The possibility of autoimmunity or auto-reactivity in ME/CFS

[Marky]

This thread was split from
Open Medicine Foundation (OMF) News

It is certainly true that not all autoimmune disease show useful benefit from rituximab. However, lupus does benefit - as now confirmed after 20 years with a large controlled trial. Type 1 diabetes may not strictly be autoimmune. There is certainly not much evidence of B cell mediation. It does fall under a wider umbrella of immunological disease, however, so if 'autoimmune' is being used loosely it makes the point that rituximab may not be relevant.

I don't think Oystein Fluge and Olav Mella believe anything particularly. They have always been very cautious about proposing hypotheses and emphasising that they are speculations being tested.

As @Sid mentioned, the original impetus for looking at autoimmunity has largely fizzled out with failure to find anything replicable in terms of B cell changes as well as the lack of effect of rituximab. I now think of it as unlikely to be what we are looking for. There may be a few people with autoimmune diseases like lupus effectively misdiagnosed as ME, that is about all.

I thought we could not conclude autoimmunity is likely out of the picture as long as we dont know how to target long lived plasma cells? I mean b-cells dont really matter at that point if im not mistanken, as the autoimmune plasma cells survive either way and pump out antibodies to self antigens.

I still think autoimmunity is an likely reason that can explain the chronic nature of ME

 

[Marky]

You can target long living plasma cell pretty easily with bortezomib. Its just not an autoimmune disease.

What do you base that conclusion on?

 

[Hoopoe]

The something in the blood could be the product of some part of the immune system that we didn't know existed.

Fluge and Mella knew before others that there was something in the blood due to the cell culture experiments they did. They thought that could be an antibody that interfered with energy production.

 

[Marky]

What do you base that conclusion on that it is ? A failed Rituximab trial ? A lot of failed ivig trials ? Scheibenbogens 20% "response rate" with Immunadsorption ?

I have not concluded that it is, but you have concluded that its not autoimmune.

As im saying it does not matter that Rituximab study failed if long lived plasma cell are involved.

There is a phase 2 on cyclo that was promising but inconclusive

The Ivig trials have alwo been inconclusive, som showed effect and some did not. They are also old with not the best methodology.

You are making a conclusion prematurily.

 

[Jonathan Edwards]

You can target long living plasma cell pretty easily with bortezomib. Its just not an autoimmune disease.

As far as I know bortezomib does not kill a high percentage of non-malignant plasma cells. It is used to kill neoplastic cells in myeloma. If it was that easy we or others would have used it a decade ago.

 

[Jonathan Edwards]

As im saying it does not matter that Rituximab study failed if long lived plasma cell are involved.

I agree with you that autoimmunity is not ruled out. It is just that the clues that suggested it have not panned out. The serendipitous finding of improvement in lymphoma patients no longer stand up as evidence for autoimmunity since if the treatment had worked that way rituximab should have worked as well.

I still think there is a possibility that a good proportion of ME cases involve a persistent abnormal T cell activation in a hidden compartment, but that would not strictly be autoimmunity.

 

[Marky]

As far as I know bortezomib does not kill a high percentage of non-malignant plasma cells. It is used to kill neoplastic cells in myeloma. If it was that easy we or others would have used it a decade ago.

Interesting. So it targets mainly the plasma cells with the M-protein? Just curious

 

[Marky]

I agree with you that autoimmunity is not ruled out. It is just that the clues that suggested it have not panned out. The serendipitous finding of improvement in lymphoma patients no longer stand up as evidence for autoimmunity since if the treatment had worked that way rituximab should have worked as well.

I still think there is a possibility that a good proportion of ME cases involve a persistent abnormal T cell activation in a hidden compartment, but that would not strictly be autoimmunity.

I agree. Im starting to think that the improvement in the pilot patiens might have been due to the cocktail of immunosuppressive drugs they took for cancer, not themself individually.

Im open for the t cell suggestion too, as u may or may not remember i have a persistent expression on my cd4 and cd8 cells of unknown meaning. Might not mean anything of course.

But yes, it might not be a "classic" case of autoimmunity, maybe another kind of immune dysfunction (pardon me if this is immunobabble he he)

 

[Hoopoe]

I still think there is a possibility that a good proportion of ME cases involve a persistent abnormal T cell activation in a hidden compartment

Is there a disease where this is known to occur?

 

[FMMM1]

I agree with you that autoimmunity is not ruled out. It is just that the clues that suggested it have not panned out. The serendipitous finding of improvement in lymphoma patients no longer stand up as evidence for autoimmunity since if the treatment had worked that way rituximab should have worked as well.

