- The exact cause of lupus remains unclear.
- Past studies have shown that certain viral infections, like Epstein-Barr virus (EBV), may be a trigger for lupus.
- A new study provides evidence on how EBV may actually be the driving force behind lupus.
“For decades, epidemiologic and immunologic studies have shown unusually strong associations between EBV and lupus, but the field lacked a mechanistic explanation,” William Robinson, MD, PhD, professor of medicine, in the division of immunology and rheumatology at Stanford University, told Medical News Today. “Nearly all people with lupus have evidence of prior EBV infection, and they generate unusually strong immune responses to EBV.”
Robinson is the senior author of a new study recently published in the journal Science Translational Medicine, providing evidence on how EBV may actually be the driving force behind lupus.
According to Robinson, EBV is a very common
“Most people are infected as children or as teenagers — EBV is the cause of mono — and approximately 95% of people worldwide are infected by the time they are adults,” he explained.
After infection, Robinson said, EBV does not fully go away — instead, it hides inside a very small number of
“Most of the time, these infected B cells remain quiet, but in some people, EBV can reprogram these cells, changing their behavior, how they interact with other immune cells, and what antigens they present,” he told MNT.
“Until now, it was not possible to directly identify and characterize the extremely rare EBV-infected B cells that might be driving autoimmunity. We developed a new single-cell sequencing technology that enabled us to directly identify and characterize EBV-infected B cells in lupus patients, and to thereby finally answer that question.”
— William Robinson, MD, PhD
During the study, Robinson and his team found that in healthy individuals, there are fewer than 1 in 10,000 of EBV-infected B cells containing a dormant EBV viral genome.
However, in people with lupus, the number of EBV-infected B cells increased to approximately 1 in 400, which is 25 times higher.
“This was a striking and unexpected result,” Robinson said. “It shows that people with lupus have 25-fold more EBV-infected B cells circulating in their blood than healthy individuals. Even though these cells are rare, in our paper we show that they act as overactive ‘instigators’ of the autoimmune response that mediates lupus.”
Researchers also discovered that dormant EBV in a B cell can sometimes create the pro-inflammatory viral protein EBNA2.
“Our data show that EBNA2 — a viral regulatory protein expressed in certain latency phases — can bind and activate genes that induce B cells to become pro-inflammatory and to activate broad autoimmune responses that mediate lupus,” Robinson explained. “EBV also expresses other genes that activate B cells, and these other genes may also contribute to EBV reprogramming B cells to activate the autoimmune responses that mediate lupus.”
Robinson said that he believes these findings may lead to more treatments, and possibly a cure, for lupus in the future.
“Our findings provide a mechanistic target: the rare EBV-infected ‘driver’ B cells that activate the autoimmune response that mediates lupus,” he explained.
The future of lupus treatments
“Therapeutic strategies that eliminate these EBV-infected B cells — including next-generation B-cell depletion, engineered cellular therapies, or EBV-directed immunotherapies — could, in principle, interrupt the root cause rather than only controlling downstream autoimmune inflammation. That makes transformative or curative therapies conceptually possible, though clinical development will take time.”
— William Robinson, MD, PhD
When asked about the next steps for this research, Robinson said it will include validating this mechanism in larger and longitudinal patient cohorts, and investigating exactly how EBV reprograms autoreactive B cells to mediate systemic autoimmunity.
“(Also) determining if CAR T or other ultra-deep B cell depleting therapies work by depleting EBV+ driver B cells,” he added. “(And) investigating whether the mechanisms identified are active in other autoimmune diseases including MS (multiple sclerosis).”
MNT also spoke with Deepak Rao, MD, PHD, the Jonathan S. Coblyn and Michael B. Brenner Endowed Chair in Rheumatology and Immunology at Brigham and Women’s Hospital, co-director of the Center for Cellular Profiling at Brigham and Women’s Hospital, and associate professor of medicine at Harvard Medical School, about this study.
Rao commented that this report provides a very exciting mechanistic connection between EBV infection and the pathologic autoimmune response in lupus.
“We have long suspected EBV to be implicated in the development of lupus,” he explained. “This report provides an intriguing mechanism by which EBV may fuel the activation (of) the core autoimmune response in lupus.”
“It is striking that the EBV-infected B cells in patients with lupus are so strongly enriched in one specific B cell population — the ‘age-associated B cell’ phenotype, which is a core player in the autoimmune response in lupus,” Rao continued. “The work provides an impressive demonstration that EBV-infected B cells produce autoantibodies, and that these B cells can activate T cell-B cell interactions to drive production of more autoreactive B cells.”
A link to other autoimmune diseases?
“The work raises an interesting question — would a drug that fully suppresses EBV infection also suppress the pathologic autoimmune response in patients with lupus? Or, if we could effectively vaccinate all children against EBV infection, would this prevent the development of lupus in otherwise susceptible individuals? It will be very interesting to see if a similar pattern exists in other autoimmune diseases — do EBV-infected B cells in other autoimmune diseases, such as rheumatoid arthritis or Sjogren’s disease, also produce disease-associated autoantibodies?”
— Deepak Rao, MD, PHD
