Fluorescence microscope image of a mouse brain. The protective myelin layer (red) surrounds the nerve cell extensions. Cells infected with a virus are visible in light blue. Such infections cause immune cells to invade the brain and attack the myelin layer.
Image Credit: Hyein Kim, University of Basel
Scientific Frontline: "At a Glance" Summary
- Discovery of Initiation Mechanism: Researchers have identified a specific biological sequence where the Epstein-Barr virus (EBV) triggers early multiple sclerosis (MS)-like damage by allowing self-reactive B cells to bypass immune checkpoints.
- Molecular Mimicry: The mechanism relies on a viral protein (Latent Membrane Protein 1) that mimics a crucial "approval" signal usually provided by other immune cells, preventing the programmed elimination of B cells that target the body's own proteins.
- Localized Pathogenesis: Experimental mouse models demonstrated that these "out-of-control" B cells capture myelin antigens and cause localized demyelinating lesions in the central nervous system, mirroring the earliest stages of MS.
- B Cell Direct Action: The study shifts the understanding of B cells from indirect influencers of inflammation to direct agents of lesion formation, suggesting they are the primary "spark" for chronic brain inflammation.
- Therapeutic Correlation: The findings explain the clinical efficacy of current B-cell depleting therapies and emphasize that MS risk is shaped by the timing and sequence of rare immune events rather than infection alone.
- Future Prevention: This discovery highlights the potential for preventive strategies, such as targeted vaccinations designed to inhibit severe EBV infections and prevent the subsequent invasion of the brain by pathogenic B cells.
There is mounting evidence that the Epstein-Barr virus may play a part in causing autoimmune diseases like multiple sclerosis. But one puzzle remains: almost everyone gets this virus early in life, yet only a few people ever go on to develop multiple sclerosis.
Now, a team led by Dr. Nicholas Sanderson and Professor Tobias Derfuss at the Department of Biomedicine of the University of Basel and the University Hospital Basel, reports new evidence in Cell that helps resolve this puzzle. Working at the interface of clinical neurology and basic immunology, the researchers focused on B cells — a type of immune cell best known for producing antibodies.
A rare event in a highly sensitive place
Most people carry B cells that are potentially self-reactive, meaning they can recognize the body’s own proteins. Under normal conditions, this is not dangerous. When such cells encounter their target in the body’s tissues, they are briefly activated but then eliminated by strict immune safety mechanisms before they can cause harm.
The brain, however, is a uniquely sensitive environment. During infections or inflammation, B cells can temporarily enter the brain tissue. In most cases, this causes no lasting damage — but a coincidence of rare events can cause the safety mechanisms to fail.
When immune balance is disrupted
The current study shows that the Epstein–Barr virus can interfere with the normal control of B cells. One viral protein mimics a crucial “approval” signal that B cells usually require from other immune cells. As a result, self-reactive B cells can survive even when they should be shut down.
In experimental mouse models, these surviving B cells caused local damage to myelin — the insulating layer around nerve fibers — closely resembling early MS lesions. The process did not involve a widespread immune attack, but arose locally in the brain, shaped by a specific sequence of events.
“The role of EBV in MS has been quite mysterious for a long time. We have identified a series of events including EBV infection that has to happen in a clearly defined sequence to cause localized inflammation in the brain. While this is not fully explaining all aspects of MS, it might be the spark that ignites chronic inflammation in the brain,” says Tobias Derfuss, senior author of the paper.
One of several triggers for MS
Until now, B cells were thought to contribute to MS mainly through indirect mechanisms, such as influencing other immune cells. The new findings suggest that, rather than acting only indirectly, B cells may also play a direct role at the earliest stages of lesion formation. These new insights bring together several long-standing observations in MS research: the strong link to Epstein–Barr virus infection, the involvement of B cells, and the effectiveness of therapies that target them. At the same time, the researchers emphasize that this is not a single-cause explanation for MS. Instead, it describes one initiating pathway that could help explain why the disease begins — long before symptoms appear.
“Experts in the field mostly agree that both B cells and Epstein-Barr virus are somehow involved in the disease, but there is no consensus about how,” explains Nicholas Sanderson. “The model that emerges from the work of our team is very simple and therefore very persuasive. In a nutshell, we suggest that virus-infected B cells cause the lesions.”
By identifying a concrete biological mechanism at the very beginning of MS, the study shifts attention to the earliest moments when disease risk may still be shaped. Rather than focusing only on established inflammation, it highlights how timing, location, and immune history can determine whether damage occurs at all. This new understanding may help guide future strategies aimed not only at treating MS, but at preventing it. One possibility would be to tailor future vaccinations to prevent severe Epstein-Barr virus infections and thereby reduce the invasion of the brain by out-of-control B cells.
Published in journal: Cell
Authors: Hyein Kim, Mika Schneider, Yakine Raach, Panajotis Karypidis, Julien Roux, Georgios Perdikaris, Sebastian Holdermann, Laila Kulsvehagen, Anne-Catherine Lecourt, Kerstin Narr, Roman Sankowski, Martin Diebold, Ewelina Bartoszek-Kandler, Josef P. Kapfhammer, Gert Zimmer, Anne-Katrin Pröbstel, Marco Prinz, Ludwig Kappos, Nicholas S.R. Sanderson, and Tobias Derfuss
Source/Credit: University of Basel
Reference Number: bmed011326_01
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