Multiple Sclerosis Risk Variants Regulate Gene Expression in Immune Cells

Multiple Sclerosis (MS) is a complex autoimmune disease affecting the central nervous system (CNS), characterized by demyelination and axonal injury. With a strong genetic component, MS risk is driven by the interplay between environmental factors and genetic predisposition. Recent genome-wide association studies (GWAS) have identified over 200 single nucleotide polymorphisms (SNPs) associated with MS, although their precise functional roles remain elusive. These variants are thought to influence gene expression, particularly within immune cells, which play a central role in MS pathogenesis.

A study by Gresle et al. (2020) explored how MS risk variants regulate gene expression in various immune cells, such as monocytes, natural killer (NK) cells, B cells, CD4, and CD8 T cells. The researchers performed a detailed analysis of expression quantitative trait loci (eQTL) using purified immune cells from 73 untreated MS patients and 97 healthy controls. Their goal was to map the regulatory effects of these variants on gene expression and to determine whether the expression patterns differ between MS patients and controls.

Key Findings
The study identified 129 genes whose expression is significantly associated with MS risk variants across different immune cell types. These genes are regulated by MS risk SNPs in a cell-type-specific manner, meaning that certain genes are more strongly affected in specific immune cells. Interestingly, for some variants, the direction of gene expression regulation differed between MS cases and controls. For example, the rs703842 SNP was linked to decreased expression of the METTL21B gene in CD8 T cells, with a more pronounced effect in MS patients than in controls.

Furthermore, the study highlighted the rs2256814 variant, which affected the expression of the MYT1 gene in CD4 T cells, and rs12087340, which regulated the expression of RF00136 in monocytes. These variants exhibited opposing effects in MS cases compared to controls, suggesting that the disease status alters the regulatory landscape of these genes.

Gene Expression in Immune Cells:
The study also uncovered novel insights into how MS risk variants influence immune cell behavior. Both innate (monocytes, NK cells) and adaptive immune cells (B cells, CD4, and CD8 T cells) showed differential gene expression linked to MS-associated SNPs. For example, the RGS1 gene, regulated by rs2760524, exhibited different expression levels in monocytes between MS patients and controls. Such findings underscore the involvement of both arms of the immune system in MS susceptibility.

The differential regulation of genes like METTL21B and MYT1 in MS patients points to potential mechanisms by which genetic risk factors contribute to immune system dysfunction in MS. For instance, MYT1 is a transcription factor involved in neural development and may influence remyelination processes in MS, highlighting the intersection between immune regulation and CNS pathology.

Disease-Related Gene Expression Changes:
In addition to exploring the genetic regulation of gene expression, the researchers compared gene expression levels between MS patients and controls without considering SNPs. They found that the SOCS1 gene, involved in regulating immune responses, was more highly expressed in B cells of MS patients. Additionally, two other genes—SESN1 in B cells and FKBP5 in CD4 T cells—also showed significantly elevated expression in MS patients.

Implications for MS Pathogenesis
The findings from this study provide a clearer understanding of how genetic variants linked to MS regulate gene expression in different immune cell types. These regulatory mechanisms are likely crucial for shaping the immune environment that contributes to MS onset and progression. Importantly, the study's approach of examining both healthy controls and MS patients provides insights into how these regulatory effects differ depending on disease status, pointing to context-dependent gene regulation as a key feature of MS pathogenesis.

Conclusion
The research by Gresle et al. advances our understanding of the genetic underpinnings of MS by linking risk variants to gene expression changes in immune cells. These findings suggest that genetic regulation of immune cell function is a critical factor in MS susceptibility, with both innate and adaptive immune cells playing a role. Future research should explore how these regulatory variants contribute to immune cell dysfunction during different stages of MS and whether they can be targeted therapeutically.

References:
Gresle, M. M., Jordan, M. A., Stankovich, J., Spelman, T., Johnson, L. J., Laverick, L., ... & Butzkueven, H. (2020). Multiple sclerosis risk variants regulate gene expression in innate and adaptive immune cells. Life science alliance, 3(7).