Long-lived plasma cell (LLPC) theory - Similarities between CFS and Lupus?

[jnmaciuch]

So this is only a problem for invoking antibodies. For T cells we know exactly how it would work. And for the T cell diseases we get the same thing, such as Reiter's, with any number of different infections. It all fits very well. (Which is another piece of circumstantial evidence for jnmaciuch.)

But we do run into the same problem as with autoantibodies of trying to explain how a T-cell mediated disease doesn’t present with the same inflammation and tissue damage as any other T-cell mediated disease.

 

[Jonathan Edwards]

But maybe nothing to do with the specific type of antibody, but instead something about location? Is it possible maybe the normal covid or EBV antibody LLPCs somehow find their way into the brain and set up camp after an infection?

I cannot think of any way that could work. Antibodies are distributed purely by chemical diffusion and dilution throughout plasma and at a lower concentration in tissue fluid (even lower in brain). Quite different from cells which can go to specific places.

 

[EndME]

It's possible. I can't construct a good argument that satisfyingly refutes that, just intuition that may very well be wrong.

I'm guessing one could ask them why the are doing it. Of course that wouldn't really matter even if it works and it might not really matter to the data either.

The problem with trying to avoid discussions about possible placebo-like effects (including regression to the mean, natural recovery, Hawthorne etc) is that you have to invoke them anways because people in the placebo group got equally better.

Maybe something to point out: Fluge and Mella got a bit more improvements then some of the other doctors. That probably isn't efficacy related.

 

[Jonathan Edwards]

Well that’s fair, I have no idea about biology so how I would do it is under this theory look at possible drugs that target these T cells and then scan forums for anecdotes of people improving on said drugs to validate this theory.

That is entirely justified and I wouldn't knock it. The point of this forum is to help everyone get as well-informed as they can be (very much including me) so that we can follow our hunches however we like.

 

[forestglip]

I cannot think of any way that could work. Antibodies are distributed purely by chemical diffusion and dilution throughout plasma and at a lower concentration in tissue fluid (even lower in brain). Quite different from cells which can go to specific places.

Yes, not the antibody distribution independently, but the plasma cells get deposited in the brain during an infection. They spew out antibody there, potentially causing issues with neurons.

 

[Jonathan Edwards]

But we do run into the same problem as with autoantibodies of trying to explain how a T-cell mediated disease doesn’t present with the same inflammation and tissue damage as any other T-cell mediated disease.

But that isn't a problem if nobody has taken the disease seriously and investigated it. If nobody thought skin diseases were interesting then nobody would have linked psoriasis to Reiters and Ank Spond.

And although we don't have a well-described 'lymphoid tissue only' trafficking domain for T cells in the way we have skin, gut, mucosa and VCAM-1 trafficking domains as far as I can see we more or less assume that there will be one for T cells whose job us purely to regulate other immune cells.

And if it involves cells that aren't there to produce tissue damage and inflammation but just force other cells to switch off or apoptose then there is no problem at all.

It certainly isn't in any way 'the same problem'.

 

[EndME]

A little side remark: If I remember correctly I think it has been discussed elsewhere that there have been some studies that have suggested higher ANA levels in ME/CFS, but that the evidence is rather mixed and that someone should look at this properly? Is this still the consensus or has that become even less credible with DecodeME not implicating HLA regions?

 

[Jonathan Edwards]

Yes, not the antibody distribution independently, but the plasma cells get deposited in the brain during an infection. They spew out antibody there, potentially causing issues with neurons.

But that disease already has a name - multiple sclerosis - and ME/CFS shows absolutely no sign of being similar it does not have oligoclonal CSF antibody/IgG bands.

 

[ryanc97]

What drugs would work under this T cell hypothesis? So I can get to work scanning forums.

Or the CD38 hypothesis.

We’ve seen under LLPC hypothesis, basically Proteasome inhibitors. Couple of anecdotes on that one.

Me and @Jaybee00 and @Arfmeister are quite good at doing it

 

[forestglip]

But that disease already has a name - multiple sclerosis - and ME/CFS shows absolutely no sign of being similar it does not have oligoclonal CSF antibody/IgG bands.

Doesn't MS require the antibodies to be specific to myelin? If they are just regular old COVID antibodies, you wouldn't expect myelin to be destroyed. Maybe just antibodies gumming up the works, but not actually binding well to anything.

Sorry, I don't know what oligoclonal bands terminology means.

Edit: I suppose we'd expect to clearly find higher covid or EBV antibodies in CSF though, and I don't recall that.

