ME/CFS and Tregs - confused

[Sherlock]

Nope, that is the answer of PROFESSOR Edwards to his co-authors review.

Aha, nice to see that you've got a sense of humor I try myself sometimes, too.

He said:

I read the paper. It provides no evidence for T regs being important in RA.

but you haven't answered that. I was hanging around on this thread to see your answer.

...okay, there you go: Merriam Webster, eh? I don't know if that cite carries a lot of weight, though. How would you rate that from 1 to 10?

 

[halcyon]

Where on earth did you get that idea from?

Human autoimmune diseases are those with autoantibodies - lupus, RA, thyroid disease, pernicious anaemia, myasthenia. People have often thought there must be autoreactive T cells but can you point me in the direction of any consistent evidence? In all the diseases I have been involved in nobody can find any.

Sorry, but this to me is toy immunology. Very popular, but not based on any evidence that I am aware of.

This is probably immunology 101, but what type of cells cause the actual damage to tissues that get tagged with autoantibodies? Would these cells be considered "autoreactive"?

 

[Snow Leopard]

This is probably immunology 101, but what type of cells cause the actual damage to tissues that get tagged with autoantibodies? Would these cells be considered "autoreactive"?

This is a basic description of the process:

http://en.wikipedia.org/wiki/Antibody_opsonization

Complement binding can also trigger:
http://en.wikipedia.org/wiki/Complement_membrane_attack_complex

Cytokines, chemokines etc. don't magically get secreted in large amounts, but are done so for a reason - eg to help mobilise an immune response because the cell is unable to clear out the quantity of immune complexes on its own, and/or needs assistance in that location (eg in tissues).

Not really, it is work going through, which is not ready for public discussion because it needs thinking about and more controls. Maybe I could say that autoimmune B cells tend to have a certain flavour to the way they behave, or signature, and in ME one aspect of this goes in the opposite direction. It has to do with the way the immune response to an antigen evolves and changes character with time. I cannot say more without raising hares.

I appreciate that you can't discuss unpublished research, but can you give an idea of what you mean by the flavour of autoimmune B Cells? It still seems strange to me that the opposite of this could maintain self-perpetuating loops.

 

[adreno]

I am personally doubtful that T regs have much to do with human autoimmunity. Most of the stuff on T regs and autoimmunity relates to mouse disease and particularly inflammatory bowel disease which is more autoinflammatory. There is a mention of RA but I know of no good evidence for T regs being relevant to RA. These stories tend to get very oversimplified. T regs make IL-10 and IL-10 actually helps B cells make antibody - it turns off mostly T cells.

Thanks. I certainly trust your wisdom on the subject.

I was thinking that the idea of high Tregs = hypo immunity, and low Tregs = hyper immunity is oversimplified, perhaps even entirely false. Would it be possible to have high Tregs and still have autoimmunity? Or low Tregs and still have a weak immune response?

Hornig compares late ME/CFS to immunosenescence, and as I posted above, this seems to be characterized by increased natural Tregs, but reduced inducible Tregs. Isn't this an example of having both autoimmune tendencies, as well as an impaired immune response, in old age? So it might be possible that this is similar in ME/CFS?

One reason for asking is personal experience. I have allergies, which should point to low Tregs, as well as POTS. Evidence is emerging that POTS is caused by autoantibodies at adrenoceptors (again pointing to low Tregs). Finally, substances that increase immune response (beta-glucan, etc.) makes me worse. So with these things in mind, I was surprised to read that ME/CFS generally have high Tregs.

Even with these autoimmune tendencies, I never had excellent immunity, but are/were often hit by flu, strep throat, sinusitis and even pneumonia. Another reason why I think it's possible to have both autoimmunity and weak immune response towards infections at the same time.

Would you say it's worth getting tested for Tregs levels? Or any other related tests?

 

[Jonathan Edwards]

Dear Bambi,
Try:

http://www.merriam-webster.com/dictionary/psychosomatic

or

http://www.merriam-webster.com/dictionary/oedipus complex

The existence of a word in a dictionary in science is no indication it describes anything real. If this is the strength of your argument, I think you have just lost your chips.

Whenever scientists do not understand something, they babble. A BSc student who never works out that his teachers are sometimes bullshitting is never going to discover anything very exciting, in my view. Textbooks are mostly written by the boring guys who cannot think of any research of their own and need tenure.

