A NEW major study has uncovered how the Epstein–Barr virus (EBV) may directly contribute to the onset and progression of systemic lupus erythematosus (SLE). For decades, researchers have known that people with lupus are almost universally EBV-positive, but the biological mechanism behind this association remained elusive. The new work uncovers a direct pathway through which EBV can reprogramme the immune system and set off widespread autoimmunity.
EBV-Infected B Cells Take on a Rogue Identity
Using a newly developed single-cell RNA sequencing platform capable of detecting EBV-infected cells, the research team found that EBV-positive B cells in lupus patients carry a strikingly altered transcriptional signature. Instead of behaving like normal memory B cells, they shift into an antigen-presenting cell (APC)-like state, expressing genes such as CD27, ZEB2 and TBX21 (T-bet). This change equips the cells to activate T cells—an ability they should not ordinarily possess.
Further molecular analysis showed that this reprogramming is driven by the EBV nuclear antigen 2 (EBNA2), which binds directly to the regulatory regions of these APC-related genes. Recombinant antibodies derived from EBV-positive lupus B cells strongly bound nuclear autoantigens, demonstrating that the virus preferentially infects autoreactive B cells and fundamentally alters their function.
A Self-Sustaining Autoimmune Circuit
The study also found that EBV-reprogrammed B cells can activate T peripheral helper cells, which then stimulate additional autoreactive B cells—both EBV-positive and EBV-negative. This interaction forms a self-amplifying immunological loop that reinforces inflammation and accelerates systemic autoimmunity. In essence, EBV sets off a chain reaction that enables autoreactive immune cells to activate each other, sustaining disease activity far beyond the initial viral trigger.
A Mechanistic Link with Major Clinical Implications
These findings significantly strengthen the case for EBV as an active driver of lupus rather than a coincidental infection. By showing how EBV transforms autoreactive B cells into potent antigen-presenting cells, the study provides a mechanistic foundation for exploring EBV-targeted therapies, including antiviral agents, EBV-specific vaccination strategies and selective elimination of EBV-positive B cell populations. The work opens new avenues for prevention and treatment, offering the possibility of reducing disease severity or even modifying long-term prognosis.
Reference
Younis S et al. Epstein-Barr virus reprograms autoreactive B cells as antigen-presenting cells in systemic lupus erythematosus.Sci. Transl. Med.2025;DOI: 10.1126/scitranslmed.ady0210.
