A Common Virus May Hold New Clues to Lupus

Lupus may be caused by Epstein-Barr virus (EBV), according to researchers from researchers from Standford Medicine. Until now, the cause of lupus was unknown, and these findings represent a crucial step forward in understanding the biological origins of autoimmune disease.

The researchers, through RNA sequencing, found that EBV infects and reprograms B cells, driving the systemic autoimmune response in lupus. Activation of helper T cells by EBV-infected B cells initiates a downstream cascade in which these T cells further stimulate other autoreactive B cells, even those that are uninfected.¹

“This is the single most impactful finding to emerge from my lab in my entire career,” said William Robinson, MD, PhD, a professor of immunology and rheumatology and the study’s senior author. “We think it applies to 100% of lupus cases.”²

What Is Epstein-Barr Virus?

EBV is a virus caused by exposure to oropharyngeal secretions containing the virus but may also be spread via blood transfusions and organ or tissue transplantation. EBV is highly prevalent and affects 19 out of 20 Americans; however, many people are unaware they have it.²

“Practically the only way to not get EBV is to live in a bubble,” Robinson explained. “If you’ve lived a normal life, the odds are nearly 20 to 1 you’ve got it.”²

EBV is associated with multiple diseases. More commonly, EBV leads to infectious mononucleosis (mono; IM), often referred to as the “kissing disease.” However, EBV is also associated with various types of cancer—including B-cell, NK/T-cell, and epithelial cancers—and autoimmune diseases such as multiple sclerosis.³

The link between EBV and these diseases has to do with how the virus affects the immune system and stops B-cells from activating and changing normally. The research published by the Stanford researchers ties this interaction to the development of lupus.³

How EBV Reprograms B Cells in Lupus

The Stanford Medical researchers created an EBV-specific single-cell RNA-sequencing platform to show that EBV infection reprograms autoreactive antinuclear antigen B cells to drive autoimmunity in lupus.¹

RNA sequencing revealed that EBV-positive B cells are primarily CD27+CD21low memory B cells. Researchers found that these EBV-infected B cells are more common in lupus patients and have a unique molecular profile with higher levels of ZEB2, TBX21 (T-bet), and genes that help present antigens.¹

Using an integrated analysis of ChIP-seq, ATAC-seq, and RNA polymerase II occupancy data, the team identified EBV nuclear antigen 2 (EBNA2) binding at key regulatory regions of CD27, ZEB2, TBX21, and several antigen-presenting cell genes that are upregulated in EBV-positive B cells from patients with lupus.¹

By engineering recombinant antibodies from these lupus-associated EBV-positive B cells, the researchers found that they readily bound classic lupus-related nuclear autoantigens—an activity not seen in antibodies derived from healthy individuals.¹

Additional experiments showed that EBV-positive B cells in lupus can act as antigen-presenting cells capable of activating T peripheral helper cells. This, in turn, triggered the activation of EBV-negative antinuclear double-negative 2 B cells and plasmablasts, suggesting a broader cascade of autoimmune activation.¹

What This Means for the Future of Lupus Research and Care

The findings open a new chapter in lupus research, providing the strongest evidence to date that a common viral infection may underlie a disease long considered mysterious and multifactorial. Lupus affects an estimated 1.5 million Americans and disproportionately impacts women, particularly women of color.⁴ Despite decades of research, treatment options have remained limited and focused on symptom control or broad immune suppression.

Pinpointing EBV as a potential root cause could accelerate the development of targeted therapies, new diagnostic tools, and possibly preventive strategies aimed at identifying or blocking EBV-driven immune dysregulation. While more research is needed to determine how these discoveries translate into clinical practice, experts say the study lays essential groundwork for rethinking how lupus begins—and how it may one day be stopped before it starts.

REFERENCES

1. Younis S, Moutusy SI, Rasouli S, et al. Epstein-Barr virus reprograms autoreactive B cells as antigen-presenting cells in systemic lupus erythematosus. Science Translational Medicine. November 12, 2025. DOI: 10.1126/scitranslmed.ady0210

2. Stanford Medicine scientists tie lupus to a virus nearly all of us carry. Stanford Medicine. November 12, 2025. https://med.stanford.edu/news/all-news/2025/11/lupus-epstein-barr.html

3. Gequelin LC, Riediger IN, Nakatani SM, et al. Epstein-Barr virus: general factors, virus-related diseases and measurement of viral load after transplant. Rev Bras Hematol Hemoter. May 2011. doi: 10.5581/1516-8484.20110103

4. Lupus facts and statistics. Lupus Foundation of America Ohio Chapter. Accessed November 14, 2025. https://lupusgreaterohio.org/lupus-facts-and-statistics/#:~:text=About%2020%20percent%20of%20those,and%20not%20a%20reportable%20disease