Multiple sclerosis pathophysiology: a comprehensive review of genetic, environmental, and immunological drivers

Abstract

Multiple sclerosis (MS) is a complex, chronic neuroinflammatory and neurodegenerative disorder of the central nervous system. This comprehensive review synthesizes evidence to argue that the paramount challenge in MS is bridging the disconnect between anti-inflammatory therapies and ineffective neuroprotective strategies, necessitating a dual-target approach. The paper discusses the crucial roles of genetic predisposition, highlighting the HLA-DRB1*15:01 allele and other non-HLA loci, and environmental triggers, such as Epstein-Barr virus infection, vitamin D deficiency, and smoking. We detail the dysregulation of both T-cells (Th1 and Th17 subsets) and B-cells in the autoimmune attack on myelin, as well as the intricate mechanisms of neurodegeneration, axonal damage, and the challenges of remyelination. The review also incorporates emerging insights into the role of the gut microbiome and epigenetic modifications, underscoring the necessity of an integrative model to understand MS pathogenesis. Ultimately, this review provides a foundational understanding of converging biological drivers of MS. Therapeutically, currently approved disease-modifying therapies (DMTs)-including interferon-β, glatiramer acetate, oral S1P modulators, fumarates, teriflunomide, cladribine, natalizumab, and anti-CD20 monoclonals-reduce relapse frequency and MRI activity but do not eliminate disability progression, particularly in progressive MS. Acute relapses are treated with high-dose corticosteroids, with plasma exchange reserved for steroid-refractory cases. We therefore argue that future success requires integrated strategies that couple sustained control of peripheral inflammation with CNS-intrinsic neuroprotection and remyelination. Therapeutically, modern disease-modifying therapies (interferon-β, glatiramer acetate, oral S1P modulators, fumarates, teriflunomide, cladribine, natalizumab, anti-CD20 monoclonals including ocrelizumab, ofatumumab, and ublituximab) reduce relapse rates and MRI activity yet do not consistently prevent disability progression-particularly in non-active progressive MS. Acute relapses are treated with high-dose corticosteroids; plasma exchange is reserved for steroid-refractory attacks. These realities motivate mechanism-informed strategies that pair sustained immune control with CNS-intrinsic neuroprotection and remyelination.

Keywords: Disease-modifying therapies (DMTs); Genetic and environmental risk factors; Multiple sclerosis (MS); Neuroinflammation; Remyelination and neuroprotection.