 

[Jonathan Edwards]

There are some good questions about the paradoxes adreno raises. I am off to a neuroimaging conference to see if I can find someone who might be interested in the ME puzzle but I will be back later.

 

[Marco]

All that said T regs certainly are thought of as damping down cells and autoimmunity seems to be more flaring up. Which might raise the strange idea that ME is a problem with B cells that are the opposite of autoimmune. That might not seem to make any sense but without saying anything too much there is just a whiff of a suggestion in the lab that ME B cells might be strange in the opposite way to the autoimmune situation.

I understand that you don't want to say too much but I'm struggling to picture what the opposite of autoimmune/damping down might mean in the context of ME/CFS. Perhaps I'm being too literal but if autoimmune is the uncontrolled proliferation of autoreactive B cell, is the opposite then the uncontrolled proliferation of B cells reacting to 'non-self' of the control of autoreactive B cells?

You mentioned the process of creating B cells on another thread as involving 'punching holes' and that gpt me thinking about another aspect of ME/CFS - the supposed reduced NK cytotoxicity and the role of perforin/granzymes in cytotoxicity via 'punching holes'. The evidence is mixed with some studies showing elevated and some reduced perforin expression while one paper (Unger et al?) showed that perforin increases in PWME and healthy controls in response to 'stress' but that in some PWME that increase is attenuated.

This is going out on a limb but the emphasis on supposed impaired NK function in ME/CFS has focused on the potential impact on viral clearance. But there's another role for perforin produced by NK and CD8 cells in the control of autoimmunity via the elimination of autoreactive B cells.

Evidence from animal models (ahem) suggests that perforin induces autoimmunity in the NOD mouse model of type I diabetes and reduced perforin reduces disease severity (which makes sense if the cytotoxic response targets pancreatic b cells). Conversely perforin may suppress experimental autoimmune encephalitis - the 'mouse model' for MS. Just to add to the mix perforin 'deficiency' leaves mouse models highly susceptible to B cell lymphoma.

ME/CFS doesn't have the tissue damage associated with diabetes.

What if there's an autoimmune loop at work in ME/CFS but the immune system is able control the proliferation of B cells via perforin cytotoxicity. There's no obvious tissue damage but apoptotic cells would release the sort of 'cell danger response' signals that can prime and 'tickle' the microglia. Put the system under stress and an attenuated perforin response can't fully control the proliferation of B cells and you may have a subsequent and possibly prolonged immune 'flare'?

Sorry. All pie in the sky.

 

[aimossy]

There are some good questions about the paradoxes adreno raises. I am off to a neuroimaging conference to see if I can find someone who might be interested in the ME puzzle but I will be back later.

I personally have hope you will be able to recruit and get good researchers interested in this illness. Good luck!

 

[Sherlock]

This is probably immunology 101, but what type of cells cause the actual damage to tissues that get tagged with autoantibodies? Would these cells be considered "autoreactive"?

Nope, because the killer might be killing a normal cell that is wrongly coated one moment and then killing a virus infected cell that is rightly coated the next moment.

They have generic receptors for the generic base end (the Fc portion) of the Y-shaped antibodies. They don't know or care what the two very specific upper tips (the Fab portions) of the Y have bound to.

 

[Sherlock]

Not really, it is work going through, which is not ready for public discussion because it needs thinking about and more controls. Maybe I could say that autoimmune B cells tend to have a certain flavour to the way they behave, or signature, and in ME one aspect of this goes in the opposite direction. It has to do with the way the immune response to an antigen evolves and changes character with time. I cannot say more without raising hares.

Class switching? B cells as professional APCs? We need more clues

 

[Jonathan Edwards]

Sorry for being cryptic about the flavour of autoimmunity.

One of the things that goes against the old idea that autoantibodies are just made by dumb B cells doing what they are told by 'autoreactive T cells' is that in autoimmunity the classes and subclasses of antibody (IgM, IgG1,2,3,4, IgA, IgE) are all out of proportion. IgM rheumatoid factor tends to go on being made for ever instead of switching to IgG. That might be because antigen is never cleared but more odd is that some patients only switch to IgG and some only switch to IgA. In one disease all the autoantibodies are IgG3. And so on. What this seems to be telling us is that autoimmunity is not just 'making an antibody to the wrong thing' it is 'making antibodies in a dysregulated fashion'. Another thing is that autoimmune plasma cells are often short lived in comparison to normal ones.

