Researchers have uncovered the strongest evidence yet that the Epstein-Barr virus, which causes glandular fever, triggers lupus by reprogramming immune cells. The study reveals how the virus infects B-cells, leading to a hyperactive immune response that attacks healthy tissues. This finding could explain the success of certain therapies and support vaccine development.
Lupus, or systemic lupus erythematosus, is an autoimmune condition where the immune system attacks healthy tissues, causing symptoms like painful muscles and joints, rashes, and extreme tiredness. It affects around 5 million people worldwide, with about 90 percent of cases in women. While causes involve genetics, hormones, and environmental triggers like viruses, the role of the Epstein-Barr virus (EBV)—which infects 95 percent of adults and causes glandular fever—has been suspected but not mechanistically proven.
William Robinson at Stanford University and colleagues developed a single-cell RNA-sequencing platform called EBV-seq to analyze B-cells in blood samples. In 11 people with lupus, about 25 of every 10,000 sequenced B-cells were infected with EBV, compared to 0 to 3 per 10,000 in 10 healthy controls. Most infected cells were memory B-cells, which express genes ZEB2 and TBX21. These genes activate helper T-cells, recruiting more B-cells and creating a vicious cycle of immune overactivity.
The virus's protein EBNA2 binds to ZEB2 and TBX21, boosting their expression and priming the cells for this response. “Our discovery is the mechanism by which this very common virus that infects 95 per cent of us, Epstein-Barr virus, basically causes lupus,” says Robinson. He notes that genetics and environment determine why only some infected individuals develop lupus: “It’s EBV infection in the context of the genetic and environmental milieu that predisposes one to lupus that together results in them getting lupus.”
George Tsokos at Harvard Medical School agrees EBV is a main contributor in some cases, though mechanisms vary. The findings build on a 2022 link between EBV and multiple sclerosis, suggesting broader implications for autoimmune diseases. They may explain why CAR T-cell therapies, which deplete B-cells, achieve long-term remission in lupus patients by targeting EBV-infected cells, though Tsokos cautions that not all B-cells are fully eliminated.
The research supports an EBV vaccine to prevent infection and thus lupus in uninfected people, as reprogramming occurs early after exposure. However, Tsokos highlights challenges like cost, given vaccination of over 1,000 might prevent one case. The study appears in Science Translational Medicine (DOI: 10.1126/scitranslmed.ady0210).