EBV induces CNS homing of B cells attracting inflammatory T cells 2025 Laderach et al.

[Jaybee00]

Abstract​

Epidemiological data have identified Epstein–Barr virus (EBV) infection as the main environmental risk factor for multiple sclerosis, the predominant autoimmune disease of the central nervous system (CNS)<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Bjornevik, K. et al. Longitudinal analysis reveals high prevalence of Epstein–Barr virus associated with multiple sclerosis. Science 375, 296–301 (2022)." href="https://www.nature.com/articles/s41586-025-09378-0#ref-CR1">1</a>. However, how EBV infection initiates multiple sclerosis pathogenesis remains unclear. Here we demonstrate that EBV expands oligoclonal T-bet+CXCR3+ B cells that home to the CNS in humanized mice. Effector memory CD8+ T cells and CD4+ TH1 cells as well as CD4+ TH17 cells co-migrate to the brain of EBV-infected humanized mice. T-bet+CXCR3+ B cells can colonize submeningeal brain regions in the absence of other lymphocytes and attract T cells. Depletion of B cells with rituximab or blocking of CXCR3 significantly decreases lymphocyte infiltration into the CNS. Thus, we suggest that symptomatic primary EBV infection generates B cell subsets that gain access to the CNS, attract T cells and thereby initiate multiple sclerosis.

EBV induces CNS homing of B cells attracting inflammatory T cells - Nature

Epstein–Barr virus infection generates a neuroinvasive B cell subset, which recruits activated T cells to the central nervous system, promoting multiple sclerosis.

www.nature.com

 

[Jaybee00]

How does Epstein- Barr virus induce multiple sclerosis?The infection leads to B cells that get into the brain, attracting pro-inflammatory T cells (mouse model)

 

[Jonathan Edwards]

Thus, we suggest that symptomatic primary EBV infection generates B cell subsets that gain access to the CNS, attract T cells and thereby initiate multiple sclerosis.

Exactly what we said in 1999, although not specifically implicating EBV in the expansion of CNS-homing B cells. I might even be proved right one more time before I die.

 

[Utsikt]

Exactly what we said in 1999, although not specifically implicating EBV in the expansion of CNS-homing B cells. I might even be proved right one more time before I die.

So everyone keeps trying to explain why the T cells attack the CNS, and you’ve essentially said it’s because the B cells tell them to? And the clue to MS might be to get the B cells to stop whatever they are doing, not trying to mess with the T cells that are just doing what they are told?

 

[Jaybee00]

cool paper. However, mice don’t have tonsils and their NALT doesn’t look anything like EBV infection for humans, so I’m just curious whether the model is really capturing human disease processes.

Mice and I—neither have tonsils.

 

[Jonathan Edwards]

So everyone keeps trying to explain why the T cells attack the CNS, and you’ve essentially said it’s because the B cells tell them to? And the clue to MS might be to get the B cells to stop whatever they are doing, not trying to mess with the T cells that are just doing what they are told?

Got it.

 

[Hoopoe]

Wouldn't this also work for ME/CFS? Except that the T cell attack is either more subtle and not visibile on imaging, or that instead of an attack, there is a persistent danger signal that makes cells exposed to it dysfunctional. That dysfunction then maybe somehow feeds back to the immune system so that the signal is maintained.

 

[Jonathan Edwards]

Wouldn't this also work for ME/CFS? Except that the T cell attack is either more subtle and not visibile on imaging, or that instead of an attack, there is a persistent danger signal that makes cells exposed to it dysfunctional. That dysfunction then maybe somehow feeds back to the immune system so that the signal is maintained.

Thirty years ago Esiri pointed out that the lesions of MS might simply be due to local antibody production in brain activating microglia. The T cells may make things worse but B cells on their own in brain are probably very nasty.

B cells are normally forbidden from entering and surviving in almost all tissues except lymph node and spleen. They have special survival factor requirements that most tissues do not offer. However, in brain it seems that once they are in there they can manage without needing certain protective signals. In normal people B cells simply have no motivation to move in to brain - no signals are flagged on the brain capillaries to bring them in. But it seems that once they are in they can cause havoc.

In MS it seems that you absolutely have to have a certain MHC HLA-DQ variant to allow this to happen. How that works is a mystery. It now looks as if you also have to have had EBV infection and very likely EBV lurking in some circulating B cells for them to go in and cause demyelination.

I am not sure about specific brain-homing cells - which are implied in this paper. That is probably newer information.

I doubt B cells get into brain in ME/CFS. But I think it quite possible that T cells get in, and through normal doorways that are used by parts of the hind brain that deliberately pick up signals from the immune system about what is going on.

But none of that totally excludes a possibility that antibodies contribute to T cells, or microglia doing the wrong things in ME/CFS.

