Summary: New research highlights a critical link between antibodies produced against Epstein-Barr virus (EBV) and the development of multiple sclerosis (MS). Scientists discovered that these viral antibodies mistakenly target a protein called GlialCAM in the brain, triggering autoimmune responses associated with MS.
The study also revealed how combinations of genetic risk factors and elevated viral antibodies further increase the risk of developing MS. These insights may pave the way for improved diagnostics and targeted therapies, enhancing our understanding of the genetic and immunological interplay underlying this debilitating disease.
Key Facts:
- Mistargeted Antibodies: EBV antibodies mistakenly attack GlialCAM, a brain protein, potentially triggering MS.
- Genetic Links: Specific combinations of EBV antibodies and genetic risk factors substantially elevate MS risk.
- Potential Diagnostics: Elevated antibodies against GlialCAM and related proteins could serve as biomarkers for early MS detection.
Source: Karolinska Institute
In multiple sclerosis (MS), antibodies to the common Epstein-Barr virus can accidentally attack a protein in the brain and spinal cord.
New research shows that the combination of certain viral antibodies and genetic risk factors can be linked to a greatly increased risk of MS.
The study has been published in the journal PNAS and led by researchers at Karolinska Institutet, Sweden, and Stanford University School of Medicine, USA.
An estimated 90 to 95 percent of adults are carriers of the Epstein-Barr virus (EBV) and have formed antibodies against it. Many become infected as children with few or no symptoms, but in young adults, the virus can cause glandular fever. After infection, the virus remains in the body in a dormant (latent) phase without active virus production.
Attacking a protein in the brain
Everyone affected by the neurological disease MS, where the immune system attacks the brain and spinal cord, is a carrier of EBV. However, the mechanisms behind the association are not fully understood.
Now, researchers at Karolinska Institutet and Stanford Medicine have confirmed that antibodies to an EBV protein called EBNA1 can inadvertently react with a similar protein in the brain called GlialCAM, which probably contributes to the development of MS.
The new study also shows how different combinations of antibodies and genetic risk factors for MS contribute to the risk increase.
“A better understanding of these mechanisms may ultimately lead to better diagnostic tools and treatments for MS,” says Tomas Olsson, professor of neurology at the Department of Clinical Neuroscience, Karolinska Institutet, who led the research there with professor Ingrid Kockum and assistant professor Olivia Thomas.
The researchers analysed blood samples from 650 MS patients and 661 healthy people. They compared the levels of antibodies directed against the viral protein EBNA1 and the levels of misdirected antibodies against GlialCAM and two other proteins in the brain, ANO2 and CRYAB, which are also similar to EBNA1.
Increased levels of antibodies
Elevated levels of all these antibodies were detected in people with MS. High antibody levels in combination with a genetic risk factor for MS (HLA-DRB1*15:01) were associated with a further increase in risk.
The absence of a protective gene variant (HLA-A*02:01) in combination with any of the antibodies against proteins in the brain was also associated with a strong increase in risk.
“The new findings provide another piece of the puzzle that adds to our understanding of how genetic and immunological factors interact in MS,” says Lawrence Steinman, professor of neurology at Stanford Medicine, who led the research there with William Robinson, professor of immunology and rheumatology, and Tobias Lanz, assistant professor of immunology and rheumatology.
Biomarker potential
Researchers at Karolinska Institutet now plan to analyse samples collected before MS disease development to see when these antibodies appear.
“If they are already present before the onset of the disease, they may have the potential to be used as biomarkers for early diagnosis,” says Tomas Olsson.
Funding: The research was funded by the Swedish Research Council, the Swedish Brain Foundation, the EU/Horizon Europe, the Knut and Alice Wallenberg Foundation and the Margaretha af Ugglas Foundation, among others.
Tomas Olsson and Lawrence Steinman have received lecture and advisory board fees from several companies.
William Robinson and Tobias Lanz are stockholders and consultants of Ebvio and Flatiron Bio and have filed a patent with Stanford University. See the scientific article 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), which is linked to Epstein–Barr virus (EBV) infection, preceding the disease. The molecular mechanisms underlying this connection are only partially understood.
We previously described molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and three human CNS proteins: anoctamin-2 (ANO2), alpha-B crystallin (CRYAB), and glial cellular adhesion molecule (GlialCAM).
Here, we investigated antibody responses against EBNA1 and GlialCAM in a large cohort of 650 MS patients and 661 matched population controls and compared them to responses against CRYAB and ANO2. We confirmed that elevated IgG responses against EBNA1 and all three CNS-mimic antigens associate with increased MS risk.
Blocking experiments confirmed the presence of cross-reactive antibodies and molecular mimicry between EBNA1 and GlialCAM, and accompanying antibody responses against adjacent peptide regions of GlialCAM suggest epitope spreading.
Antibody responses against EBNA1, GlialCAM, CRYAB, and ANO2 are elevated in MS patients carrying the main risk allele HLA-DRB1*15:01, and combinations of HLA-DRB1*15:01 with anti-EBNA1 and anti-GlialCAM antibodies increase MS risk significantly and in an additive fashion.
In addition, antibody reactivities against more than one EBNA1 peptide and more than one CNS-mimic increase the MS risk significantly but modestly.
Overall, we show that molecular mimicry between EBNA1 and GlialCAM is likely an important molecular mechanism contributing to MS pathology.
