Anoctamin-2-specific T Cells Link Epstein-Barr Virus to Multiple Sclerosis, 2025, Olivia G Thomas et al

[Mij]

Abstract

Multiple sclerosis (MS) occurs when the central nervous system (CNS) is damaged by misguided adaptive immune responses, likely caused by a combination of environmental factors in genetically susceptible individuals. A known prerequisite for disease is Epstein-Barr virus (EBV) infection, and previous studies have demonstrated elevated Epstein-Barr virus nuclear antigen 1 (EBNA1) antibodies which cross-react with the calcium-activated chloride channel anoctamin-2 (ANO2) in persons with MS (pwMS).

ANO2-reactive antibodies have been associated with greater neuroaxonal damage in MS, although their exact effector function is still uncertain. Here, we demonstrate that ANO2 is also the target of IFNγ-producing CD4+ T cells, which are more frequent in untreated and natalizumab-treated pwMS compared to control individuals. Immunisation of SJL/J mice with either ANO2 or EBNA1 elicited cross-reactive CD4+ T cell and antibody responses in vivo. Pre-immunisation of young mice with ANO2 worsened proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE), which in older mice included atypical clinical phenotype, immune infiltration into the brain and reduced survival.

EAE exacerbation was recapitulated with the adoptive co-transfer of ANO2 and myelin antigen-specific CD4+ T cells, and ANO2-specific T cells alone could induce the cell death of ANO2-expressing glial cells in vitro. T cell clones with cross-reactivity to both EBNA1 and ANO2 antigens could be isolated from natalizumab-treated pwMS. Single cell sequencing of EBNA1 and ANO2-specific T cell receptors (TCR) from four pwMS revealed a significant overlap between their antigen-specific expanded TCR repertoires within donors and transcriptomic analysis showed cross-reactive T cells to have predominantly activated and cytotoxic phenotypes.

In summary, we report the first mechanistic evidence that EBNA1 CD4+ T cells can target the MS-associated autoantigen ANO2, thereby establishing a link between EBV infection and development of autoimmune neuroinflammatory disease.
LINK

 

[Mij]

Highlights​

Anoctamin-2 (ANO2) is targeted by T cells in approximately 57% of persons with MS

EBNA1 and ANO2 T cell responses are cross-reactive in humans and mice

ANO2 and EBNA1 T cells have overlapping TCR repertoires and pathogenic phenotypes

ANO2 immunization or ANO2-specific T cell transfer in mice leads to worsened MS-like disease

Summary ​

Epstein-Barr virus (EBV) infection constitutes a prerequisite for multiple sclerosis (MS) development, and cross-reactivity between EBV nuclear antigen 1 (EBNA1) and anoctamin-2 (ANO2) antibodies was previously demonstrated in persons with MS (pwMS). Here, we show that ANO2-specific CD4+ T are more frequent in pwMS. Immunization of SJL/J mice with ANO2 or EBNA1 led to cross-reactive CD4+ T cell and antibody responses. ANO2 pre-immunization led to exacerbated experimental autoimmune encephalomyelitis (EAE), an effect mediated by CD4+ T cells, as confirmed by adoptive transfer experiments. T cell clones with cross-reactivity to EBNA1 and ANO2 could be isolated from natalizumab-treated pwMS, and sequencing of EBNA1- and ANO2-specific T cell receptors (TCRs) revealed a significant repertoire overlap.

We thus report the first mechanistic evidence that EBNA1 CD4+ T cells can target the MS autoantigen ANO2, thereby establishing a link between EBV infection and neuroinflammation.

January 13, 2026 Open Access

 

[Arfmeister]

Anoctamin-2-specific T cells link Epstein-Barr virus to multiple sclerosis (2026). Olivia G. Thomas at al.

Similarities with Long Covid & ME?

From a X-post:



For years, Epstein–Barr virus (EBV) has been linked to multiple sclerosis. The association was strong. But the mechanism remained frustratingly abstract - until now.

This new paper in Cell (2026) finally does what’s been missing. It doesn’t just connect EBV and MS statistically - it shows how the immune system gets it wrong. Instead of focusing on antibodies, the authors look at CD4+ T cells. Long-lived memory cells. The ones that shape immune behavior over decades. They find something striking. More than half of people with MS have T cells that react to ANO2 - a normal human protein expressed in the central nervous system. ANO2 is not viral. It’s not foreign. It’s part of us.

