Pathophysiology of Multiple Sclerosis
Multiple sclerosis results from unfavorable interactions between genetic susceptibility and environmental factors—particularly Epstein-Barr virus—that trigger activation and migration of pro-inflammatory B cells and T cells into the CNS, leading to focal demyelination, axonal injury, and progressive neurodegeneration that begins early in the disease course. 1
Core Pathological Mechanisms
MS involves two interconnected pathological processes that occur simultaneously 1:
- Inflammatory component: Autoimmune-mediated demyelination driven by myelin-specific CD4+ and CD8+ T cells that attack the myelin sheath 1
- Neurodegenerative component: Irreversible demyelination, axonal transection, and neuronal loss that causes permanent disability 1
The disease is characterized by widespread focal degradation of the myelin sheath with variable axonal and neuronal injury 2
Immunological Mechanisms
T Cell-Mediated Pathology
The primary drivers of CNS damage are specific T helper cell populations 3, 4:
- Th1 cells produce interferon-γ and are essential for differentiation of encephalitogenic CD8+ T cells 3
- Th17 cells produce interleukin-17 and cross the blood-brain barrier to directly target myelin in the CNS 3, 5
- Th17.1 cells share hallmarks of both Th1 and Th17 subsets and play a pivotal role in disease pathogenesis 5
- CD8+ T lymphocytes participate in the development of MS lesions and are found abundantly in CNS tissue 6
These autoreactive lymphocytes are found in high levels in CNS lesions and cerebrospinal fluid of MS patients, contributing to blood-brain barrier breakdown and activation of resident astrocytes and microglia 4
B Cell Contributions
B cells contribute through multiple mechanisms 1:
- Antibody production, including anti-myelin basic protein antibodies 3
- Antigen presentation to T cells 1
- Production of pro-inflammatory cytokines that amplify the immune response 3
Regulatory Cell Dysfunction
Aberrant function of regulatory T cells (Tregs) and Th9 cells contributes to loss of immune tolerance and perpetuation of inflammation 3
Environmental Triggers and Risk Factors
Epstein-Barr virus is recognized as the key environmental trigger that leads to immune dysregulation in genetically susceptible individuals 1, 2
Additional environmental factors include 2:
- Vitamin D deficiency and low sunlight exposure are associated with increased MS risk 1, 2
- Dietary factors, with diets lower in saturated fat and higher in polyunsaturated fatty acids potentially protective 2
- Geographic variability, with higher incidence in regions with lower sunlight exposure 2
Pathological Lesion Types
Subpial Demyelination
Subpial demyelination is associated with meningeal inflammation and intrathecal pro-inflammatory profiles, and appears highly specific for MS based on pathology studies, though it goes largely undetected even with advanced MRI techniques 7
Chronic Active Lesions
Up to 57% of chronic MS lesions are active or mixed (active and inactive), characterized by ongoing inflammatory activity at lesion edges despite appearing chronic on conventional imaging 7
Clinical Course
The disease manifests in two main forms 2:
- Relapsing-remitting MS (RRMS): Affects approximately 85% of cases with discrete attacks followed by recovery periods 2
- Primary-progressive MS (PPMS): Affects approximately 15% of cases with gradual worsening from onset 2
MS is a continuous, progressive, lifelong disease with a variable course that includes a long latent period from initial infection to symptom onset, followed by progressive acceleration 2
Critical Pathophysiological Pitfall
Current disease-modifying therapies primarily target the inflammatory component rather than promoting remyelination or neuroprotection, which explains why they reduce relapse rates by 29-68% but do not reverse existing damage 1, 8. The neurodegenerative component begins early in the disease course and continues even when inflammation is controlled, emphasizing the importance of early aggressive treatment 1