I still think there is a possibility that a good proportion of ME cases involve a persistent abnormal T cell activation in a hidden compartment, but that would not strictly be autoimmunity.

Very interesting i.e. "persistent abnormal T cell activation in a hidden compartment". Would it be possible to test for this and if so then how?

 

[Jonathan Edwards]

Is there a disease where this is known to occur?

It is almost certainly what is going on in psoriasis, and the seronegative arthropathies, like ankylosing spondylitis. Nobody knows what the source of T cell activation is but it clearly present, at least in psoriasis. Other bits of evidence for these being T cell activation problems are the association with MHC Class I genes, involved in cytotoxic T cell activity rather than antibody production, and genetic links to cytokine receptors used by T cells. Steroids make all these conditions better short term, so that again confirms inappropriate immune cell activation, but longer term steroid use is limited by toxicity.

 

[Jonathan Edwards]

Very interesting i.e. "persistent abnormal T cell activation in a hidden compartment". Would it be possible to test for this and if so then how?

Unfortunately it is remarkably difficult to demonstrate exactly what T cells are doing wrong. T cell populations in blood look pretty normal. T cells that traffic to specific compartments show up in those compartments - i.e. in skin for psoriasis and gut for Crohn's disease but nobody knows what is annoying them. If T cells were annoyed just in lymph node and speed, where there are masses of T cells anyway it would be difficult to find the problem I think.

Just possibly it might be that PWME have larger spleens - that would be measurable with MRI. But if there is a difference it must be marginal because someone would have noticed very large spleens by now.

 

[Jonathan Edwards]

As far as I know bortezomib does kill a high percentage of non-malignant plasma cells. And i does get used for decades. CIDP is one of the hardest to treat "autoimmune" diseases which reacts as badly as Cfs to normal medication. So bortezomib is used with some success.

https://www.researchgate.net/public...series_of_10_patients_treated_with_bortezomib

I spent ten years asking haematologists if any of the bortezomib drug family would deal with residual plasma cells in autoimmunity, and I asked some of the world experts on myeloma and on immunoablative therapies for autoimmunity. I was always told that it was not so easy. You do not get agammaglobulinemia with bortezomib at tolerable doses as far as I know - and that is what is needed.

The CIDP study does not look very exciting. Two patients ended up dying because the bortezomib did not work and they tried something even worse. CIDP was one of the earliest autoimmune diseases to be treated with rituximab by Alan Pestronk and Todd Levine in 1997 but it is a tough condition to handle even when drugs work quite well.

 

[Jaybee00]

I still think there is a possibility that a good proportion of ME cases involve a persistent abnormal T cell activation in a hidden compartment, but that would not strictly be autoimmunity.

What type of T cells? By activation you mean they are pumping out cytokines? If so, wouldn’t this have shown up on tests?
If there is abnormal T cell activation, wouldn’t cyclophosphamide or Campath treat this?

Also, what exactly is a hidden compartment?

Thanks.

 

[Jonathan Edwards]

What type of T cells?

CD8 T cells would be likely to be involved because they are involved in antibody-independent immune responses. CD4 T cells might very likely also be implicated but in the disease examples we have, such as psoriasis and ask spend, nobody really knows which cells are the primary problem.

By activation you mean they are pumping out cytokines? If so, wouldn’t this have shown up on tests?

T cell cytokines probably operate almost entirely locally over distances of a few microns at most -pretty much with cell contact. Circulating cytokines are probably mostly derived from macrophages and other stroll cells. In psoriasis there isn't necessarily much to find other than the local rash.

If there is abnormal T cell activation, wouldn’t cyclophosphamide or Campath treat this?

Cyclophosphamide does not deal with T cells at tolerable doses and can actually promote T cell activity, possibly by selective effects on suppressor cells. Campath 1H might well deal with the problem and I have encouraged people to try Campath in conditions like any spondylitis and psoriatic arthropathy. Unfortunately doctors are very frightened of using Campath because of the long term T cell depletion it produces. If we want to deplete T cells that seems misguided but I have never been in a position to try it myself.

The argument for trying Campth in ME is I think marginal but not to be dismissed. Before doing so it would be useful to know if anyone who has had Campath for other reasons also had ME and noticed changes.

Also, what exactly is a hidden compartment?

