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It is something that scientists have been thinking about for years: the link between a previous infection and the development of serious autoimmune diseases. For example, rheumatoid arthritis is associated with a bacterial infection. And patients with multiple sclerosis almost always have had an infection with the Epstein-Barr virus (EBV) just before the disease starts.
But how exactly this interaction works, and how strong the link between the infection and the autoimmune disease is, is a complex puzzle. Researchers at Stanford Medicine added a new piece to that puzzle. They published about this on Wednesday Science Translational Medicine.
The researchers delved into the relationship between a previous infection with EBV and the development of the serious autoimmune disease systemic lupus erythematosus (SLE). EBV, a herpes virus, is best known as the cause of mononucleosis, also known as glandular fever or infectious mononucleosis. SLE is a serious disease in which the immune system attacks all kinds of tissues and organs in the body.
Dormant virus
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Years ago, scientists noted that many people with lupus were also infected with EBV, but it remained unclear what this interaction looks like. The Stanford Medicine group used a new research method to see at cell level which cells contain EBV DNA.
The fact that EBV was found in the cells of people with lupus is not surprising in itself. About 9 in 10 in the general population experience an infection with the virus. This goes unnoticed for about half of the people. Once infected, the virus never leaves your body. It remains present in the cells, kept dormant by the immune system. Virtually all people with lupus are also EBV positive.
The virus hides in B cells, which are part of the immune system. In this way, the virus can disrupt the functioning of the infected immune cells.
Overgrowth of the wrong B cells
The exact cause of lupus has still not been determined, but it is clear that B cells also play an important role there. This type of white blood cell produces antibodies against invaders, such as viruses and bacteria, and also works as a signal cell to other types of immune cells to take action.
But in people with lupus there is a proliferation of ‘wrong’ B cells that attack the body’s own cells, so-called autoreactive B cells. The big question is still: why is that? The researchers at Stanford Medicine found new indications that EBV would play a determining role in this. They found that one in 500 B cells in people with lupus is infected with EBV, while in healthy people it is one in ten thousand cells.
The researchers also showed that the presence of EBV stimulates the autoreactive B cells to become active and to activate other immune cells. In other words: if enough autoreactive B cells are activated by EBV, it triggers a strong immune response that also involves all kinds of immune cells that are not infected with EBV. It is a starting point for a severe autoimmune reaction.
‘Route can go both ways’
A “technically beautiful study,” says professor of experimental rheumatology René Toes of the Leiden University Medical Center (LUMC), “which shows for the first time at cell level that B cells from people with lupus are infected with EBV.” However, according to him, there is a big question that this research does not answer: is lupus caused by a proliferation of immune cells that are infected with EBV, or is it the other way around? Does lupus cause a flare-up of the virus?
“The route could go in two directions,” adds immunologist Jolien Suurmond from the LUMC. “These researchers state that autoreactive B cells will proliferate due to the presence of EBV in those cells. But in lupus it is also known that certain immune cells that are supposed to clear viruses work less well.” According to her, this could mean that the lupus allows the EBV-infected cells to grow unchecked. “And people with lupus use medications that make your immune system less able to clear viruses.”
And then there is the key question, which the Stanford researchers also raise: if almost everyone is infected with EBV, why doesn’t everyone suffer from autoimmune diseases? The American researchers suspect that this has to do with the circulation of different variants of the Epstein-Barr virus, but do not provide a definitive answer.
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