Distinct Multiomic Signatures of Environmental Exposure Drive Immune Dysregulation and Disease Activity in Early Multiple Sclerosis

BACKGROUND AND OBJECTIVES: Environmental factors are pivotal in determining multiple sclerosis (MS) susceptibility, yet their specific influence on the immune system at the time of diagnosis remains incompletely understood. The aim of this study was to map the systemic effects of modifiable risk factors, specifically smoking, body mass index (BMI), serum vitamin D, UV exposure, and latent viral immunity, on immune function in patients with treatment-naive MS. METHODS: A multiomics analysis was performed on a monocentric cohort of 96 treatment-naive patients. The study used a combination of bulk transcriptomics across 6 immune cell lineages, serum proteomics, cell-cell communication modeling, and high-dimensional flow cytometry to identify unique immunologic patterns linking environmental exposures to disease pathology. RESULTS: Smoking was found to induce an upregulation of the tissue-homing receptor GPR15 across lineages, particularly in NK cells, which correlated with higher disability levels. Smoking also amplified a proinflammatory milieu (increased CXCL17 and LAMP3). Higher potential UV exposure seemed to counteract these effects by lowering IFI30 and LYZ expression; notably, elevated IFI30 correlated with the presence of gadolinium-enhancing lesions. Regarding metabolic factors, high BMI exerted a linear effect on monocyte metabolism, driving cholesterol biosynthesis (MVD and SQLE) and increasing proinflammatory markers (FABP4 and LEP) associated with blood-brain barrier compromise. DISCUSSION: These findings elucidate the molecular mechanisms by which modifiable risk factors contribute to MS pathology. The data imply distinct clinical approaches for risk management: while smoking cessation must likely be absolute to reverse pathogenic trafficking signals (such as GPR15 upregulation), the linear effect of BMI suggests that incremental weight loss confers proportional immunologic benefits. These insights strongly support the integration of lifestyle interventions as a core component of early MS management.