The Epstein-Barr Virus May Cause Lupus

‘Mono’ Virus May Also Cause Lupus

By Humberto Basilio edited by Tanya Lewis

For years scientists have suspected that the Epstein-Barr virus (EBV)—a type of herpesvirus that infects 94 percent of the global population by adulthood and causes mononucleosis (aka “mono”)—might be one cause of lupus, an autoimmune disorder. But these assumptions were based mostly on anecdotal reports.

Now researchers at Stanford University and their colleagues have confirmed that the virus can “reprogram” immune cells that produce antibodies in a way that triggers and sustains lupus. Their small study, published today in Science Translational Medicine, provides the first evidence of this virus-disease link, the authors say.

“We think that this is a transformational discovery,” says Stanford rheumatologist William Robinson, one of the study’s co-authors. Robinson and his team suggest that their results could aid development of a vaccine that prevents lupus.

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Lupus is a chronic autoimmune disease in which the body’s immune system mistakenly attacks its own healthy tissues and organs. It can affect the joints, skin, kidneys, heart, lungs, blood, brain and other parts of the body. Although at least five million people worldwide live with lupus, its cause has remained a mystery.

Recently, EBV was found to cause another autoimmune disease—multiple sclerosis. A 2022 paper co-authored by Robinson showed that EBV triggers multiple sclerosis by priming the immune system to attack the body’s own nervous system—a process similar to what happens in lupus.

Epidemiological studies have shown that people with lupus also often have high levels of antibodies against EBV proteins and that signs that the virus is reactivating tend to coincide with lupus flare-ups.

EBV has also been linked to nasopharyngeal and stomach cancer. Scientists have found that billions of B cells—a type of white blood cell that produces antibodies to fight pathogens—are affected when a person is infected with the virus. But studying B cells’ role in autoimmune diseases such as lupus has been much harder because only about one in 1,000—or even one in 10,000—of these cells is infected, Robinson says.

In their study, Robinson and his colleagues developed a new, EBV-specific single-cell sequencing technique that was capable of detecting the B cells that were infected by the virus. They isolated individual B cells from the blood samples of 11 people with lupus and 10 without the disease. The team found that EBV-infected B cells were about 25 times as abundant in people with lupus than they were in healthy control participants.

The researchers found that EBV infects and reprograms B cells to drive autoimmune attacks. Instead of defending the body, these infected cells begin presenting the body’s own molecules, triggering a chain reaction that fuels the chronic inflammation that is characteristic of lupus.

Each B cell recognizes a specific cellular flag through unique receptors on its surface and can later secrete antibodies. The researchers tested the antibodies produced by these EBV-infected cells and found that many of the antibodies mistakenly recognized cellular components that were known to cause tissue damage in lupus.

The new study is “groundbreaking” because it provides the answer to the long-standing question about how EBV infections are linked to lupus, says Akiko Iwasaki, an immunologist at the Yale University School of Medicine, who was not involved in the research. By showing evidence of the mechanism through which EBV drives lupus, the paper’s authors “provide perhaps the strongest rationale yet for pursuing EBV vaccines to prevent lupus,” Iwasaki says.

Harvard Medical School rheumatologist George Tsokos agrees that the results are “important and exciting.” But he says that discussing vaccines as a way to prevent lupus is premature for now. Still, the findings open many new questions, including whether the same mechanism drives multiple sclerosis, notes Tsokos, who also wasn’t involved in the research.

The results “will help us move from global, nonspecific treatments to precise therapies” for lupus, says Stanford immunologist Shady Younis, a co-author of the new study. Some of these therapies include the use of antivirals, but the current ones are ineffective. A more targeted therapy could bring major benefits, in contrast with nonspecific treatments that affect all immune cells—including essential ones.

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