Lupus, a chronic autoimmune disease that affects an estimated five million people worldwide, has long puzzled researchers.

The condition occurs when the immune system turns against healthy tissues, triggering widespread inflammation that can lead to persistent fatigue, joint pain, and the characteristic facial rash. 

 While genetics, hormones, and environmental factors have all been linked to lupus, scientists have yet to pinpoint a single cause.  For decades, viral infections — particularly the Epstein–Barr virus (EBV) — have been suspected as potential triggers.

Now, a groundbreaking study published in Science Translational Medicine provides some of the clearest evidence yet that EBV may be a driving force behind the disease  Dr. William Robinson, professor of immunology and rheumatology at Stanford University and senior author of the study, says the medical community has known about the strong association between EBV and lupus, but lacked a clear mechanistic explanation.

“Nearly all people with lupus have evidence of prior EBV infection, and they generate unusually strong immune responses to EBV,” he explained. 

EBV, a common herpesvirus that spreads through saliva, infects about 95% of people globally by adulthood.

After infection — often occurring during childhood or adolescence and sometimes presenting as mononucleosis — the virus remains in the body for life, lying dormant in a small number of B cells, the immune cells responsible for producing antibodies.  In most individuals, these infected B cells remain harmless.

But using a newly developed single-cell sequencing technology, Robinson’s team has finally been able to isolate and analyze the rare EBV-infected B cells in people with lupus.   What they discovered was striking.  In healthy individuals, fewer than one in 10,000 B cells carry dormant EBV.

In people with lupus, that number jumps dramatically — to about one in 400. “It shows that people with lupus have 25-fold more EBV-infected B cells circulating in their blood,” Robinson said. “Even though these cells are rare, we show that they act as overactive ‘instigators’ of the autoimmune response that mediates lupus.” 

The study further revealed that in some cases, the dormant virus can activate a viral protein known as EBNA2, which in turn switches on genes that push B cells toward a highly inflammatory, autoreactive state. These reprogrammed cells not only produce harmful autoantibodies but also stimulate T cells, amplifying the autoimmune attack.

The findings open the door to a new generation of lupus treatments — ones that target the root cause rather than simply managing symptoms.

Robinson believes therapies designed to eliminate these rare EBV-infected “driver” B cells could lead to transformative, possibly even curative, breakthroughs. Next-generation B-cell depletion therapies, engineered immune cells, and EBV-directed immunotherapies are among the potential approaches. 

The next phase of research will involve validating the findings in larger patient groups and exploring whether similar mechanisms are involved in other autoimmune conditions, including multiple sclerosis. Researchers also plan to investigate whether existing treatments, such as CAR T-cell therapy, work by depleting EBV-positive B cells. 

Dr. Deepak Rao, a leading rheumatologist at Brigham and Women’s Hospital who was not involved in the study, described the findings as an important milestone. He noted that the EBV-infected B cells in lupus patients were strongly enriched in a specific immune cell population known as age-associated B cells — key drivers of autoimmunity.

“This report provides an intriguing mechanism by which EBV may fuel the activation of the core autoimmune response in lupus,” he said. 

The study not only strengthens the long-suspected connection between EBV and lupus but also raises compelling new questions about how a common childhood virus can spark such a devastating disease in some individuals. As research advances, scientists are hopeful that unlocking the mysteries of EBV may finally bring the medical community closer to a cure for lupus.