Scientists have found the clearest evidence yet that Epstein-Barr virus (EBV) – which nearly all of us carry for life – is directly responsible for hijacking our immune system's cells to cause lupus, a chronic disease that affects up to a million Americans.
“This is the single most impactful finding to emerge from my lab in my entire career,” said senior author William Robinson, MD, Chief of the Division of Immunology and Rheumatology at Stanford Department of Medicine. “We think it applies to 100% of lupus cases.”
Robinson and his team at Stanford Medicine uncovered a particularly sneaky mechanism that EBV possesses, which essentially hijacks the body's defences to switch sides and mount an attack on the immune system. It's estimated that 90-95%, of US adults carry EBV, which is transmitted in saliva – and even if you're asymptomatic, you're stuck with this bug for life.
“Practically the only way to not get EBV is to live in a bubble,” Robinson said. “If you’ve lived a normal life,” the odds are nearly 20 to 1 you’ve got it.
On a molecular level, EBV is part of the family of viruses that includes chickenpox and herpes, able to dump its genetic material into the nuclei of cells it infects, where it can hide out of sight and undetected by the immune system. Often the virus stays dormant, but under some conditions it reactivates and takes over the cell's functions, replicating and spreading to other cells and hosts via saliva.
A cell type EBV likes to hide out in the most is the B cell, a white blood cell that has two key roles in the immune system. First, B cells make antibodies – proteins that recognize and latch onto invading pathogens – and, second, they act as antigen-presenting cells, meaning they show pieces of those invasive microbes on their surface to alert and activate other immune cells. This helps intensify the immune system's response.
Using an ultra-sensitive sequencing technology developed at Stanford, as well as bioinformatics and cell-culture experimentation, the scientists discovered that in healthy, EBV-positive people, of the billions of B cells we all have, fewer than one in 10,000 carry the virus. But in people with lupus erythematosus (lupus), it's more like one in 400 – or a 25-fold increase.
While the virus spends most of its existence dormant in the cell, it can stir and force the cell to make a particular viral protein known as EBNA2. Here, the researchers demonstrated how this protein acts as a switch (a transcription factor), turning on genes in the B cell that had until that moment been inactive. Unfortunately, a couple of those genes provide the blueprint for additional transcription factors, which then switch on pro-inflammatory genes.
"In our study, we discovered that Epstein-Barr virus, or EBV, infects and reprograms these same autoreactive B cells," said Robinson. "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."
This cascade of genetic changes ultimately leads to the infected B cells going into overdrive and activating helper T cells. Those T cells then recruit many more immune cells that then attack the body’s own nuclear material, creating the widespread autoimmune reaction seen in lupus. At this stage, even uninfected B cells will join the fight and trigger the inflammatory response.
"For decades, scientists suspected EBV was connected to lupus, but the evidence was always indirect," Robinson said. "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."
Because nearly every single one of our cells has a nucleus, antinuclear antibodies can attack organs and tissues throughout the body, leading to damage in the skin, kidneys, joints, heart and nervous system. Lupus overwhelmingly affects women – we still don't know why – and while many people keep lupus in check through medication, about 5% of sufferers experience life-threatening complications.
The findings also raise the possibility that the same EBV-driven mechanism could be driving other autoimmune disorders we don't fully understand. Previous research has hinted at EBV involvement in multiple sclerosis, rheumatoid arthritis and Crohn’s disease, and EBNA2 activity has been detected in the immune cells of people with those conditions.
In the US, it's estimated that around 70 people in 100,000 develop lupus – which is obviously much lower than Americans harboring EBV-infected cells. The researchers hypothesize that perhaps only certain EBV strains are able to turn B cells into the antigen-presenting cells that go on to recruit antinuclear B cells. Genetic differences in immune regulation may also play a role in how easy a job the virus has in hijacking and recruiting cells.
"We think two things have to happen," Robinson explained. "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," he added. "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."
The bad news is there's still no way to get rid of EBV once infection has taken place, even though researchers are working on developing a vaccine that would stop transmission – however, it'd need to be administered in infancy, given that odds of exposure during childhood and teenage years are incredibly high.
Robinson and colleagues have now founded EBVio Inc, a company investigating a lupus treatment known as ultradeep B-cell depletion. It essentially flushes out circulating B cells, which over time are replaced by new virus-free cells made in the bone marrow.
"For the first time, we have a clear biological explanation of how Epstein-Barr virus can lead to lupus," Robinson said. "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."
This groundbreaking research is a turning point in our understanding lupus, a disease whose roots have been mysterious for decades, and opens the door to developing new prevention and treatment strategies – for both EBV and lupus.
The study was published in the journal Science Translational Medicine.
Source: Stanford Medicine
