In vitro B cell experiments explore the role of CD24, CD38 and energy metabolism in ME/CFS, 2023, Armstrong et al

[Jonathan Edwards]

Sure but in those cases we see progressive tissue damage and [edit: constant] differences in immune populations even just doing a single cell screen of circulating or local cells at the site of damage.

Not always and for a good number of common disorders our understanding of how antibodies work locally are close to zero - scleroderma, dermatomyositis, Sjögren's...

[Edit: it would be a magic bullet solution indeed if there was a way that antibodies caused a problem that only lead to the feeling of being sick, by a completely different and unknown mechanism than the ones we already know about that mediate sickness behavior during infection.]

On the contrary, I would see it as very much in line with all the others - each one involves a different effector mechanism and that is why we call it a different disease. Rarely, several autoantigens are involved in a single stereotypic pathway like centromere and topo-1. The whole point about antibodies is that the degree of variation in CDR allows them to mimic pretty much any functional protein or smaller ligand.

Moreover, we know that there are a lot of autoantibodies that do nothing at all. It would make sense for there to be some that fell in between - produced the very minimum of effect in terms of cellular changes but still produced symptoms.

 

[jnmaciuch]

Moreover, we know that there are a lot of autoantibodies that do nothing at all. It would make sense for there to be some that fell in between - produced the very minimum of effect in terms of cellular changes but still produced symptoms

But also globally primed B cells for CD38 induction ex vivo

 

[Jonathan Edwards]

But also globally primed B cells for CD38 induction ex vivo

Yup. The subtle shifts in things like VH4-34 usage in lupus are invisible unless you know exactly what you are looking for on immunofluorescence of lymphoid tissue that is hard to sample. There may be similar subtle architectural shifts in ME/CFS for all we know.

 

[jnmaciuch]

The subtle shifts in things like VH4-34 usage in lupus are invisible unless you know exactly what you are looking for on immunofluorescence of lymphoid tissue that is hard to sample.

1) CD38 induction in this paper was not a subtle shift visible only if you knew where in the body to look.

2) could you point me to the evidence that VH4-34 is globally induced in B cells by the disease state in lupus other than through the expansion of autoreactive clones? Otherwise it’s not a comparable example.

Being the explanatory black box they are, antibodies are always going to be a viable explanation for any currently unexplained disease because any combination of clinical features can be explained away as “antibodies do weird things and we don’t fully understand them.”

But it does stretch believability to claim that an antibody problem is simultaneously so subtle and isolated that we don’t see what tissue it’s affecting or signs of the cytokines it’s producing to cause an enduring disease state, and also so global that it will result in a clear difference in the response of randomly sampled B cells ex vivo. Unless you want to claim that it’s two separate enduring abnormalities.

 

[Jonathan Edwards]

But it does stretch believability to claim that an antibody problem is simultaneously so subtle and isolated that we don’t see what tissue it’s affecting or signs of the cytokines it’s producing to cause an enduring disease state

It may stretch your believability but having worked with autoimmune disease for 50 years it seems to me entirely in line with other mysteries!!

 

[jnmaciuch]

It may stretch your believability but having worked with autoimmune disease for 50 years it seems to me entirely in line with other mysteries!!

yes that is your response every time haha

 

[Jonathan Edwards]

yes that is your response every time haha

Well you can use it too in time and get away with it if you alter the course of immune disease management!!

 

[jnmaciuch]

And someone correct me if I'm wrong--the trials of plasmapheresis have been pretty disappointing, right? I find it difficult to reconcile how we'd have a lack of miracle improvement anecdotes from pwME who had 90% of their antibodies removed, even just in the short term, if antibodies mediated ME/CFS. Especially considering how miracle improvement stories tend to abound for every other thing desperate pwME have tried.

 

[Jonathan Edwards]

And someone correct me if I'm wrong--the trials of plasmapheresis have been pretty disappointing, right?

Plasmapheresis is disappointing for almost everything. Do we have people with 90% of antibodies depleted? Those who have had various sorts of pheresis seem to have reported benefits quite often even if we tend to be sceptical.

Problems from antibodies do not necessarily go away immediately. And if the mediators of symptoms are produced as a downstream effect of some antibody interaction then they might continue for a while. Maybe the mediators are mediated by stirred up interactions between B cells and T cells somewhere that in themselves do not involve secreted Ig.

I am not saying I favour any particular model but I think one has to thin outside the box a bit. Even though Sjogren's is almost certainly mediated by antibody I doubt that lymphoid aggregates in salivary glands resolve with plasmapheresis.

 

[jnmaciuch]

I am not saying I favour any particular model but I think one has to thin outside the box a bit. Even though Sjogren's is almost certainly mediated by antibody I doubt that lymphoid aggregates in salivary glands resolve with plasmapheresis.

Sure, like I said before, you can always say that antibodies behave weirdly and heterogeneously and therefore you can't disprove their involvement. What I'm looking for is evidence for which "antibodies-mediating-disease" is the most plausible explanation. People getting better after plasmapheresis would be one such piece of positive evidence, though it's lack doesn't disprove antibody involvement.

The fact that depleting IgG by half with dara seems to show more convincing evidence of improvement in a small cohort than depleting IgG by a larger fraction via plasmapheresis does require some out of the box thinking to reconcile.