So why would antiviral T cells target it? The answer turns out to be EBV. Specifically, T cells originally trained against EBNA1, a key EBV antigen. The same T cell clones that recognize EBNA1 also recognize ANO2. Same receptors. Same clones. Two very different targets. This is the turning point. MS doesn’t look like overactive immunity here. It looks like misdirected immune memory. The immune system learns EBV early in life and carries that memory forever. In some people, that memory is reused - but aimed at the wrong target. These are not quiet, harmless memory cells. They show an activated, cytotoxic profile. They are ready to act. EBV infects almost everyone. Yet only a small fraction develop MS.

So something else must decide who is at risk. That something else is antigen presentation. In this study, cross-reactive T cells are enriched in people carrying HLA-DRB1*15:01. HLA doesn’t cause disease. It shapes what the immune system learns to see. If your HLA molecules present EBNA1 peptides that closely resemble ANO2 peptides, you create the conditions for molecular mimicry. When these cells are activated in animal models, disease becomes more severe. More inflammation, more relapses, more damage.
Crucially, this pathology is not antibody-driven. It is driven by persistent, antigen-experienced T cells that don’t switch off.

Now take a step sideways. This mechanism is not unique to multiple sclerosis. In long COVID, EBV reactivation appears again and again. Often dismissed as incidental. Possibly it isn’t. Acute SARS infection creates intense inflammatory and immunological stress. In that environment, latent viruses - especially EBV - can reawaken. Not in everyone. Not always easy to document. But often enough to matter. Reactivated EBV means renewed exposure to EBV antigens, including EBNA1. And that sustains EBV-specific T cell clones!

This study shows why that matters. Those clones can carry an autoimmune side effect - molecular mimicry that redirects them toward self-tissue. Seen this way, SARS-CoV-2 may not be the sole culprit. It may act as a trigger, amplifying EBV-focused immune activity in a genetically permissive host. Add immunological imprinting. The immune system tends to reuse familiar strategies, even when circumstances change. In the MS study, cross-reactive T cells cluster in activated and cytotoxic states. These are precisely the cells you don’t want making targeting errors. Translated to long COVID. Chronic immune stimulation + latent viruses + HLA context increase the risk that antiviral immunity becomes pathological. The common thread is persistence.

In MS, EBV persists for life. In long COVID, multiple sources of chronic immune signaling may coexist. MS now gives us a clean mechanistic proof. Other post-infectious conditions may be variations on the same theme. This doesn’t mean everyone with long COVID has autoimmunity. It means the terrain is dangerous - and biology sets the limits.

https://www.cell.com/cell/fulltext/S0092-8674(25)01481-3

 

[DHagen]

I realize that this is largely beside the point of a very interesting and potentially significant finding concerning possible mechanisms underlying both MS and LC, but sometimes I get inordinately upset when I experience difficulty understanding something and I find that I am unable to determine whether this failure is down to my broken and deteriorating brain or whether what I am looking it just might actually be nonsense.
I am able to follow this summary more or less without difficulty until the very end.

In MS, EBV persists for life. In long COVID, multiple sources of chronic immune signaling may coexist. MS now gives us a clean mechanistic proof. Other post-infectious conditions may be variations on the same theme.

Fine. Got it.

This doesn’t mean everyone with long COVID has autoimmunity.

Ok - I am not sure if this is meant to imply that a similar process/mechanism might be at play in Long Covid, but we cannot be sure, or whether it is meant to suggest that some pwLC might have an autoimmune problem and others have something else going on (which sounds more like a problem with the term LC than anything else...); either way, this seems mostly clear.

It means the terrain is dangerous - and biology sets the limits.

...What the hell is this? What is "the terrain" in this metaphor? The immune system? The human body? Existence? And what is "biology" limiting? And how? What does "biology" even mean here?

 

[Arfmeister]

Ok - I am not sure if this is meant to imply that a similar process/mechanism might be at play in Long Covid, but we cannot be sure, or whether it is meant to suggest that some pwLC might have an autoimmune problem and others have something else going in (which sounds more like a problem with the term LC than anything else...); either way, this seems mostly clear.


...What the hell is this? What is "the terrain" in this metaphor? The immune system? The human body? Existence? And what is "biology" limiting? And how? What does "biology" even mean here?

Lol. Made me chuckle a bit.
I think the science writer who wrote this thread, got exhausted by the end and just put in some generic sentences to make a ‘nice finish’.
So note : this is not the one of the authors of the study, but some healthcare consultant/influencer who has a special interest in Long Covid (he might have it by himself I don’t know). He writes it up nicely and make the connection with other illnesses.