For decades, scientists have grappled with a perplexing medical mystery: the connection between Epstein-Barr virus (EBV), an incredibly common virus that infects over 90% of the world’s population, and multiple sclerosis (MS), a debilitating autoimmune disease that affects a much smaller fraction. While epidemiological studies have forged an increasingly strong link, the biological ‘how’ has remained elusive. How does a nearly ubiquitous virus contribute to a condition where the body’s own immune system attacks the central nervous system (CNS)?
Now, a groundbreaking study published in Nature by Läderach and colleagues provides a stunningly clear answer. By meticulously tracing the journey of infected immune cells, they have uncovered the precise strategy EBV appears to use: it doesn’t just infect cells, it transforms them into Trojan horses, giving them a passport to enter the brain and seed the very inflammation that defines MS. This discovery bridges a critical gap in our understanding and illuminates a promising new path for therapeutic intervention.
The Making of a Rogue Immune Cell
At the heart of this story are B cells, a type of white blood cell crucial to our immune system. Normally, they produce antibodies to fight off invaders. However, EBV has a knack for hiding within these B cells, sometimes for a lifetime. The new research reveals that the virus does more than just hide; it actively reprograms a subset of these B cells, essentially giving them a new identity and a destructive mission.
Through a series of elegant experiments using humanized mice, the researchers found that EBV infection expands a specific population of B cells characterized by two key proteins: T-bet and CXCR3. Think of the CXCR3 protein as a molecular homing beacon. These newly ‘imprinted’ B cells are now programmed to seek out specific chemical signals in the body called chemokines (specifically CXCL9, CXCL10, and CXCL11). In an unfortunate twist for individuals susceptible to MS, these chemokines appear to be present in the central nervous system. The EBV-infected B cells, now equipped with their CXCR3 homing device, follow these signals directly to the brain’s doorstep.
Using advanced techniques like single-cell transcriptomics and stunning 3D light-sheet imaging of cleared brains, the scientists were able to watch this infiltration happen. They observed these rogue B cells trafficking from the blood and accumulating in the perivascular and meningeal spaces—the delicate tissues surrounding the brain and its blood vessels. This was the first critical step: the virus had successfully smuggled its cellular agents across the heavily guarded blood-brain barrier.
Trafficking First, Inflammation Next
Crucially, the study demonstrates that these initial B-cell infiltrators are not the primary cause of the nerve damage seen in MS. Instead, their role is positional. Once they have established a foothold within the CNS, they begin the second phase of their mission: summoning a far more aggressive arm of the immune system.
These EBV-imprinted B cells begin to pump out their own cocktail of chemokines, including the same CXCL9 and CXCL10 that guided them there, along with others like CCL3, CCL4, and CCL5. This chemical barrage acts as a clarion call to another type of immune cell: T cells. In MS, it is activated T cells that are largely responsible for attacking the myelin sheath that protects nerve fibers, leading to the devastating neurological symptoms of the disease.
The study confirmed this recruitment process. Supernatants from the EBV-transformed B cells were potent attractants for activated T cells. When the researchers neutralized these chemokines or pharmacologically blocked the T cells’ CXCR3 receptors, the migration was significantly reduced. This elegant finding supports a clear, two-step model: “trafficking first, inflammation next.” The B cells are the scouts that breach the fortress and open the gates; the T cells are the army that follows, wreaking havoc inside.
New Targets for Smarter Therapies
This detailed mechanistic insight has profound implications for treating MS. For years, a highly effective class of drugs for relapsing MS has been anti-CD20 therapies (like rituximab), which work by depleting the body’s B-cell population. While effective, this is a blunt approach, and it has shown limited efficacy in the progressive forms of the disease. The new research suggests we can be much more strategic.
If the initiating step is the trafficking of B cells into the CNS, then perhaps we can simply block their entry. The study tested this very idea in their humanized mouse model. They found that administering a CXCR3 inhibitor—a drug that essentially jams the B cells’ homing beacon—successfully reduced the number of immune cells entering the brain. Furthermore, when they combined the CXCR3 inhibitor with rituximab, they saw the most significant effect, suggesting a powerful synergy between depleting B cells and preventing any remaining ones from reaching their target.
This elevates chemokine-guided positioning to a ‘druggable axis’—a specific, targetable step in the disease process. It opens the door for combination therapies that could be more effective and potentially have fewer side effects than broad immunosuppression.
The Road Ahead
By identifying T-bet+CXCR3+ B cells as the key effectors connecting a latent virus to focal neuroinflammation, Läderach and colleagues have solved a major piece of the MS puzzle. Their work provides a compelling explanation for how a common virus can trigger a devastating autoimmune disease in susceptible individuals.
Of course, important questions remain. What are the initial cues within the CNS that establish the chemokine gradients in the first place? Can we identify the specific antigens these rogue B cells are presenting to T cells? And most tantalizingly, could we develop an EBV-specific vaccine or therapy to eliminate these upstream drivers altogether? Answering these questions will be the next chapter in the fight against MS, but for now, this research provides a clear roadmap and a renewed sense of hope for millions worldwide.
References
Bjornevik, K., Cortese, M., Healy, B. C., Kuhle, J., Mina, M. J., Leng, Y., … & Ascherio, A. (2022). Longitudinal analysis reveals high prevalence of Epstein–Barr virus associated with multiple sclerosis. Science, 375(6578), 296-301. https://doi.org/10.1126/science.abj8222
Cancro, M. P. (2020). Age-associated B cells. Annual Review of Immunology, 38, 315–340. https://doi.org/10.1146/annurev-immunol-092419-031121
Läderach, F., et al. (2025). EBV induces CNS homing of B cells attracting inflammatory T cells. Nature. https://doi.org/10.1038/s41586-025-09378-0
Lanz, T. V., Brewer, R. C., Ho, P. P., Moon, J. S., Jude, K. M., Fernandez, D., … & Robinson, W. H. (2022). Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature, 603(7900), 321-327. https://doi.org/10.1038/s41586-022-04432-7
Ontaneda, D., Thompson, A. J., Fox, R. J., & Cohen, J. A. (2017). Progressive multiple sclerosis: a review. JAMA, 318(9), 825–835. https://doi.org/10.1001/jama.2017.11838
