Lupus can cause extreme fatigue, skin rashes, and joint and muscle pain.
Syahrir Maulana/Alamy
The virus that causes glandular fever, also known as mononucleosis or kissing disease, appears to infect and reprogram the body’s immune cells, causing some people to develop the autoimmune disease lupus.
Lupus, or systemic lupus erythematosus, occurs when the immune system becomes overactive, with sustained activity of immune cells called B cells and T cells leading to attacks on healthy tissue. This causes a variety of symptoms, including muscle and joint pain, rashes, and extreme fatigue. The causes of lupus are not well understood, but it likely involves an interaction between genetics, hormonal factors, and environmental triggers, such as viruses and disruptions to our microbiome.
People with lupus – about 90% of whom are women – tend to have relatively high numbers of antibodies to the Epstein-Barr virus (EBV), which causes glandular fever. However, EBV infects most adults worldwide, usually without symptoms, while lupus affects approximately 5 million people worldwide.
To understand how they might be linked, William Robinson of Stanford University in California and colleagues developed a single-cell RNA sequencing platform called EBV-seq to discover which B cells — which produce antibodies to neutralize pathogens — are infected with EBV in people with lupus, and determine which genes are expressed by these cells to produce RNA molecules.
In blood samples from 11 people with lupus, researchers found that about 25 out of 10,000 sequenced B cells were infected with EBV. On the other hand, in 10 people without pathology, 0 to 3 B cells sequenced out of 10,000 were infected by the virus.
Most of the infected cells were a type of B cell called memory B cells, which remember past pathogen threats so they can mount a faster response the next time they appear.
Robinson and colleagues showed that these infected memory B cells express genes called ZEB2 And TBX21triggering a chain reaction that activates another type of immune cell, called T helper cells, which recruit uninfected B cells. This accelerates immune activity in a vicious cycle to the point where it begins to attack the body.
The finding that the virus appeared to trigger memory B cells to act in this way by producing a protein called EBNA2, which bound to ZEB2 And TBX21 genes, stimulating their activity. “Our discovery is the mechanism by which this very common virus that infects 95 percent of us, the Epstein-Barr virus, essentially causes lupus,” says Robinson.
As for why most people with EBV don’t develop lupus, Robinson thinks some people’s genetics predispose them to having B cells that are more likely to mistakenly target healthy cells. “It is EBV infection in the context of the genetic and environmental background that predisposes to lupus and together leads to the onset of lupus,” he says.
“EBV is not necessarily likely to play a role in all cases of lupus, because the mechanisms involved in lupus expression are so varied, but in individual patients I am sure it will be one of the major contributors,” says George Tsokos of Harvard Medical School, who reported that the virus induced unusual T-cell responses in people with lupus more than 40 years ago.
A strong link was discovered between EBV and multiple sclerosis, another autoimmune disease, in 2022, and the new findings show how the virus could lead to such disorders more widely, Robinson says.
Additionally, they could explain why some CAR-T cell therapies have shown impressive results in lupus clinical trials. These treatments, which involve genetically modifying a person’s T cells to attack specific targets, were developed to treat blood cancers that occur when B cells multiply out of control and often deplete the B cells. “These CAR T cell treatments appear to result in what we call long-term durable remission, where [lupus] patients are no longer taking the drugs, suggesting they might even cure people. And we think it’s possible that they can do this by getting rid of [of] or by depleting EBV-infected B cells,” says Robinson.
But the potential of these therapies as a treatment for lupus remains unrecognized, Tsokos says, in part because, although B cell levels appear to drop in the blood of people who have received CAR T cells, these cells often hide in the bone marrow, and we don’t yet have data showing that they are all eliminated.
This work also supports the development of a vaccine against the Epstein-Barr virus, transmitted through saliva, to potentially prevent a range of autoimmune diseases. “A vaccine has the potential to prevent EBV infection and thus could prevent lupus in the future,” says Robinson, but he adds that it would not prevent the disease in people already infected with EBV, because B cell reprogramming appears to occur early after infection.
Tsokos thinks the rollout of any EBV vaccine will depend on cost and weighing its benefits against side effects, because it would likely require vaccinating more than 1,000 people to stop a single case of lupus, he says.
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