Mapping the complexity of multiple sclerosis: a novel perspective on genetic, environmental, and neurobiological insights.

Multiple sclerosis (MS) is the most common chronic demyelinating disease of the central nervous system (CNS) that mainly affects young adults. MS is a neuroinflammatory disease traditionally classified as an autoimmune disorder; however, its exact cause remains unknown. A wide variety of etiology and risk factors have been proposed to contribute, among which genetics and environment are the leading ones. The heterogeneity of MS can be attributed to a variety of factors, including diverse pathobiological mechanisms. In this narrative review, before discussing the most prevalent etiologies of MS and risk factors, we look at the main neurobiological pathways, blood-brain barrier (BBB) breakdown, and glymphatic system dysfunction. Several intrinsic factors, including genetics and epigenetic implications, hormones, immune system dysregulation, age, and microbiome, have definite roles in developing and worsening MS severity. However, external factors like viruses, bacteria, bioclimate impacts, environmental toxins, lifestyle factors, stress, and psychological factors revealed different or controversial impacts on MS disease. On the other hand, some nascent ones, such as intestinal dysbiosis and COVID-19, need to be further experimentally and clinically investigated. Both may contribute to MS by promoting inflammation and triggering autoimmune responses. Although it assumes that more than one factor contributes to MS development, finding the leading underlying cause and, consequently, the probable involvement mechanisms certainly could help take appropriate, efficient, and personalized therapeutic strategies.