It’s only March but research published earlier this year in two of the most prestigious scientific journals, Science and Nature, appear to have shifted the landscape of multiple sclerosis (MS) research.
MS is a debilitating neuroimmunological disease with a prevalence of nearly 1 million people in the US and 90,000 people in Canada. While the disease can usually be managed with available medications and lifestyle changes, there is no known cure for MS. Therefore, gaining a better understanding of what causes the disease could illuminate potential therapies.
What is multiple sclerosis?
The stories of people with MS speak to the resilience needed to cope with the disease. The journey often begins with a symptom like numbing in the limbs, and over time, there is diminished motor control. Eventually, a person with MS could require assistance and the use of a wheelchair, or in general, may require a lot of assistance to carry out their daily functions.
The progression of MS is a result of increased chronic inflammation of the central nervous system, characterized by damage to the myelin sheath that wraps around the section of neurons called axons. These myelin sheaths normally provide insulation essential to the efficient conduction of nerve impulses. As myelin becomes damaged in MS, the faulty conduction between neurons in the central nervous system and from peripheral neurons to motor neurons can compromise the brain’s ability to control the body’s muscles and organs.
What is the cause of multiple sclerosis?
Both genetic susceptibility and environmental factors are thought to cause MS based on observations that MS often—but not always—runs in families and has a high prevalence in Northern countries. Environmentally, it has been linked to low vitamin D levels and to infection by the Epstein-Barr virus (EBV).
EBV is prevalent worldwide, often with a lifelong latent infection in human B cells with little or no adverse effects. Over the last two decades, a strong case has emerged for the involvement of EBV in MS at different levels of severity and across clinical presentation, including pediatric, relapsing-remitting, and progressive MS.
Study shows strong links between Epstein-Barr virus and multiple sclerosis
In January of this year, the link between EBV and MS gained strong scientific backing based on a longitudinal study conducted by researchers at Harvard University and published in Science. The study followed 10 million US military personnel over a 20-year period, during which researchers periodically collected blood serum samples. During the course of the study, 801 people with no prior MS pathology were diagnosed with the disease, allowing researchers to examine similarities between individuals and compare them to matched controls who did not develop MS. Except for one individual, what those diagnosed with MS had in common was infection with EBV prior to their MS diagnosis and even prior to the detection of early MS-related biomarkers in their blood. The researchers found that infection with EBV led to a 32-fold increase in risk of MS—a staggering increase that was not seen with other viruses and that could not be explained by any other known risk factor for the disease—making it the known leading cause for MS.
Molecular mimicry underlies the MS autoimmune response
Researchers have previously proposed a few mechanisms for how EBV infection causes MS, but the most plausible mechanism now seems to be molecular mimicry, according to a second study recently published in Nature. Researchers at Stanford University along with their international collaborators found a clue in the cerebrospinal fluid of people with MS: an antibody that immune cells use to recognize the EBV transcription factor EBNA1 was also binding to a protein found naturally in our nervous system, called GlialCAM. Thus, instead of only responding to EBV, B cells activated by this antibody also launched an attack against brain cells with GlialCAM, which is needed for normal brain function. This autoimmune response underlies the inflammation and myelin degradation seen in the progression of MS.
Implication of these studies
If infection-induced autoantibodies are truly the cause of MS—and potentially other autoimmune and neuroinflammatory disorders, for example, systemic lupus erythematosus and neuromyelitis optica spectrum disorder—then treatments could focus on vaccines, antivirals, or targeted killing of the B cells that are producing the autoantibodies.
Though these recent studies add significant scientific evidence to the ongoing debate of the cause of MS, proclaiming a definitive answer would be premature. Since only a small fraction of people who are infected with EBV go on to develop MS, EBV infection is likely necessary but not sufficient to cause MS. Future studies that include more people with diverse disease presentation could also provide insight into whether the autoantibody mechanism is a general mechanism for MS or only applies to a subset of MS.
Despite their limitations, these two MS studies provide some of the strongest evidence that the general mechanism of MS could be a case of mistaken identity between foreign viral and native nervous system proteins.