Multiple sclerosis (MS) is an autoimmune disease of unknown etiology. It is the result of an immune system attack against the body’s own tissues destroying the myelin sheath. This leads to inflammation and neuronal damage, causing symptoms such as vision impairment, muscle weakness, pain, and disability. The exact cause of the immune system attack is not known but it is thought to be the result of a combination of genetic and environmental factors.1
MS Risk Factors
Factors that may increase the risk of developing MS include age, HLA haplotype, female sex, a family history of the disease, Epstein-Barr virus infections, Caucasian descent, temperate climate, vitamin D deficiency, other autoimmune diseases, and smoking.
Incidence of MS
The incidence rate of MS is estimated to be approximately 3.6 cases per 100,000 person-years in women and 2.0 cases per 100,000 person-years in men.2 The risk of developing MS is about 1 in 1000 in the general population but increases when a person has a first-degree relative, such as a parent, sibling, or child, with the disease. Research in identical twins has shown that if one of the twins has MS, the chance of the other one also developing the disease is as high as 1 in 4.3
Genetic Factors Responsible for MS Onset
Although MS is not a heritable disease, genetic factors increasing the risk of developing the disease can be inherited. Research has identified about 200 genes that may increase the risk of MS.3
The main susceptibility allele to MS is HLA DRB15:01, which increases the risk of developing MS about 3-fold.3 In nearly all populations analyzed, this allele has been consistently associated with MS.
There is also a protective allele against MS, HLA A02. It is thought that this allele may eliminate viruses connected with MS.1
Immunological Events Leading to MS Development
Many immune cells are involved in the immune response observed in MS. The two main groups of cells involved are B and T lymphocytes.4
In MS, activated T lymphocytes enter the central nervous system through the vasculature and release proinflammatory cytokines, which damage the myelin sheath, nerve fibers, and Schwann cells.
Activated T lymphocytes also activate the B lymphocytes and recruit them to the inflammation site. In this case, B lymphocytes produce antibodies against myelin, causing nerve damage.
Regulatory T lymphocytes also malfunction in MS and fail to reduce inflammation. Cytotoxic T lymphocytes attack and destroy cells bearing certain characteristics.
The HLA-DRB1 gene is expressed in antigen-presenting cells. The protein that it encodes for presents certain antigens to CD4 T cells.3 It is thought that the DRB15:01‐binding pocket allows autoantigens related to the central nervous system to optimally bind to it. This drives the T lymphocytes to attack the central nervous system.1
In people who are HLA‐DR15‐positive, the auto-proliferation of type 1 helper T lymphocytes is also elevated. This is thought to be mediated by memory B cells in an HLA‐DR‐dependent manner.1
HLA DRB15:01 is present in 25% to 30% of the population in Northern Europe and the US.
Consequences of Demyelination
In MS, the demyelination of the axons disrupts the conduction of nervous influx and modifies the axolemma and membrane components.5
An area of demyelination at the site of a lesion produces a conduction block. In some cases, adaptive responses from the axon may restore conduction across the demyelinated segment. However, this is no longer fast but instead continuous and slow. In other cases, the conduction block may persist.
Demyelinated axons also become more excitable and generate ectopic impulses at the site of demyelination. These events lead to symptoms of MS such as spasms, ataxia, tingling, pain, and dysarthria.
Demyelinated axons may also become active in response to mechanical deformations. This leads to Lhermitte’s sign in patients with MS.
Active lesions can also alter the diameter of the axons at the site of demyelination and modify axonal cytoskeletal proteins as well as surface molecules. These changes can lead to the failure of myelin repair.
Chronic demyelination leads to fixed axonal injury and loss in MS.
Complications Associated With MS
The demyelination of axons in MS can lead to a number of complications, including vision impairment, issues with balance and gait, and bladder, bowel, and sexual dysfunction.6 The disease may also affect patients’ mental status, causing symptoms such as anxiety and depression, as well as affecting cognitive abilities such as memory, concentration, and verbal fluency.
In rare cases, MS can cause breathing issues and hearing loss.7 The disease has also been associated with an increased incidence of seizures. However, the exact underlying mechanism of this is not well understood.8
- Waubant E, Lucas R, Mowry E, et al. Environmental and genetic risk factors for MS: an integrated review. Ann Clin Transl Neurol. 2019;6(9):1905–22. doi:10.1002/acn3.50862
- Alonso A, Hernán MA. Temporal trends in the incidence of multiple sclerosis: a systematic review. Neurology. 2008;71(2):129–35. doi:10.1212/01.wnl.0000316802.35974.34
- Parnell GP, Booth DR. The multiple sclerosis (MS) genetic risk factors indicate both acquired and innate immune cell subsets contribute to MS pathogenesis and identify novel therapeutic opportunities. Front Immunol. 2017;8:425. doi:10.3389/fimmu.2017.00425
- What causes MS? National Multiple Sclerosis Society. Accessed June 8, 2021.
- Lubetzki C, Stankoff B. Demyelination in multiple sclerosis. Handb Clin Neurol. 2014;122:89-99. doi:10.1016/B978-0-444-52001-2.00004-2
- Multiple sclerosis. Mayo Clinic. Accessed June 8, 2021.
- MS symptoms. National Multiple Sclerosis Society. Accessed June 8, 2021.
- Kelley BJ, Rodriguez M. Seizures in patients with multiple sclerosis: epidemiology, pathophysiology and management. CNS Drugs. 2009;23(10):805–15. doi:10.2165/11310900-000000000-00000
Reviewed by Kyle Habet, MD, on 7/1/2021.