Exploring Sex-Based Mechanisms of Inflammation and Neurodegeneration in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by both immune-mediated inflammation and progressive neurodegeneration. While both processes occur in all individuals with MS, females more often present with heightened inflammatory activity, whereas males tend toward accelerated neurodegeneration and disability progression. This review synthesizes current evidence on biological, hormonal, genetic, epigenetic, and environmental mechanisms underlying sex-based differences in relapsing-remitting MS (RRMS), the most common MS subtype. We integrate findings from human studies, animal models, and molecular research to examine the contribution of genetics and epigenetic regulation including sex chromosomes, single nucleotide polymorphisms (SNPs), and microRNAs (miRNAs) to MS pathophysiology. We discuss the influence of sex hormones, including estrogen, progesterone, and testosterone, and environmental risk factors such as Epstein-Barr virus infection and vitamin D3 deficiency. Evidence suggests that X-linked immune-related genes, hormone - immune interactions, and sex-specific epigenetic regulation shape differential immune responses and neuronal vulnerability in males and females with MS. miRNAs emerge as critical molecular bridges linking genetic susceptibility, hormonal milieu, and environmental exposures to downstream inflammatory and neurodegenerative pathways. Understanding the mechanisms driving sex differences in MS may enable the development of targeted interventions addressing both neuroinflammation and neurodegeneration. Integrated miRNA - mRNA analyses, explicitly powered to assess sex as a biological variable, hold promise for identifying novel biomarkers and therapeutic targets. Such approaches could inform more personalized treatment strategies and improve long-term outcomes for all people with MS.