Almost everyone becomes infected with the Epstein-Barr virus (EBV) at some point in their life. The infection often has no symptoms, but the virus remains permanently in the body’s cells. A study now shows how the dormant virus can trigger the autoimmune disease lupus. A single viral protein called EBNA2 can activate B cells, which then react against the body’s own structures. They get help from other immune cells, which leads to diverse forms of the disease. The findings confirm the previously suspected connection between EBV and lupus and could help find new treatment options.
Anyone who is infected with the Epstein-Barr virus (EBV) as a child usually doesn’t notice anything. In adolescents and adults, however, the infection can cause Pfeiffer’s glandular fever. But regardless of whether the EBV infection occurs with or without symptoms: the virus, which is a herpes virus, remains permanently in the body afterwards. It inserts its DNA into the nucleus of some of our cells, including the B cells of our immune system. Around 94 percent of all adults carry the virus. Previous studies have suggested links between EBV and various autoimmune diseases, including multiple sclerosis, rheumatism and lupus.
Reprogramming of immune cells
A team led by Shady Younis from Stanford University in California has now demonstrated for the first time a mechanism through which the Epstein-Barr virus triggers the autoimmune disease lupus erythematosus. “We believe that this applies to 100 percent of lupus cases, says Youni’s colleague William Robinson. The key therefore lies in the interaction with the B cells. Using a newly developed method for RNA sequencing of individual cells, the researchers identified which B cells in lupus patients and healthy controls were infected by EBV. “In healthy controls, only one out of 10,000 B cells examined was infected with EBV, whereas in people with lupus one was 400, i.e. 25 times as many,” reports the research team.
In order to find out how the virus affected the infected cells, the team next analyzed which cell and viral genes were read. In most cases, the virus lies dormant in the cells. In some cases, however, it causes its host cell to produce a viral protein called EBNA2 (EBV nuclear antigen 2). This in turn acts as a type of molecular switch that activates a number of genes in the B cell’s genome – including those that trigger inflammatory reactions.
Attack on your own body
This is problematic because around 20 percent of our B cells are naturally autoreactive, meaning they are directed against structures in our own body. Normally, these cells are downregulated and are in a resting state where they do no harm. However, when they are activated by the viral EBNA2 protein, they go into fight mode. The previously inactive B cells transform into antigen-presenting cells that recruit additional immune cells in order to initiate a defense reaction against the presented antigen – in this case against parts of the cell’s own nucleus.
This leads to an immunological vicious circle: The EBV-infected antigen-presenting B cells activate T helper cells, which in turn activate other, even uninfected B cells, which also target components of the cell nucleus. This out-of-control immune reaction can destroy numerous cell types in all parts of our body – because almost all of our cells have a nucleus. This leads to the diverse symptoms of lupus, which can range from fatigue, fever and joint pain to serious organ damage and neurological disorders. The researchers were able to reconstruct this mechanism in cell cultures.
Significance for other autoimmune diseases?
“Our results provide a mechanistic basis that EBV is a driver of lupus by activating autoreactive B cells and reprogramming them into antigen-presenting cells, which in turn have the potential to trigger autoimmune reactions,” explain the researchers. In their view, the same mechanism could also play a role in other autoimmune diseases, including multiple sclerosis, rheumatoid arthritis and Crohn’s disease. However, the current study cannot provide an answer to the question of why autoimmune diseases are not much more common given the widespread distribution of the Epstein-Barr virus. Robinson speculates that only certain EBV strains may be able to trigger the discovered mechanism. The genetic predisposition of those affected could also play a role.
The new findings may also help develop more targeted treatments for lupus. There are already therapies that target B cells. The techniques used in the study could help identify patients for whom this treatment is particularly promising.
Source: Shady Younis (Stanford University, California, USA) et al., Science Translational Medicine, doi: 10.1126/scitranslmed.ady0210