Unlocking a Long-Standing Mystery: Epstein-Barr Virus and Lupus

Q&A with William Robinson, MD, PhD

Artwork courtesy of Jennie Ellison.

November 12, 2025 - by Rebecca Handler

For more than two decades, William H. Robinson, MD, PhD, Chief of the Division of Immunology and Rheumatology at Stanford Department of Medicine, has been on a mission to decode the immune system’s paradoxes — how it protects the body, and how, in diseases like lupus, it mistakenly targets the very system it was meant to defend. A physician-scientist trained at Stanford and the University of California, San Francisco, Robinson has built one of the field’s leading research programs dedicated to uncovering the molecular roots of autoimmunity and translating those insights into new diagnostics and therapies.

Now, his lab has helped solve one of immunology’s longest-standing mysteries: how the common Epstein-Barr virus (EBV), best known for causing mononucleosis (“mono”), can set off lupus.

In a landmark study published in Science Translational Medicine, Robinson and colleagues reveal that EBV, a virus carried by approximately 95% of people worldwide, can directly infect and reprogram the very immune cells responsible for lupus — a finding that bridges decades of epidemiological clues with a concrete biological mechanism.

“Lupus is a disease where the immune system, meant to defend us, turns its weapons inward,” Robinson said. “We found that Epstein-Barr virus hijacks the very B cells that cause this process, reprogramming them into cells that drive autoimmune inflammation.”

The discovery not only clarifies the long-suspected role of EBV in lupus but also offers a roadmap for understanding how viral infections might ignite other autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. The research was supported in part by the Lupus Research Alliance, a nonprofit organization which called the findings “a breakthrough that provides a mechanistic model for how a common viral infection may trigger autoimmunity.”

In this Q&A, Robinson shares insights from the research, and what it could mean for patients living with lupus.

You’ve spent much of your career studying the immune system’s mysteries. What first drew you to lupus, and to the question of how viruses like EBV might be involved?

Lupus is the quintessential systemic autoimmune disease — complex, mysterious, and disproportionately affecting women. From early in my career, I was fascinated by how the immune system, which is meant to protect us, could turn so powerfully against the body’s own cells. In lupus, the immune attack targets the nucleus, the control center of the cell, and yet for decades we did not understand why this happens.

What are B cells, and why are they central to this discovery?

B cells are a type of white blood cell that produce antibodies to fight infection — essentially the immune system’s weapon designers. In a healthy immune system, these antibodies recognize viruses or bacteria and help clear them. But in autoimmune diseases like lupus, certain B cells lose their ability to distinguish between “self” and “non-self.” These misdirected B cells, which we call autoreactive, start producing antibodies that attack the body’s own molecules, such as those in the cell nucleus.

In our study, we discovered that Epstein-Barr virus, or EBV, infects and reprograms these same autoreactive B cells. Once infected, the cells no longer behave normally, they become what we call “driver” cells, meaning they send persistent inflammatory signals that activate, sustain and amplify the autoimmune response. That process appears to be at the heart of lupus.

William H Robinson, MD, PhD

This discovery solves a decades-long puzzle linking EBV and lupus. Was there a personal “light-bulb moment” when you realized your team was seeing the missing connection?

Yes. The moment came when we produced antibodies from B cells infected with EBV in patients with lupus — and found that those antibodies bound tightly to the nucleus of cells. That was the breakthrough. It showed that EBV had directly infected the very B cells that create the autoantibodies responsible for lupus.

For decades, scientists suspected EBV was connected to lupus, but the evidence was always indirect. This was the first time we could see that the virus itself was inside the disease-driving cells, reprogramming them into pro-inflammatory B cells that could explain how lupus begins.

You discovered that EBV infects a specific type of B cell in lupus patients. Why is that important?

This was key because it helps explain how a common virus can lead to such a rare disease. Normally, autoreactive B cells are tightly controlled. They exist in small numbers and are kept inactive so they can’t cause harm. But EBV changes that. When the virus infects these cells, it essentially flips a switch: the cells become hyperactive, release inflammatory molecules, and start producing antibodies that attack healthy tissue.

Your team developed a sequencing tool called “EBV-seq.” How did that make this discovery possible?

EBV is extremely good at hiding in the body. It can go dormant inside immune cells and produce very little viral material, making it nearly invisible with standard methods. We developed EBV-seq to find those hidden traces. It’s a specialized single-cell sequencing technology that can detect the tiny bits of EBV RNA produced by infected cells.

This allowed us to look at individual B cells, one by one, and identify which ones were carrying the virus — and what genes were switched on inside them. That’s how we could see that EBV was specifically infecting autoreactive B cells and changing their behavior to promote inflammation.

You also found that some antibodies recognize both the virus and human proteins. How does this “mistaken identity” help trigger autoimmunity?

This phenomenon is called molecular mimicry. It happens when part of a virus looks so similar to a human protein that the immune system can’t tell them apart. So, when your immune system attacks the virus, it accidentally starts attacking your own tissues too.

In EBV, a viral protein called EBNA1 closely resembles human nuclear proteins, the same ones targeted in lupus. However, our data suggest that mimicry alone isn’t enough to cause disease. The more important process seems to be that EBV infects those already misdirected B cells and keeps them switched on. That combination, infection plus reprogramming, is what turns a minor immune mistake into a chronic disease.

If nearly everyone carries EBV, why do only some people go on to develop lupus?

That’s one of the great questions we’re still investigating. We think two things have to happen. First, a person must have those autoreactive B cells — the ones capable of targeting their own tissues. Second, EBV must infect those specific cells, not just the normal ones.

We’re also studying whether certain strains of EBV are more likely to trigger autoimmunity. It may be that most people are infected with harmless versions of the virus, but a few encounter strains that can reprogram immune cells in a dangerous way, especially if their immune system is genetically more vulnerable.

Your paper mentions that similar viral mechanisms could underlie other autoimmune diseases, like multiple sclerosis. Do you see this as part of a larger pattern?

Yes, and that’s what makes this discovery so exciting. We believe this EBV-driven mechanism, where the virus infects autoreactive B cells and transforms them into inflammatory, disease-driving cells, may be at work in multiple autoimmune diseases.

If this pattern holds true, it suggests there may be a common underlying process across different autoimmune diseases. By targeting the EBV-infected cells at the root of that process, we might one day be able to treat, or even prevent, several of these conditions at once.

Millions of people live with lupus or other autoimmune conditions. What’s the most important takeaway from this discovery?

For the first time, we have a clear biological explanation of how Epstein-Barr virus can lead to lupus. That understanding could completely change how we approach prevention and treatment.

There’s already evidence that therapies which deeply deplete B cells – essentially wiping out the infected and autoreactive ones – can send lupus into long-term remission, even without ongoing medication. Our lab is investigating whether that remission happens because those EBV-infected “driver” cells are being eliminated. If so, that would move us closer to potential cures.

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