 

[Hoopoe]

I doubt B cells get into brain in ME/CFS. But I think it quite possible that T cells get in, and through normal doorways that are used by parts of the hind brain that deliberately pick up signals from the immune system about what is going on.

From what I understand these are parts of the brain involved in homeostasis. Things like fluid balance and blood pressure, release of hormones.

 

[Jonathan Edwards]

From what I understand these are parts of the brain involved in homeostasis. Things like fluid balance and blood pressure, release of hormones.

Yes, and innate immune signals like endotoxin recognition.

 

[forestglip]

It now looks as if you also have to have had EBV infection and very likely EBV lurking in some circulating B cells for them to go in and cause demyelination.

I remember another thread with discussion about it being EBV infected B cells going into the brain and causing trouble.

Would it not be trivial to look at the brain B cells post mortem to see if they all have EBV inside? Is it harder than I'm thinking to even find the B cells?

 

[Jonathan Edwards]

Would it not be trivial to look at the brain B cells post mortem to see if they all have EBV inside? Is it harder than I'm thinking to even find the B cells?

An interesting idea. You might be able to pick up EBV DNA or protein in B cells on tissue sections, using the same sort of material Esiri used.

One thing that struck me as a ridiculously simple explanation was that EBV makes B cells get large - they become the 'atypical mononuclear cells' of 'infectious mononucleosis'. These cells could easily just block brain capillaries and wander out into brain tissue. But for most of us, including the people with the right DQ at the time of their 'mono' infection, this does not seem to happen. In MS the B cells go in to brain in episodes, months or years later.

One intriguing thing in a recent paper is that although people with MS have more antibody in CSF, they do not have more antibody to EBV there. These cells are unlikely to be anti-EBV cells.

 

[Sasha]

An interesting idea. You might be able to pick up EBV DNA or protein in B cells on tissue sections, using the same sort of material Esiri used.

We might have some ME/CFS brain tissue, maybe as part of this MEA project or this Netherlands Brain Bank ME/CFS project - maybe others? I'd thought there was a long-running ME/CFS brain bank in the UK but maybe it exists only in my own brain.

 

[forestglip]

One thing that struck me as a ridiculously simple explanation was that EBV makes B cells get large - they become the 'atypical mononuclear cells' of 'infectious mononucleosis'. These cells could easily just block brain capillaries and wander out into brain tissue.

I'm having trouble picturing how being bigger could make it easier to cross the BBB.

One intriguing thing in a recent paper is that although people with MS have more antibody in CSF, they do not have more antibody to EBV there. These cells are unlikely to be anti-EBV cells.

Yep, that's the thread I linked.

 

[forestglip]

We might have some ME/CFS brain tissue, maybe as part of this MEA project or this Netherlands Brain Bank ME/CFS project - maybe others? I'd thought there was a long-running ME/CFS brain bank in the UK but maybe it exists only in my own brain.

Oh I was talking about MS where there's more reason to believe we'd actually find these B cells. Maybe something to look at in ME/CFS too though just in case.

 

[Jonathan Edwards]

I'm having trouble picturing how being bigger could make it easier to cross the BBB.

Well, if you are a little round ball whooshing through a tiny tube lined with elastic tiles that can allow things to move through the gaps between them and the most important step in a whooshing ball getting the chance to go through is sticking to a patch of tiles then if the ball is so big it has to squeeze through then maybe that serves the same purpose.

Capillaries are just big enough to let red cells through easily and white cells through with a bit of streamlining. A B cell that is five times too big might easily come to a halt I suspect.

 

[forestglip]

Ok thanks that makes sense. Maybe still tough to squeeze through the tiles, but with millions of problematic B cells stopping, a few might make it through by chance.

B cell that is five times too big might easily come to a halt I suspect.

Five times bigger! I was imagining like 20% bigger.

 

[Jonathan Edwards]

On smear (cells flattened out a bit) normal B cell looks like the dark cell right in the middle - barely bigger than a red cell and 95% nucleus. The 'mono' cell to its left is about three times the diameter - maybe ten or more times the volume.

 

[jnmaciuch]

I'm having trouble picturing how being bigger could make it easier to cross the BBB.

I think the paper actually doesn’t support the idea that EBV infected B cells are getting into the brain easier. They didn’t observe different frequencies of B cell infiltration between their EBV and control conditions. What was slightly different was the proportions of a specific T-bet+ CXCR3+ subset of B cells, which seemed to colocalize with HLA-DR+ T cells.

So the story this presents is that B cells get into the brain regardless, often at low quantities, but something about being EBV-infected leads a certain subtype of B cells to recruit HLA-DR+ T cells, which then leads to the brain damage.

 

[forestglip]

The 'mono' cell to its left is about three times the diameter - maybe ten or more times the volume.

Very cool, thanks.