TOPLINE:

Epstein-Barr virus (EBV) infected and reprogrammed autoreactive B cells in patients with systemic lupus erythematosus (SLE) to become activated antigen-presenting cells. EBV-infected B cells in patients with SLE showed increased antigen-presenting capabilities, unlike those in healthy control individuals, and may serve as drivers of systemic autoimmune responses.

METHODOLOGY:

• Researchers analyzed peripheral blood samples from 11 patients with SLE and 10 healthy control individuals, collected at Stanford University, Stanford, California, using EBV-specific single-cell RNA sequencing to investigate the role of EBV in the pathogenesis of SLE.
• Participants were confirmed EBV-positive by elevated anti-EBV nuclear antigen-1 antibody titers.
• EBV-infected B cells were identified based on unique molecular identifier counts of the EBV gene. The study used EBV sequencing, cellular indexing of transcriptomes and epitopes by sequencing, B cell-receptor sequencing, and single-cell RNA sequencing in order to sequence EBV genes, B cell-receptor repertoires, and transcriptomes.
• Differentially expressed genes were compared between EBV-positive and EBV-negative B cells to identify transcriptional changes.

TAKEAWAY:

• Patients with SLE vs healthy control individuals had approximately 25-fold higher proportions of EBV-positive blood B cells, with a mean frequency of nearly 25 per 10,000 sequenced B cells (range, 2.3-82) vs 1 per 10,000 (range, 0-3) in healthy control individuals (P < .001).
• EBV-infected B cells in patients with SLE predominantly exhibited a CD27-positive, CD21-low memory B-cell phenotype; these EBV-positive cells showed upregulation of antigen-presenting cell pathways and transcriptional programs linked to B-cell activation and interferon-stimulated genes, compared with EBV-negative CD27-positive, CD21-low memory B cells, and cells from control individuals.
• EBV nuclear antigen-2 was identified as a potential regulator of genes involved in antigen presentation in EBV-infected B cells, with RNA polymerase II occupancy at the transcription start sites of CD27, CD70, ZEB2, and TBX21.
• Recombinant antibodies were expressed from B-cell receptors expressed by EBV-infected B cells, where of the 69 SLE EBV-positive B cell monoclonal antibodies tested, 64% bound to an epithelial cell line derived from HeLa cells, whereas none of the 10 healthy control or 15 multiple sclerosis EBV-positive B cell-derived antibodies showed binding.

IN PRACTICE:

“Our findings provide a potential mechanistic basis for the role of EBV in the initiation and persistence of autoimmunity in SLE. This framework may also be relevant to other EBV-associated autoimmune conditions,” the authors of the study wrote.

SOURCE:

The study was led by Shady Younis, PhD, Stanford University. It was published online on November 12, 2025, in Science Translational Medicine.

LIMITATIONS:

Technical limitations of EBV-specific RNA sequencing in detecting low-abundance viral transcripts restricted the ability to classify EBV-positive B cells by latency or lytic phase. The use of frozen instead of fresh peripheral blood mononuclear cells may have affected transcriptomic results and EBV gene expression. Immunosuppressive therapy in patients with SLE may have reduced immune control of EBV, potentially contributing to increased frequencies of EBV-positive B cells and expression of EBV-reactivation genes. 

DISCLOSURES:

The study was supported by grants from the National Institutes of Health, a US Department of Veterans Affairs Merit Award, a Congressionally Directed Medical Research grant, the Henry Gustav Floren Trust, and other sources. Three authors declared being inventors on a patent application for targeting EBV-infected B cells to treat EBV-associated autoimmune diseases. Two authors disclosed being co-inventors on a patent for targeting EBV RNAs to deplete EBV-transformed cells and treat associated diseases. Four authors reported being co-founders and stockholders of Ebvio, Inc., of whom two authors also reported being cofounders and stockholders of Flatiron Bio, LLC, and one of these two reported serving as a director of both Ebvio and Flatiron Bio.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.