Summary: New research identifies a direct connection between antibodies formed against the Epstein-Barr virus (EBV) and the onset of multiple sclerosis (MS). Scientists found that antibodies targeting the EBV protein EBNA1 can cross-react with a brain protein called GlialCAM, provoking autoimmune responses that are implicated in MS.
The study further shows that specific combinations of elevated viral antibodies and genetic risk factors amplify the likelihood of developing MS. These findings improve our understanding of how genetic susceptibility and the immune response to EBV interact and may guide the development of better diagnostic tests and targeted therapies.
Key Facts:
- Mistargeted antibodies: Antibodies against EBV (EBNA1) can mistakenly bind GlialCAM, a protein in the central nervous system, potentially initiating autoimmune damage seen in MS.
- Genetic interaction: Carrying established MS risk alleles together with high antibody levels substantially raises disease risk.
- Biomarker potential: Elevated antibodies against GlialCAM and related CNS proteins may serve as early biomarkers to help identify people at greater risk for MS.
Source: Karolinska Institute
Background
Multiple sclerosis is an autoimmune disorder in which the immune system attacks the brain and spinal cord. Almost all people with MS are carriers of Epstein-Barr virus (EBV), but the molecular steps linking EBV infection to MS have not been fully defined. The new study, led by teams at Karolinska Institutet and Stanford University School of Medicine and published in PNAS, clarifies one such mechanism.
An estimated 90–95% of adults have been infected with EBV and carry antibodies to the virus. EBV typically establishes a latent infection after initial exposure, which may be asymptomatic in childhood or cause glandular fever when infection occurs later. The research team focused on immune responses to EBV that may cross-react with human proteins in the central nervous system.
Cross-reactivity between EBNA1 and CNS proteins
The researchers examined how antibodies to EBNA1, an EBV nuclear antigen, can cross-react with several human CNS proteins that share similar sequences. In particular, they confirmed molecular mimicry between EBNA1 and GlialCAM, and also evaluated responses against ANO2 and CRYAB, two additional brain proteins with sequence similarity to EBNA1. Their findings indicate that cross-reactive antibodies are more common and more strongly elevated in people with MS compared with healthy individuals.
Blood samples from 650 people with MS and 661 matched controls were analyzed for IgG responses to EBNA1 and to the three CNS-mimic antigens. The team detected higher antibody levels against EBNA1, GlialCAM, ANO2, and CRYAB in the MS group. Blocking experiments supported the presence of cross-reactive antibodies, and responses to adjacent peptide regions of GlialCAM suggested epitope spreading—a process in which immune recognition expands to neighboring parts of a protein.
Interaction with genetic risk factors
Genetic context substantially influenced risk. Elevated antibody responses were particularly pronounced among carriers of the main MS risk allele HLA-DRB1*15:01. When high antibody levels were combined with HLA-DRB1*15:01, the associated increase in MS risk was additive and significant. Conversely, the absence of the protective HLA-A*02:01 allele together with the presence of antibodies against any of the CNS proteins also correlated with a marked rise in risk.
The study further showed that having antibody reactivity against multiple EBNA1 peptides and against more than one CNS-mimic protein modestly increased MS risk compared with single reactivities, supporting the idea that a broader, cross-reactive immune response may be more pathogenic.
Clinical implications and next steps
These results add a clearer molecular link between EBV infection and MS by demonstrating that molecular mimicry between EBNA1 and GlialCAM likely contributes to disease pathology. The authors propose that measuring antibodies against EBNA1 and GlialCAM—and tracking their appearance over time—could help identify individuals at elevated risk and assist in earlier diagnosis.
Researchers at Karolinska Institutet plan to analyze pre-diagnostic samples to determine whether these antibodies are present before clinical onset. If confirmed, this would support the use of such antibody profiles as biomarkers and might open avenues for interventions that target specific immune responses.
Funding and disclosures
The study was funded by the Swedish Research Council, the Swedish Brain Foundation, the EU/Horizon Europe, the Knut and Alice Wallenberg Foundation, the Margaretha af Ugglas Foundation, and others. Tomas Olsson and Lawrence Steinman have received lecture and advisory fees from various companies. William Robinson and Tobias Lanz are stockholders and consultants for Ebvio and Flatiron Bio and have filed a patent with Stanford University. See the original paper for a complete list of conflicts of interest.
About this multiple sclerosis research news
Author: Press Office
Source: Karolinska Institute
Contact: Press Office – Karolinska Institute
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Antibody reactivity against EBNA1 and GlialCAM differentiates multiple sclerosis patients from healthy controls” by Tomas Olsson et al. PNAS
Abstract
Antibody reactivity against EBNA1 and GlialCAM differentiates multiple sclerosis patients from healthy controls
Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS) that is epidemiologically linked to prior infection with Epstein–Barr virus (EBV). The molecular mechanisms that link EBV to MS are incompletely defined. The authors previously identified sequence similarities between the EBV transcription factor EBNA1 and three human CNS proteins: anoctamin-2 (ANO2), alpha-B crystallin (CRYAB), and glial cellular adhesion molecule (GlialCAM).
In this large cohort study of 650 MS patients and 661 matched population controls, the investigators measured antibody responses against EBNA1 and the three CNS-mimic proteins. They confirmed that higher IgG responses to EBNA1, GlialCAM, ANO2, and CRYAB associate with increased MS risk. Blocking experiments demonstrated cross-reactive antibodies consistent with molecular mimicry between EBNA1 and GlialCAM, and responses to adjacent GlialCAM peptides support epitope spreading.
Antibody responses were particularly elevated in carriers of the major risk allele HLA-DRB1*15:01, and combinations of HLA-DRB1*15:01 with anti-EBNA1 and anti-GlialCAM antibodies increased MS risk in an additive way. Reactivity against multiple EBNA1 peptides and multiple CNS-mimics further raised risk modestly. Overall, the data indicate that molecular mimicry between EBNA1 and GlialCAM is likely an important mechanism contributing to MS pathology.