Epstein-Barr virus reprograms autoreactive B cells as antigen-presenting cells in systemic lupus erythematosus, Younis et al., 2025

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Editor’s Summary​

Epstein-Barr virus (EBV) has been making waves as a candidate driver of diseases like multiple sclerosis and Long Covid. It has also long been linked to systemic lupus erythematosus (SLE), although the “why” behind this link has not been defined. Here, Younis et al. provide evidence for a link between EBV infection and disease development. The authors found, using a new strategy to identify EBV-infected cells by RNA sequencing, that infected B cells were transcriptionally distinct from their uninfected counterparts. EBV-infected B cells exhibited features associated with antigen presentation, and this programming seemed likely to be directly driven by the EBV protein EBNA2. These EBV-infected B cells with antigen-presenting abilities had the capacity to activate autoreactive helper T cells, setting off a chain reaction where those T cells could activate other autoreactive B cells, including uninfected ones. In vitro studies in B cell lines provided functional support for this hypothesis. These data suggest that EBV infects and reprograms autoreactive B cells that, in turn, drive the systemic autoimmune response in SLE.

Abstract​

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by antinuclear antibodies (ANAs). Epstein-Barr virus (EBV) infection has been epidemiologically associated with SLE, yet its role in pathogenesis remains incompletely defined. Here, we developed an EBV-specific single-cell RNA-sequencing platform and used it to demonstrate that EBV infection reprograms autoreactive antinuclear antigen B cells to drive autoimmunity in SLE. We demonstrated that, in SLE, EBV+ B cells are predominantly CD27+CD21low memory B cells that are present at increased frequencies and express ZEB2, TBX21 (T-bet), and antigen-presenting cell transcriptional pathways. Integrative analysis of chromatin immunoprecipitation sequencing (ChIP-seq), assay for transposase-accessible chromatin sequencing (ATAC-seq), and RNA polymerase II occupancy data revealed EBV nuclear antigen 2 (EBNA2) binding at the transcriptional start sites and regulatory regions of CD27, ZEB2, and TBX21, as well as the antigen-presenting cell genes demonstrated to be up-regulated in SLE EBV+ B cells. We expressed recombinant antibodies from SLE EBV+ B cells and demonstrated that they bind prototypical SLE nuclear autoantigens, whereas those from healthy individuals do not. We further found that SLE EBV+ B cells can serve as antigen-presenting cells to drive activation of T peripheral helper cells with concomitant activation of related EBV− antinuclear double-negative 2 B cells and plasmablasts. Our results provide a mechanistic basis for EBV being a driver of SLE through infecting and reprogramming nuclear antigen-reactive B cells to become activated antigen-presenting cells with the potential to promote systemic disease–driving autoimmune responses.

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I started to do a deep dive on the paper and realized quickly that it’s just a monstrous amount of analyses and the important part is really just whatever can be interpreted from the last set of experiments. I am probably not the best person to comment on those.

Overall my impression is that this paper received a large amount of media hype, and some parts of it are somewhat interesting, but I’m not sure it’s really breaking ground on a mechanistic connection between EBV and autoimmunity
 
My memory is that we looked at EBV seropositivity and lupus in the 1980s. Itt might even have been published by Patrick Venables and my mother (Joan Edwards). I am pretty sure lupus cases were found in EBV naive individuals. And of course the age of incidence profile for lupus starts going up before mono does. If these diseases involve a stochastic initial event with amplification in a system of many billions of cells it sees unlikely that you can model that in a tissue culture experiment.

EBV may well be permissive for lots of autoimmune diseases but since it is almost ubiquitous the only relevant health policy would seem to be eradication and that is not going to happen.
 
From a commentary piece EBV and the making of lupus (2025) —

Younis et al. could not determine whether EBV reactivation is a driver of SLE flares or a consequence of them and whether the “driver” B cell phenotype is SLE-specific. Because the healthy controls examined were likely distant from EBV infection or reactivation, it remains to be determined whether such EBV+ B cell features would be observed after primary infection in most individuals or only in those prone to develop SLE. More age-matched longitudinal studies will be necessary to solve these kinetic questions.
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Although limited by the relatively small cohort investigated in the setting of a highly heterogeneous disease, the study may nevertheless provide a mechanistic rationale for the impressive clinical efficacy of the CD19-targeted chimeric antigen receptor (CAR) T cell therapies that profoundly deplete peripheral and tissue-resident B cells. CD19-targeted CAR T cell therapies would also eliminate B cells functioning as APCs, thereby providing an explanation as to why B cell depletion proves effective even in disease pathways uncoupled from pathogenic autoantibody production. From their initial conception, CAR T cells engineered with antibody-like specificity were envisioned as a strategy to reach deep tissue targets and eliminate otherwise difficult-to-reach viral reservoirs. EBV-seq now offers a possibility to determine whether CD19 CAR T cell therapy can accomplish the formidable task of durably depleting B cells latently infected by EBV.
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CD19-targeted CAR T cell therapies would also eliminate B cells functioning as APCs, thereby providing an explanation as to why B cell depletion proves effective even in disease pathways uncoupled from pathogenic autoantibody production.

