Strongest evidence yet that the Epstein-Barr virus causes lupus

virus Glandular fever, also known as mononucleosis or kissing disease, appears to infect and reprogram immune cells in the body, leading 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 an attack on healthy tissue. It causes a variety of symptoms, including muscle and joint pain, rashes and extreme fatigue. The causes of lupus are not fully understood, but it is likely due to an interaction geneticshormonal factors and environmental triggers such as viruses and disruptions to our microbiome.

People with lupus – about 90 percent of them are women – tend to have relatively a large number of antibodies against the Epstein-Barr virus (EBV), which causes glandular fever. However, EBV infects the majority of adults worldwideusually asymptomatic, whereas lupus affects about 5 million people worldwide.

To find out how they might be related, William Robinson at Stanford University in California and colleagues developed a single-cell RNA sequencing platform called EBV-seq to determine which B cells, which produce pathogen-neutralizing antibodies, are infected with EBV in people with lupus and to find out which genes are expressed by these cells to produce RNA molecules.

In blood samples from 11 people with lupus, the researchers found that about 25 of every 10,000 B cells sequenced were infected with EBV. In contrast, in 10 people without the disease, 0 to 3 out of every 10,000 B cells sequenced were infected with the virus.

Most of the infected cells were a type of B cell called memory B cells, which remember past pathogenic threats so they can mount a faster response the next time they arise.

Robinson and colleagues showed that these infected memory B cells express genes called ZEB2 And TVH21starting a chain reaction that activates another type of immune cell called helper T cells, which recruit uninfected B cells. This increases immune activity in a vicious cycle to the point where it begins to attack the body.

Crucial to demonstrating the causal role of EBV in the development of lupus was the discovery that the virus appears to induce memory B cells to act in this way by producing a protein called EBNA2, which binds to ZEB2 And TVH21 genes, increasing their activity. “Our discovery is the mechanism by which this very common virus that infects 95 percent of us, Epstein-Barr virus, essentially causes lupus,” Robinson says.

As for why most people with EBV do not develop lupus, Robinson believes that some people genetics predispose them to produce B cells, which are more likely to mistakenly infect healthy cells. “It is EBV infection, in the context of the genetic and environmental environment, that predisposes a person to lupus, which collectively leads to lupus disease,” he says.

“EBV will not necessarily play a role in every case of lupus because the mechanisms involved in the manifestation of lupus are very diverse, but I believe that in individual patients it will be a major factor,” says George Tsokos at Harvard Medical School, who reported that the virus caused unusual T-cell responses in people who had lupus more than 40 years ago.

A strong connection was found between EBV and multiple sclerosisanother autoimmune disease in 2022, and the new findings show how the virus could cause such disorders more broadly, Robinson says.

Moreover, they could explain why some CAR T-cell treatments have been shown to be effective. impressive results in clinical trials for lupus. These treatments, which involve genetically engineering someone's T cells to attack specific targets, were developed to treat blood cancers that occur when B cells run out of control and often exhaust the B cells. “These CAR T cell treatments appear to lead to what we call long-term durable remission when [lupus] patients refuse all medications, suggesting they may even cure people. And we think it's quite possible that they can achieve this by getting rid of [of] or depletion of EBV-infected B cells,” says Robinson.

But the jury is still out on the potential of this treatment for lupus, Tsokos says, in part because while levels of B cells appear to fall in the blood of people receiving CAR T cells, the cells often hide in the bone marrow and we don't yet have data to show they are all cleared.

Work also contributes to development Epstein-Barr virus vaccinewhich is transmitted through saliva, to potentially prevent a number of autoimmune diseases. “The vaccine could potentially prevent EBV infection and thereby prevent future lupus,” Robinson says, but adds that it will not prevent the disease in people already infected with EBV because B cell reprogramming appears to occur soon after infection.

Tsokos believes the rollout of any EBV vaccine will depend on cost and how its benefits compare with any side effects, because you would likely have to vaccinate more than 1,000 people to stop even one case of lupus, he says.