBP polymorphism rs12959006 was genotyped, and its association with MS relapse rate and serology for Herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) was examined. Lymphocyte activation was also studied through CD69 expression, exploring potential correlations with the SNP genotype and patient sex.

Key Findings
The rs12959006 polymorphism was significantly associated with a higher number of relapses, but this effect was predominantly observed in male patients. Male carriers of the T allele (rs12959006∗TT) showed a more substantial increase in relapse rates compared to females. Furthermore, higher antibody titers for anti-HHV6 IgG were correlated with increased relapses, suggesting a viral influence on MS disease course. In vitro activation analysis showed a trend toward lower CD69 expression in male patients carrying the rs12959006∗T allele, which could indicate a defective immune response control, potentially exacerbating MS progression in this subgroup.

Discussion
This study emphasizes the role of genetic factors in MS progression, particularly highlighting sex-specific effects. While MS is more prevalent in females, males often experience more severe disease outcomes. The rs12959006 SNP within the MBP gene may contribute to these differences, potentially offering a genetic marker for relapse risk in male patients. The interaction between viral infections like HHV-6 and the MBP gene further supports the hypothesis that both genetic and environmental factors drive MS pathogenesis.

The study also adds to the growing body of evidence supporting the concept of molecular mimicry, where viral proteins like those of HHV-6 may resemble autoantigens such as MBP, triggering an autoimmune response in genetically predisposed individuals. The identification of MBP-specific autoreactive T-cells in MS patients strengthens this connection.

Conclusion
The study presents strong evidence for the association of the rs12959006 SNP with a higher relapse rate in male MS patients, underlining the need for sex-specific analyses in genetic studies of MS. Additionally, the findings suggest that viral factors such as HHV-6 may play a critical role in exacerbating disease activity, possibly through mechanisms of molecular mimicry. Future research should focus on replicating these results in larger, diverse cohorts and investigating the clinical utility of rs12959006 as a predictive marker for MS relapse, particularly in male patients.

References:
Espino-Paisán, L., Agudo-Jiménez, T., Rosales-Martínez, I., López-Cotarelo, P., García-Martínez, M. Á., Domínguez-Mozo, M. I., ... & Álvarez-Lafuente, R. (2020). A polymorphism within the MBP gene is associated with a higher relapse number in male patients of multiple sclerosis. Frontiers in immunology, 11, 771.