Misdirected Antibodies May Explain Why Viral Infection Can Lead to Multiple Sclerosis

Research published at the start of 2022 suggested that the Epstein-Barr virus (EBV) is a causal factor in the development of the neurodegenerative condition multiple sclerosis (MS). Now, a new study published in Science Advances has explored how the body’s response to the virus can be misdirected to attack the brain and spinal cord.

Epstein-Barr virus: A successful pathogen

EBV is a highly successful virus that is thought to have infected more than 90% of the global population. The virus can be spread through bodily fluids like saliva, blood and semen. In the great majority of people, infection with the virus has little consequence beyond occasional bouts of glandular fever, also called infectious mononucleosis. However, the virus has a life-long latency and can bury itself in our cells’ control centers, called nuclei, where it can remain for extended periods of time.

Last year, a study of 10 million military personnel found that infection with EBV bestows a 32-fold increased risk of developing MS, which is 10 times higher than any other known disease factor. This was the culmination of decades of research that proposed a link between the virus and MS. Significant questions remain about what mechanisms predispose certain people to develop MS in response to EBV infection. The new study represents a first step towards teasing out these disease mechanisms.

“MS is an incredibly complex disease, but our study provides an important piece in the puzzle and could explain why some people develop the disease,” says Olivia Thomas, co-first author of the paper and a postdoctoral researcher at the Department of Clinical Neuroscience at the Karolinska Institute. “We have discovered that certain antibodies against EBV, which would normally fight the infection, can mistakenly target the brain and spinal cord and cause damage.”

Inaccurate antibodies

Viral infection with EBV prompts the body’s immune system to release molecules called antibodies that are meant to target the virus for destruction. The researchers analyzed blood samples from over 700 MS patients and a matched number of healthy people from the Swedish Nationwide Epidemiological Investigation of MS dataset, finding that some of these antibodies, aimed at a protein in the EBV called EBNA1, can accidentally bind to a similar protein called CRYAB. This is a protein found in the human brain and spinal cord. CRYAB’s role is to prevent protein aggregation during cellular inflammation.

The effect of these poorly aimed antibodies may be to damage the nervous system, causing balance, mobility and fatigue problems in people with MS. These antibodies were found in 23% of people with MS and 7% of healthy blood samples.

“This shows that, whilst these antibody responses are not required for disease development, they may be involved in disease in up to a quarter of MS patients,” says Olivia Thomas. “This also demonstrates the high variation between patients, highlighting the need for personalized therapies. Current therapies are effective at reducing relapses in MS but unfortunately, none can prevent disease progression.”

The researchers also found that T cells, which are also important agents in the body’s response to MS, can likely cross-react to both EBNA1 and CRYAB.  Mattias Bronge, an affiliated researcher at the Department of Clinical Neuroscience at the Karolinska Institute and the paper’s other co-author, says, “We are now expanding our research to investigate how T cells fight EBV infection and how these immune cells may damage the nervous system in MS and contribute to disease progression.”

Reference: Thomas OG, Bronge M, Tengvall K, et al. Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis. Sci. Adv. 2023;9(20):eadg3032. doi:10.1126/sciadv.adg3032

This article is a rework of a press release issued by the Karolinska Institute. Material has been edited for length and content.