This is a complete joke. The autoimmunity research community still cannot wrench itself away from the story that T cells are driving disease when everything we know says it is B cells. What pathways are 'uncoupled from pathogenic antibody production' in lupus?

The great irony is that this obsession with T cells and antigen presentation arose in the wake of the immunofluorsecence studies I did at the Royal Free in 1979 - which simply showed that there were macrophages expressing DR in joints, as an fool would assume there would be but was nice to confirm. People like Weyand and Schlomchik spent years trying to prove that B cells were important because of antigen presentation but if you think about it for five minutes that makes no sense, since what happens after they present antigen is they make antibodies and thse are what do the damage.

Everybody forgets that before I introduced B cell depletion people had been killing T cells for ten years and had shown conclusively that it made no difference (the Campath-1H study).


Talk about flat earth society.
 
Prof. Akiko Iwasaki created a thread on X to summarise the paper
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1. A groundbreaking paper by @younis_sh1 et al. @stanfordimmuno provides an answer to the long-standing question about how EBV infections are linked to lupus. A short thread to explain the key findings.

2. The authors developed a new method called EBV-seq, enabling them to overcome the barrier of studying rare cells (~25 per 10,000 B cells in lupus patients) that are infected by EBV. Note that in healthy people, only 1/10,000 B cells are EBV-infected.

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3. First, the authors found that EBV infects autoreactive B cells that express anti-nuclear antibodies in lupus patients, but not in healthy people or in patients with multiple sclerosis.

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4. Second, the authors found that the viral protein EBNA2 binds to the regulatory regions of key genes (CD27, ZEB2, TBX21) that reprogram infected B cells into efficient antigen-presenting cells.

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5. Third, EBV+ B cells loaded with chromatin antigens can activate T helper cells and drive expansion of autoreactive B cell clones (even the EBV-uninfected ones) that produce anti-nuclear antibodies - effectively serving as the "disease driver" cells.

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6. EBV is implicated in other autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, Sjögren’s syndrome, as well as post-acute infection syndromes (Long COVID, ME/CFS) and malignancies. Vaccines and antivirals to block EBV are urgently needed. (end)
 
Jonathan Edwards said:
Talk about flat earth society.
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Professor Robinson has contact information here (link) if you want to have a discussion and clarify some things about this lupus study. I hear he is one of the "good" guys for looking into understudied diseases and "rare" disease patients. I get the impression he really wants to make a difference from people I've spoken too.

He could be extremely helpful for ME/CFS research if we could entice him as his labs have a lot of great equipment and people. We just need some direction on what to look at from an immune standpoint.

Shady Younis contact info is here (link)
 
wigglethemouse said:
3. First, the authors found that EBV infects autoreactive B cells that express anti-nuclear antibodies in lupus patients, but not in healthy people or in patients with multiple sclerosis.
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I think this is slightly misleading—B cells reacting to those antigens weren’t found in any significant number in HCs anyways, if I’m remembering the paper correctly. So basically people with lupus have anti-nuclear [edit: reactive B-cells], and some of those were EBV+.

wigglethemouse said:
5. Third, EBV+ B cells loaded with chromatin antigens can activate T helper cells and drive expansion of autoreactive B cell clones (even the EBV-uninfected ones) that produce anti-nuclear antibodies - effectively serving as the "disease driver" cells.
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This is also a qualm that I had with the paper. We already knew that B cells can internalize antigen bound to its BCR and present it to T cells. They showed from their sequencing that EBV+ cells express more genes related to antigen presentation. But they did not show that this functionally lead to more antigen presentation, or more “spreading” to other B cells.

Crucially, in this last experiment, they were using B and T cells from SLE patients that already recognized anti-nuclear antigens, so the healthy control comparison isnt really equivalent. And they didn’t have a condition without EBV (because they needed EBV-transformed lymphoblasts for the assay). So there’s really no way to evaluate the functional role of EBV here compared to what would happen without it. If I’ve missed some crucial detail here I’d be happy to be corrected
 
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