The virus responsible for glandular fever, also referred to as mononucleosis or the kissing disease, has been shown to infect and modify the body’s immune cells, leading to the development of the autoimmune disease lupus in some individuals.

Lupus, or systemic lupus erythematosus, arises when the immune system becomes overly active, attacking healthy tissues due to the persistent activity of immune cells known as B cells and T cells. This can result in various symptoms such as muscle and joint pain, rashes, and profound fatigue. The exact cause of lupus remains unclear, though it likely involves a combination of genetic, hormonal, and environmental factors, including infections and microbiome imbalances.

Among those with lupus—about 90% are women—there tends to be a higher prevalence of antibodies against Epstein-Barr virus (EBV), the virus causing glandular fever. While EBV infects most adults globally and typically remains asymptomatic, lupus impacts roughly 5 million individuals worldwide.

To explore the connection, William Robinson and his team at Stanford University devised a single-cell RNA-seq technology called EBV-seq to identify which B cells (responsible for producing antibodies against pathogens) in lupus patients are infected with EBV and which genes are being expressed by those cells.

In their research, they found that in blood samples from 11 lupus patients, approximately 25 out of every 10,000 sequenced B cells were infected with EBV. Conversely, in 10 asymptomatic individuals, only up to 3 in every 10,000 sequenced B cells were found to carry the virus.

The majority of infected cells were identified as memory B cells, which retain information about previous pathogenic exposures to facilitate a quicker response upon re-exposure.

Robinson and his colleagues demonstrated that these infected memory B cells express genes such as ZEB2 and TBX21, initiating a chain reaction that activates another immune cell type known as helper T cells, subsequently recruiting uninfected B cells. This escalates immune activity in a harmful cycle, eventually beginning to target the body itself.

A significant finding affirming the causal role of EBV in lupus erythematosus was the observation that the virus seems to promote the activation of memory B cells via a protein called EBNA2. ZEB2 and TBX21 activate relevant genes and amplify their activity. “What we discovered essentially reveals how this very common virus, affecting 95% of us, the Epstein-Barr virus, leads to lupus,” says Robinson.

As for why most individuals infected with EBV do not go on to develop lupus, Robinson hypothesizes that some people have a genetic predisposition that causes their B cells to erroneously target healthy cells. “The genetic and environmental contexts of EBV infections predispose individuals to lupus, and these factors combine to provoke the disease,” he asserts.

“EBV may not be implicated in all lupus cases, due to the diverse mechanisms involved in the disease’s development. However, in specific patients, we maintain that EBV serves as a primary cause,” he explains. George Tsokos reports from Harvard Medical School: The virus instigated an abnormal T-cell response, noted in individuals with lupus over 40 years ago.

A strong correlation between EBV and multiple sclerosis, another autoimmune disorder, was identified in 2022, and Robinson suggests that these new insights highlight how the virus can trigger such conditions more broadly.

This may also clarify why certain CAR T-cell therapies have yielded promising results in lupus clinical trials. These treatments, which genetically modify a patient’s T cells to target specific antigens, were originally designed for blood cancers that arise when B cells proliferate uncontrollably and are often reduced in number. “These CAR T-cell therapies seem to result in lasting remissions. [lupus] Patients have been able to discontinue all medications, implying that the therapy might potentially even cure some individuals. We believe they may achieve this by removing [B cells] or depleting EBV-infected B cells,” Robinson suggests.

Nonetheless, Tsokos cautions that the efficacy of this therapy for lupus remains uncertain, partly because while B cell levels in the blood of patients treated with CAR T cells appear diminished, these cells can often conceal themselves in the bone marrow, and there is currently no evidence confirming that all of them are being eliminated.

The research also underscores the potential for developing a vaccine to combat the saliva-transmitted Epstein-Barr virus, which may help avert various autoimmune diseases. “Such a vaccine could be pivotal in preventing EBV infections and thereby lupus in the future,” Professor Robinson states, though he notes it would not mitigate symptoms for individuals already infected with EBV, as B cell reprogramming appears to occur shortly after infection.

Tsokos believes the broad adoption of the EBV vaccine will hinge on weighing its costs against benefits and side effects. He notes that preventing a single case of lupus might necessitate vaccinating over 1,000 individuals.