T cells belong to at least four separate trafficking compartments - gut, skin, mucosal and everything else. So we have four T cell arthropathies - Crohn's, psoriatic, Reiter's and ankylosing spondylitis. I think it quite plausible that there is in fact yet another T cell compartment - that does not go out into any of the peripheral tissues but remains confined to lymphoid tissue. B cells remain confined to lymphoid tissue in normal immune responses. For all the functional variants of T cells there are usually 'null' groups. So there might be a 'null-trafficking' group. The interesting implication would be that persistent activation of these cells would not produce any visible local pathology but might still produce systemic symptoms due to signalling mechanisms. These might not be systemic cytokine release but might involve neural signals or other hormonal signals.[/QUOTE]

 

[FMMM1]

CD8 T cells would be likely to be involved because they are involved in antibody-independent immune responses. CD4 T cells might very likely also be implicated but in the disease examples we have, such as psoriasis and ask spend, nobody really knows which cells are the primary problem.



T cell cytokines probably operate almost entirely locally over distances of a few microns at most -pretty much with cell contact. Circulating cytokines are probably mostly derived from macrophages and other stroll cells. In psoriasis there isn't necessarily much to find other than the local rash.



Cyclophosphamide does not deal with T cells at tolerable doses and can actually promote T cell activity, possibly by selective effects on suppressor cells. Campath 1H might well deal with the problem and I have encouraged people to try Campath in conditions like any spondylitis and psoriatic arthropathy. Unfortunately doctors are very frightened of using Campath because of the long term T cell depletion it produces. If we want to deplete T cells that seems misguided but I have never been in a position to try it myself.

The argument for trying Campth in ME is I think marginal but not to be dismissed. Before doing so it would be useful to know if anyone who has had Campath for other reasons also had ME and noticed changes.



T cells belong to at least four separate trafficking compartments - gut, skin, mucosal and everything else. So we have four T cell arthropathies - Crohn's, psoriatic, Reiter's and ankylosing spondylitis. I think it quite plausible that there is in fact yet another T cell compartment - that does not go out into any of the peripheral tissues but remains confined to lymphoid tissue. B cells remain confined to lymphoid tissue in normal immune responses. For all the functional variants of T cells there are usually 'null' groups. So there might be a 'null-trafficking' group. The interesting implication would be that persistent activation of these cells would not produce any visible local pathology but might still produce systemic symptoms due to signalling mechanisms. These might not be systemic cytokine release but might involve neural signals or other hormonal signals.

[/QUOTE]

This is incredibly interesting @Jonathan Edwards - thank you very much.

I wonder if there are any clues to the existence of the known (problem) T cell sub-groups in our genome and if another (problem) group could be identified via GWAS? What fingerprint would you expect to see in this type of disease?

Basically, how would you test this hypothesis?

 

[Jonathan Edwards]

This is incredibly interesting @Jonathan Edwards - thank you very much.

I wonder if there are any clues to the existence of the known (problem) T cell sub-groups in our genome and if another (problem) group could be identified via GWAS? What fingerprint would you expect to see in this type of disease?

Basically, how would you test this hypothesis?

The simplest way to test it would probably be finding all the people with ME who by chance have been treated with Campath-1H or something similar. An ablative dose, as might be used for treatment of leukaemia etc. should solve the problem.

GWAS might reveal MHC gene associations but it would not have to, so not so much a test as a potential corroboration.

 

[FMMM1]

This is incredibly interesting @Jonathan Edwards - thank you very much.

I wonder if there are any clues to the existence of the known (problem) T cell sub-groups in our genome and if another (problem) group could be identified via GWAS? What fingerprint would you expect to see in this type of disease?

Basically, how would you test this hypothesis?

The simplest way to test it would probably be finding all the people with ME who by chance have been treated with Campath-1H or something similar. An ablative dose, as might be used for treatment of leukaemia etc. should solve the problem.

GWAS might reveal MHC gene associations but it would not have to, so not so much a test as a potential corroboration.

Thank you very much for your reply @Jonathan Edwards

Re Campath-1H or something similar a bit like the Rituximab study then - wipe em out and see if it solves the problem.

Is anyone aware of a large study of MHC sequencing in ME?

 

[Jonathan Edwards]

Is anyone aware of a large study of MHC sequencing in ME?

MHC has been looked at and the results are not clear cut. Fluge and Mella
reported an association in that region to HLA-DQ and HLA-C I think. HLA-C would fit.

 

[JemPD]

Fascinating few posts Jonathan thank you

The simplest way to test it would probably be finding all the people with ME who by chance have been treated with Campath-1H or something similar.

Any ideas how we might do that, it sounds very much worth doing?

Perhaps MEA / AfME / MEAction would be willing to put out a call for feedback?