Systemic lupus erythematosus (SLE) is the prototypic multisystem autoimmune disease. The underlying mechanism of pathogenesis of SLE is complex and remains incompletely elucidated, arising from the interplay of genetic susceptibility, environmental triggers, loss of immune tolerance, and subsequent type I interferon-mediated immune dysregulation.1 The immune dysregulation results in the chronic activation of B and T lymphocytes, stimulating the production of antinuclear antibodies (ANA) and the deposition of immune complexes that precipitate multiorgan damage. Epstein-Barr virus (EBV) is a ubiquitous herpesvirus that is responsible for a spectrum of human diseases. EBV infection typically occurs early in childhood, with more than 50% of children seropositive by age 3 years and over 90% by age 8 years.2 Infection in the first decade of life is usually asymptomatic, while primary infection during adolescence may result in infectious mononucleosis. In a large Chinese retrospective study, the most common diseases associated with EBV reactivation were pneumonia, nasopharyngeal carcinoma, and autoimmune diseases.3 EBV exhibits the typical herpesvirus structure with a large double-stranded DNA genome enclosed in an icosahedral capsid bearing viral capsid antigens. The virus infects B lymphocytes and enters latency, persisting for life within the long-lived memory B-cell population of the host.4 In 2022, a landmark longitudinal study by Ascherio et al.5 showed that the risk of multiple sclerosis (MS) increased 32-fold after EBV infection, while the risk remained negligible in EBV-negative individuals. The study provided the first definitive evidence establishing EBV infection as a causal factor for an autoimmune disease. Due to the high background seroprevalence of EBV, it is thus more challenging to recruit large populations to determine significant differences between disease and control groups. EBV has always been of particular interest in the study of SLE. EBV infection has been epidemiologically linked to SLE, but whether it is a causative agent or a disease driver remained unclear for many decades. The recent work by Younis et al.6 marks a pivotal shift in the field, demonstrating that EBV can reprogram rare autoreactive B cells into highly efficient antigen-presenting cells (APCs) that ignite and sustain autoimmunity in SLE. Younis et al.6 used advanced single-cell RNA sequencing to demonstrate that latent EBV within B cells can reprogram them to APCs to break tolerance and lead to the development of antinuclear autoimmunity. The authors analyzed peripheral blood from 11 SLE patients and 10 healthy controls, finding a significantly higher frequency of EBV-infected B cells in SLE patients (mean of approximately 25 per 10,000 B cells) compared to controls (0 to 3 per 10,000 B cells). By integrating EBV-sequencing and single-cell transcriptomics, the researchers identified the EBV+ population in SLE patients as predominantly CD27+CD21low memory B cells. These cells showed an upregulation of genes involved in antigen processing and presentation, increased B cell activation, and interferon module expression, compared to EBV+ B cells from healthy controls. Further mechanistic analysis using ChIP-seq, ATAC-seq suggested that the viral protein EBNA2 may upregulate APC function genes, thereby promoting the activation of APC pathways. The study group 6 also performed B-cell Receptor (BCR) repertoire sequencing to demonstrate that EBV+ B cells in SLE patients were predominantly singletons and encode antinuclear antigen BCRs. To validate the mechanism in vitro, Younis et al.6 used EBV-transformed lymphoblastoid B cell lines (LCLs) to test whether EBV+ B cells could activate autoreactive T and B cell responses by presenting SLE antigens. The functional assays indeed confirmed that EBV+ LCLs derived from SLE patients were autoreactive and could stimulate the production of ANAs, in contrast with healthy controls. These results collectively demonstrate that a small, but highly potent, population of EBV+ “driver” B cells activates helper T cells, which in turn causes the clonal expansion of the more numerous EBV-negative autoreactive B cells responsible for producing the autoantibodies characteristic of SLE. These findings also raise the possibility that EBV-driven immune activation may contribute not only to disease initiation but also to the clinical and immunologic heterogeneity of SLE. Because HLA alleles frequencies vary across ancestries, EBV antigen processing/presentation may differ between ethnic groups, and patients with higher lytic EBV activity and Latent Membrane Protein 1 expression may show stronger type I interferon signatures and more severe phenotypes, suggesting a genetic–viral basis for clinical heterogeneity in SLE.7 An important limitation of the study by Younis et al.6 is the modest peripheral-blood cohort and the reliance on in vitro functional validation. The central mechanistic inferences draw on EBV-transformed LCLs and on EBNA2 binding maps derived from established EBV + B cell lines, which may not fully recapitulate the in vivo state of EBV+ autoreactive B cells in lupus tissues. Extending these observations beyond the blood to organ-specific immune niches remains a critical imperative. In tissues such as the kidney and skin, the interplay between local antigen presentation and interferon-rich microenvironments may serve as the true engine of pathogenic amplification, necessitating deeper spatial exploration. The authors also note technical constraints in detecting low-abundance viral transcripts (limiting latency/lytic assignment) and the use of frozen peripheral blood mononuclear cells, with potential confounding by immunosuppressive therapy on EBV controls. Nevertheless, the discovery that EBV acts as an initiator and promoter of autoimmunity in SLE is a major breakthrough with far-reaching future implications. Firstly, this research provides a mechanism for the efficacy of deep B-cell depletion therapies (e.g., CD19 CAR-T cells) in refractory lupus, and identifies a promising new therapeutic target in SLE. Notably, this concept has therapeutic precedent: eradication of HCV with direct-acting antivirals can induce meaningful and durable regression of associated indolent B-cell lymphomas.8 Further studies should investigate if targeting only EBV-infected autoreactive B cells would be sufficient to treat established SLE, or if depletion of other pathogenic subsets, like the EBV-negative DN2 B cells and plasmablasts, is also necessary. EBV-sequencing may be a strategy to determine whether B-cell depletion therapies have accomplished durable depletion of B-cells latently infected by EBV. Secondly, while there is currently no licensed EBV vaccine available, this opens the door to using an EBV vaccine as a future primary prevention strategy to protect genetically susceptible individuals from developing SLE. Beyond SLE, this study may inspire and accelerate research into the pathogenesis of other EBV-associated autoimmune diseases, such as rheumatoid arthritis and Sjögren's disease. This landmark study resolves a decades-old mystery about the role of EBV in lupus, and could pave the way for a new generation of therapeutics for SLE and other autoimmune rheumatic diseases. All authors conceived, drafted, and approved the final manuscript. None. The authors declare no conflicts of interest.
Tan et al. (Mon,) studied this question.
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