Early-Life Genetic Risk for Multiple Sclerosis Shapes T Cell Composition in Childhood
Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by inflammatory demyelination of the central nervous system, arising from a complex interplay between genetic susceptibility and environmental exposures. Genome-wide association studies have identified hundreds of common genetic variants contributing to MS risk, most of which implicate immune-related pathways. However, the biological mechanisms through which this polygenic risk manifests prior to clinical disease onset remain poorly understood. The study by de Mol and colleagues addresses this gap by examining whether genetic risk for MS is already associated with measurable alterations in T cell composition during early childhood, long before any neurological symptoms emerge.
A Population-Based Pediatric Study Design
The investigators leveraged data from the Generation R Study, a large, population-based birth cohort in the Netherlands, focusing on children aged six years. By combining high-quality genotype data with detailed flow-cytometric immunophenotyping, the authors analyzed both absolute T cell counts and specific CD4⁺ and CD8⁺ T cell subsets. Polygenic risk scores (PRSs) for MS were calculated using summary statistics from the International Multiple Sclerosis Genetics Consortium, enabling the researchers to capture the cumulative effect of numerous genetic variants rather than relying on single loci. This design provided a robust framework to investigate early immunological correlates of MS genetic risk in the general population.
Polygenic Risk Scores and T Cell Homeostasis
A central finding of the study was that higher MS polygenic risk was not associated with total T cell numbers but was significantly linked to the relative distribution of T cell lineages. Specifically, children with higher MS-PRSs exhibited reduced frequencies of CD8⁺ T cells, particularly within the naïve compartment. This reduction resulted in a markedly increased CD4⁺/CD8⁺ T cell ratio. Importantly, the CD4⁺/CD8⁺ ratio is a stable immunological parameter across childhood and adulthood, and its elevation has consistently been reported in patients with established MS. The observation that this imbalance is already detectable at six years of age suggests that genetic risk for MS exerts measurable effects on immune system architecture early in life.
Dominant Contribution of the Major Histocompatibility Complex
Further analyses revealed that the observed associations were largely driven by variants within the major histocompatibility complex (MHC) region. Two genome-wide significant MS risk variants, tagging HLA-DRB115:01 (MHC class II) and an HLA-B–related variant (MHC class I), showed opposing effects on CD4⁺ and CD8⁺ T cell numbers. The HLA-DRB115:01 risk allele was associated with higher CD4⁺ T cell counts, whereas the HLA-B–linked variant correlated with increased CD8⁺ T cell numbers and was relatively protective. These findings underscore the central role of antigen presentation pathways in shaping T cell development and suggest that genetically determined differences in thymic selection may bias the CD4⁺ versus CD8⁺ T cell balance from early childhood.
Lack of Association with Environmental Risk Factors
Notably, the study found no significant association between MS polygenic risk and key environmental risk factors, including Epstein–Barr virus seropositivity, cytomegalovirus seropositivity, or serum 25-hydroxyvitamin D levels at age six. This indicates that, at least at this developmental stage, genetic risk for MS influences immune cell composition independently of these environmental exposures. These results align with Mendelian randomization studies suggesting that genetic susceptibility and environmental factors may act through partially distinct biological pathways, potentially converging later in life to promote disease onset.
Implications for MS Pathogenesis
The findings support a model in which MS-associated genetic variants subtly alter immune system development well before clinical disease becomes apparent. A genetically driven reduction in naïve CD8⁺ T cells, combined with a relative excess of CD4⁺ T cells, may create a permissive immunological environment for the later activation and expansion of autoreactive T cells. Such an imbalance could lower the threshold for pathological immune responses when additional triggers, such as viral infections or vitamin D deficiency, are encountered during adolescence or adulthood. Thus, altered T cell homeostasis may represent one of the earliest steps in MS immunopathogenesis.
Future Directions and Clinical Relevance
This study highlights the value of integrating genetic risk profiling with detailed immunophenotyping in population-based cohorts. Longitudinal follow-up of these children will be essential to determine whether early-life alterations in the CD4⁺/CD8⁺ ratio predict later MS-related immune dysfunction or clinical disease. Ultimately, such insights could contribute to the identification of early biomarkers of MS risk and inform preventive strategies aimed at immune modulation before irreversible neurological damage occurs. By demonstrating that MS genetics shape the adaptive immune system during childhood, this work provides a critical link between polygenic risk and early biological mechanisms underlying multiple sclerosis.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
de Mol, C. L., Looman, K. I., van Luijn, M. M., Kreft, K. L., Jansen, P. R., van Zelm, M. C., ... & Neuteboom, R. F. (2021). T cell composition and polygenic multiple sclerosis risk: a population‐based study in children. European Journal of Neurology, 28(11), 3731-3741.
