What are the causes of Multiple Sclerosis (MS)?

Causes of Multiple Sclerosis

Multiple sclerosis results from complex interactions between genetic susceptibility and environmental triggers—particularly Epstein-Barr virus infection—that lead to immune system dysregulation, causing inflammatory destruction of myelin in the central nervous system. 1

Genetic Factors

Genetic predisposition is necessary but not sufficient to cause MS on its own. 1, 2

• Over 200 single-nucleotide polymorphisms have been identified that increase MS risk 3
• These genetic variants create susceptibility but require environmental triggers to manifest as disease 4
• The disease shows ethnic variation, with higher prevalence in Black individuals compared to White individuals, and lowest rates in people of Asian ethnicity 1

Environmental Triggers

Infectious Agents

Epstein-Barr virus (EBV) stands out as the key environmental trigger with the strongest evidence linking it to MS development. 1

• Multiple pathogens have been implicated including EBV, human herpesvirus 6, varicella-zoster virus, cytomegalovirus, Helicobacter pylori, Chlamydia pneumoniae, and Borrelia burgdorferi 4
• These infectious agents can manipulate host gene expression, causing immune dysregulation and triggering the inflammatory cascade 4
• Bacterial pathogens like Mycoplasma pneumoniae and Chlamydia pneumoniae have also been associated with MS development or exacerbation 5

Vitamin D Deficiency and Sunlight Exposure

• Low vitamin D levels and reduced sunlight exposure are associated with increased MS risk 1, 3
• Evidence for causal association between vitamin D deficiency and MS has strengthened in recent years 3
• Geographic variability in MS prevalence correlates with sunlight exposure patterns, with higher incidence in regions with lower sun exposure 1

Other Environmental Factors

• Obesity during adolescence increases MS risk, with evidence supporting a causal relationship 3
• Smoking is definitively associated with increased MS risk 3
• Dietary factors may play a role, with diets lower in saturated fat and higher in polyunsaturated fatty acids potentially protective 1
• Changes in gut microbiota are emerging as possible disease risk modulators 3

Pathogenic Mechanism

The disease initiates when genetic susceptibility meets environmental triggers, activating pro-inflammatory B cells and T cells that migrate into the CNS. 1

• This immune cell infiltration—including T cells, B cells, and myeloid cells—causes focal demyelinating lesions in the brain and spinal cord 6
• The cascade involves blood-brain barrier breakdown, widespread focal degradation of myelin sheaths, and variable axonal and neuronal injury 1, 3
• Both adaptive and innate immune systems become activated, with B cells playing a particularly important role 3
• Meningeal inflammation, cortical demyelination, and early axonal loss contribute to progressive disability 3

Clinical Implications

MS manifests as a continuous, progressive, lifelong disease with a long latent period from initial infection to symptom onset. 1

• The disease affects females more than males (though not at the commonly cited 2:1 ratio) 1
• Approximately 85% of patients present with relapsing-remitting MS (RRMS), while 15% have primary-progressive MS (PPMS) from onset 1, 7
• Current disease-modifying therapies target the inflammatory component rather than promoting remyelination 1, 8