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

[Jonathan Edwards]

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

I absolutely agree. Iwasaki seems to have no clue.

 

[Jonathan Edwards]

I hear he is one of the "good" guys for looking into understudied diseases and "rare" disease patients.

Being a good guy isn't much use if you don't understand complex immune dynamics. The problem with ME/CFS is that it is an order of magnitude more difficult than RA and lupus. You need people who can think very clearly. (Fortunately, some of our members are pretty good at that.)

 

[ME/CFS Science Blog]

nd 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

See what you mean.

They show that lupus patients have an increased number of these EBV-infected B cells, that these are reprogrammed, for example, to remain active, and present antigens, that they respond to antinuclear antigens, and that they can activate T-cells. But the smoking seems to be missing: the latter might also be happening with other B-cells of lupus patients, regardless of whether they are infected with EBV or not.

For example, in this section:

We expressed mAbs derived from BCRs expressed by 69 SLE EBV+ B cells, 15 multiple sclerosis EBV+ B cells, and 10 HC EBV+ B cells and characterized them for reactivity to HEp-2 cells using immunostaining and to prototypical SLE antigens using enzyme-linked immunosorbent assay (ELISA). Of 69 SLE EBV+ B cell mAbs, 44 (64%) bound HEp-2 cells (Fig. 7, A and B). In contrast, none of the 10 HC or 15 multiple sclerosis EBV+ B cell mAbs bound HEp-2 cells or SLErelevant antigens.

I was wondering if you might see the same results in the three groups if you take B cells that aren't EBV-infected.

 

[jnmaciuch]

They show that lupus patients have an increased number of these EBV-infected B cells, that these are reprogrammed, for example, to remain active, and present antigens, that they respond to antinuclear antigens, and that they can activate T-cells. But the smoking seems to be missing: the latter might also be happening with other B-cells of lupus patients, regardless of whether they are infected with EBV or not.

Exactly.

I was wondering if you might see the same results in the three groups if you take B cells that aren't EBV-infected.

[Edit: Yep, if you are only capturing a very small amount of cells, you're likely to capture a much higher number of anti-nuclear reactive B cells just by random sampling in the condition that, definitionally, has a high number of those specific B cells]

We already know that a percentage of the population who never develop lupus will have some B cells that recognize those same nuclear antigens. The hypothesis that they are trying to test here is that lupus is much more likely to develop if someone already had some those autoreactive B cells, a couple of them happened to get infected by EBV, and the latent EBV made those cells much more likely to behave in a way that culminated in runaway autoimmunity.

It's a good hypothesis, but what they would have to show to support it is that some controls had those autoreactive B cells, but significantly fewer (or none) of them were EBV+. They wouldn't have been able to use this method of confirming antigen reactivity to do that--it would simply be too many BCRs to screen. At best they could try some sort of likelihood approximation to estimate how many B cells for each participant probably recognize those antigens based on BCR sequence similarity to known sequences.

So I understand logistically why they chose to focus only on EBV+ cells, but the problem is that these results could just as easily be explained by a simple numbers game rather than anything mechanistically relevant.

[Edited for clarity]

 

[Creek]

Prof. Akiko Iwasaki created a thread on X to summarise the paper

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.
...
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)

Thank you, Wiggle! Having ME-related reading disabilities, I'm so grateful for a synopsis I could skim to find the exact info I came looking for.
On seeing this news, I wondered, did they mention ME? And there we are in Item 6.

Does this item 6 mean that new connections with all these diseases were identified via this research, or more likely just that they acknowledged that EBV has been previously implicated?

 

[Jonathan Edwards]

Does this item 6 mean that new connections with all these diseases were identified via this research, or more likely just that they acknowledged that EBV has been previously implicated?

I think it is just hand waving to be honest. You need to take what Immunotwitterati like Iwasaki say with a pinch of salt. I think the main conclusion is that this doesn't really tell us anything new about how lupus works and in the days when EBV was studied in RA the conclusion was a lemon.