A new study from researchers at Karolinska Institutet and Stanford University has shown how a combination of viral antibodies and genetic factors of people carrying the Epstein-Barr virus (EBV) can contribute to the immune system’s attack on the brain and spinal cord leading to multiple sclerosis (MS). The research, published in the Proceedings of the National Academy of Sciences (PNAS), identifies how the immune system’s response to EBV proteins can inadvertently target similar proteins in the brain leading to the demyelination of nerves that is the hallmark of MS.
“The new findings provide another piece of the puzzle that adds to our understanding of how genetic and immunological factors interact in MS,” said Lawrence Steinman, MD, a professor of neurology at Stanford, and the study’s corresponding author.
Epstein-Barr virus is very common, with an estimated 90–95% of adults being carriers. Most people remain asymptomatic or experience mild symptoms when infected, but the virus can cause serious conditions in some, including MS. The connection between EPV and MS has been known for some time, but the precise mechanism behind this link has remained unclear until now.
For their work, the research team analyzed blood samples from 650 MS patients and 661 healthy controls. They measured levels of antibodies against the EBNA1 protein and GlialCAM, ANO2, and CRYAB proteins that share structural similarities with EBNA1. The study found that elevated antibodies produced against EBNA1 may mistakenly react with the brain protein GlialCAM, which likely plays an important role in the immune system’s attack on the central nervous system (CNS) that characterizes MS.
In lab tests, the investigators also found that the immune system’s response to EBNA1 could spread to other regions of GlialCAM. This is known as epitope spreading, meaning that the immune response initially focused on one part of the protein gradually extends to nearby regions. This process helps explain why multiple antibodies can be found in MS patients, each contributing to the disease in different ways.
Co-corresponding author Tomas Olsson, MD, PhD, a professor of neurology at the Karolinska Institute and one of the leaders of the study, noted the importance of the findings: “A better understanding of these mechanisms may ultimately lead to better diagnostic tools and treatments for MS.” The research confirms that molecular mimicry, where antibodies against EBV inadvertently target similar proteins in the brain, is a critical factor in the development of MS.
The research also uncovered a key genetic risk factor, the HLA-DRB1*15:01 allele, which increases the likelihood of developing MS when combined with elevated antibody levels against EBNA1 and GlialCAM. The investigators showed that the combination of high levels of these antibodies, along with the genetic risk factor, significantly raised the risk of MS in the study’s participants.
The researchers now plan to investigate whether the antibodies that act against EBNA1 and GlialCAM appear in blood samples before MS onset and could serve as biomarkers for early diagnosis. The study also identified a possible avenue for therapeutic intervention. If the antibodies can be detected early enough, it could guide targeted treatments aimed at preventing or slowing the progression of MS by focusing on modulating the immune response to prevent it from attacking the central nervous system.