If I had more data points for which antibodies were the most convincing explanation, I could easily get on board the same train as you and come up with a million ways to reconcile seemingly contradictory data points. But I don't have that. Barring that, it would help to at least have some clear way to explain how this problem could be worsened by exertion (besides a hand wave to the idea that lots of things change with exertion), or how it specifically aligns with the symptoms and time frames of PEM or other hallmark clinical features of the illness, or how it could be triggered by an infection. Which is also lacking. So we're back to the same point of discussion we've come to before, where the reasons for thinking B cells are because they mediate some other diseases and that you've studied them a lot.

 

[ScoutB]

These discussions are so interesting to read as a layman -- so glad you guys are here

What I'm looking for is evidence for which "antibodies-mediating-disease" is the most plausible explanation.

Do you have thoughts on the studies transferring IgG from patients to mice (only done so far in Fibromyalgia and LC, not ME/CFS, as far as I know). Would those studies support the relevance of antibodies to ME/CFS if the same was shown (and replicated) in our case?

These are the three studies I know of Passive transfer of fibromyalgia symptoms from patients to mice; Transfer of IgG from Long COVID patients induces symptomology in mice; Pathogenic IgG from long COVID patients with neurological sequelae triggers sensitive but not cognitive impairments upon transfer into mice. (In case anyone reading this is wondering, the potentially interesting part of these studies was that patient IgG caused effects in mice that control IgG and IgG-depleted serum did not).

 

[Jonathan Edwards]

So we're back to the same point of discussion we've come to before, where the reasons for thinking B cells are because they mediate some other diseases and that you've studied them a lot.

No, the reasons for considering B cells are that they mediate an acquired immune response and Oystein and Olav have anecdotal evidence for anti-B cell therapy being helpful. My involvement with B cells has nothing to do with my view here. Only with my ability to comment. I could equally comment on tissue macrophages, or fluid dynamics, or other things I have studied over the years.

I guess my thought would be that whatever acquired mechanism we could propose instead, maybe involving an epigenetic shift in resident tissue cell behaviour can as easily be mediated by some strange antibody behaviour as by anything else and so far we don't have any other plausible explanations as far as I can see.

 

[Jonathan Edwards]

Do you have thoughts on the studies transferring IgG from patients to mice (only done so far in Fibromyalgia and LC, not ME/CFS, as far as I know).

As the person supposed to be defending the antibody position here (for some reason) my thought would be not much. Transfer of human Ig to mice is fraught with problems and generally pretty uninterpretable. I am beginning to think that Andreas Goebel may have hit on something interesting for a rare form of 'fibromyalgia' but I am being fairly generous. I think it is more likely that he just got into the antibody idea for the wrong reasons and that antibodies may turn out to be involved after all.

 

[forestglip]

Transfer of human Ig to mice is fraught with problems and generally pretty uninterpretable.

Could you elaborate? If they can convincingly show that it is specifically the IgG that causes a change (with IgG depleted control solutions and whatnot), then I would think there is something in the IgG having a toxic effect.

Is it that part about isolating IgG, or is it that differences in lifestyle might lead to the changes in IgG?

 

[MelbME]

Can you define what you mean by inflammation is this context? Is seems to mean something different to every person, so it’s difficult to keep track.

I'm talking about the inflammation that occurs during acute infection/injury in this context.

 

[jnmaciuch]

and so far we don't have any other plausible explanations as far as I can see.

I wouldn't agree with that, but obviously I'm biased

 

[EndME]

The fact that depleting IgG by half with dara seems to show more convincing evidence of improvement in a small cohort than depleting IgG by a larger fraction via plasmapheresis does require some out of the box thinking to reconcile.

If plasmapheresis never really works for antibody mediated diseases what out of the box thinking is needed?

 

[jnmaciuch]

If plasmapheresis never really works for antibody mediated diseases what out of the box thinking is needed?

I wouldn't agree with Jonathan's assessment there that it's completely defunct--just from my university I know of a couple cases of patients receiving pretty apparent clinical benefit. But it is rarely used since there's no justification to even try it unless the patient is in critical condition and no other first-line therapies are effective enough, and I acknowledge it can be inconsistent (just like the inconsistencies with B cell depletion for many of those cases).

[Edit: besides, the whole reason for thinking antibodies in fibro is because a subset of patients was observed to have a pretty strong benefit from it]

 

[Utsikt]

I'm talking about the inflammation that occurs during acute infection/injury in this context.

But that’s different from PVFS, no?

If it’s post-viral, we’re presumably past the acute stage, which is when you suggested there was inflammation that might later lead into ME/CFS if I understood correctly.

And are we talking about the JE kind of inflammation or just the presence or some cytokines or immune activity in general?

It is defined as a tissue change mediated by blood vessels, with dilatation, fluid and protein exudation and cell emigration. It makes the part red, hot, swollen, painful and malfunctioning, although these things vary in degree (chronic inflammation is not very red and may be painless).

 

[jnmaciuch]

Do you have thoughts on the studies transferring IgG from patients to mice (only done so far in Fibromyalgia and LC, not ME/CFS, as far as I know). Would those studies support the relevance of antibodies to ME/CFS if the same was shown (and replicated) in our case?

I agree with Jonathan there, cross-species Ig transfer is pretty messy. If there was a very very clear phenotypic difference that strongly resembled ME/CFS (as much as you could get from an animal model, anyways) then maybe it would warrant a further look, but I’d still be pretty skeptical.