 

[ryanc97]

@Jaybee00 need to find as much non CD38 LLPC depleting anecdotes as possible and let’s see.

 

[V.R.T.]

I am not sure that the information given above tells us much about efficacy. I would not expect inhibitory effects on CD38 to be relevant. What is relevant is cell killing, which is unrelated. It says something about differences in killing but what matters is simply the effect on Ig levels in humans. Differences in pharmacology exist for rituximab and ocrelizumab etc but may not make a lot of difference to usage. There may well be patent reasons for making claims like this.

@Jonathan Edwards i just followed the link posted above on this thread through into this other thread and stumbled across this comment from several months ago - am I right in understanding that what you said then is the opposite of your position now - that you now think the inhibitory effect on cd38 may well be what causes the daratumumab response if it's real?

Can you say what it is that changed your mind? Is it DecodeME and your host vs host theory/discussions, or is it something you can't divulge just yet? Forgive me if you have already explained this, the discussion has been quite fast moving for the last week or so.

 

[jnmaciuch]

Sorry, I don't know what oligoclonal bands terminology means.

it’s a common test for MS—basically you take serum and cerebrospinal fluid and put the proteins in wells on one side of a gel. Then you set up an electrical gradient that repels the proteins across the gel. The ones with similar electrochemical properties get pushed the same distance away and show up as a “band” due to their overlapping density.

you’re looking for clonal restriction, meaning that a higher proportion of Ig have the same electrochemical properties and are therefore likely to be clones of eachother. This happens when an antigen is recognized by a B cell, which causes it to proliferate and make more of that same antibody. In MS, you’re looking for the bands specifically in CSF samples meaning that the clonal expansion comes from recognizing something in the CNS. In non-pathological conditions, you’ll get a “smear” because your protein sample is more of a completely random assortment. Obviously it’s not infallible, but it’s a good indication that antibodies are reacting to something specific in the CNS

hopefully I’ve hit the right balance between explaining clearly and not oversimplifying to the point of being inaccurate

 

[forestglip]

Obviously it’s not infallible, but it’s a good indication that antibodies are reacting to something specific in the CNS

Thanks. Am I understanding right then that even if covid specific plasma cells were injected into the brain but not actually specific to anything there, you'd still see the bands show up from their antibodies?

 

[jnmaciuch]

Thanks. Am I understanding right then that even if covid specific plasma cells were injected into the brain but not actually specific to anything there, you'd still see the bands show up from their antibodies?

Jonathan could probably provide a better answer—my guess is that you’d see a band for a short period of time after injection, but without continuous stimulation at that site, they’d either migrate to other areas or die off.

 

[Utsikt]

In order to propose an antibody-mediated mechanism, you’d have to do a lot of finagling just to explain why we don’t see the tissue damage and suite of cytokines that nearly always go in tandem [edit: with] autoantibody recognition.

I’m lagging behind in the thread so it might already have been addressed, but I’m assuming you mean autoantibody-mediated here?

 

[ryanc97]

The brainfog and cognitive fatigue can be explained by a lack of oxygen or blood or nutrients to the brain. Unlikely any permanent brain damage.

Just want to say there is no other forum where patients and researchers interact together like this, it is quite impressive.

 

[jnmaciuch]

But that isn't a problem if nobody has taken the disease seriously and investigated it. If nobody thought skin diseases were interesting then nobody would have linked psoriasis to Reiters and Ank Spond.

And although we don't have a well-described 'lymphoid tissue only' trafficking domain for T cells in the way we have skin, gut, mucosa and VCAM-1 trafficking domains as far as I can see we more or less assume that there will be one for T cells whose job us purely to regulate other immune cells.

And if it involves cells that aren't there to produce tissue damage and inflammation but just force other cells to switch off or apoptose then there is no problem at all.

It certainly isn't in any way 'the same problem'.

I'll give you that it has one more thing in the "pro" column than an autoantibody theory

 

[jnmaciuch]

I’m lagging behind in the thread so it might already have been addressed, but I’m assuming you mean autoantibody-mediated here?

That is what I was referring to there. Though a general antibody-related theory still faces similar problems of needing to finagle a creative explanation for why an antibody response doesn't present with detectable inflammation. And would need to explain what exactly is continuously being recognized for years or decades by those antibodies if it is not an autoantigen

 

[ryanc97]

Is it even possible for there to be some kind of autoantibody that binds to haemoglobin and disrupts oxygen delivery to the brain and tissues?

ME muscles fatigue very quickly. Either some kind of AAB that somehow restricts blood flow or oxygen delivery? Possible?

Just thinking randomly here.