So there is a 'flavour' to autoimmune B cells - rather in the way that IgE switching is the flavour of B cells in allergy. The details are extraordinarily complicated - to the extent that when Dr Cambridge explains all the data to me my eyes start to glaze over after five minutes - I cannot handle it. Epitope patterns, subclasses, Vh gene usage and all sorts give different flavours to different diseases. But in some respects they all seem to come out of the same kitchen. This is not about being autoreactive per se, or overactive even, it is about certain skewings of the gene usage that say "Gordon Ramsay' or 'Marco Pierre White' cooked this one. And there are some very early signs, which I am nearly regretting even whispering about, that ME B cells were cooked by Michelle Roux instead. And his recipe has some opposite features - he adds pepper to the dessert, and not the entree. It may all turn out different next week but these are the sorts of clues that I like to see. Something not quite expected.

That's about as explicit as I can be.

 

[MEMum]

You are an absolute star Professor!
Thanks so much for all you are doing in ME research, and for explaining things on this forum.
We really appreciate your input and dedication.

 

[melamine]

Hornig compares late ME/CFS to immunosenescence, and as I posted above, this seems to be characterized by increased natural Tregs, but reduced inducible Tregs. Isn't this an example of having both autoimmune tendencies, as well as an impaired immune response, in old age? So it might be possible that this is similar in ME/CFS?

What Hornig says about this makes sense to me. Here is a simple reality that no theories can dispute: I have immune deficiency and autoimmunity, and they developed in tandem if labs are any indication. My understanding is that it's not an unusual situation. How it relates to classic autoimmune and ME theory, I don't know. I find the idea that ME is like premature mitochondrial aging, appealing.

The only time my IL-10 was measured, a few years ago, it was mildly elevated. Common inflammatory markers such as RF, Sed rate, CRP, for me, have nearly always been well within normal and sometimes on the low side, so doctors looking at those only are led to believe I don't have a problem with inflammation. Judging by my symptoms, those markers would seem to be not very useful, and I'm guessing that is true of many others with ME. It's not that some with ME will not have elevations in these, but that they don't seem to get at the heart of the kind of inflammation relating more specifically to ME.
I think @Jonathan Edwards last post was very instructive:

What this seems to be telling us is that autoimmunity is not just 'making an antibody to the wrong thing' it is 'making antibodies in a dysregulated fashion'. Another thing is that autoimmune plasma cells are often short lived in comparison to normal ones.

...

 

[adreno]

HPA axis exhaustion leads to accumulation of Tregs:

Vestn Ross Akad Med Nauk. 2011;(8):24-33.

[Regulatory T-cells: modern approaches to optimization of their numbers].

Pukhal'skiĭ AL, Shmarina GV, Aleshkin VA.

Abstract

Regulatory T-cells (Tregs) are important components of the complex adaptive system of the body responsive to environmental challenges. Tregs ensure peripheral tolerance and play an important role in control of inflammatory reactions. Several subsets of Tregs have been described. Naturally occurring CD4+CD25+ Tregs are recognized as a major subset of immune cells responsible for peripheral immune self-tolerance. Another subtype of Tregs is inducible. Such Tregs are generated in the periphery and realize their suppressive potential largely in the form of anti-inflammatory activity. The latter plays an important role in cooperation of three principal anti-inflammatory mechanisms that developed in the course of evolution: macrophages possessed of suppressive activity, Tregs, and stress hormones.

Normally, all the three mechanisms of inflammation control are in equilibrium. However, the balance may be disturbed with ageing due to repeated episodes of stress and HPA axis activation. As a result, secretion of stress hormones coupled to antigen overload leads to Treg accumulation. In the course of time activation of the HPA axis is replaced by its inhibition manifested both as a decrease of the baseline cortisol level and a reduction of stress-induced cortisol response. Cortisol present in blood at low concentrations is no longer capable of controlling inflammation and Tregs become a principal mechanism of anti-inflammatory machinery. Superfluous Treg accumulation results in the development of functional somatic syndromes, such as chronic fatigue syndrome, and (in some patients) in the growth of tumours resulting from the suppression of anticancer immunity.

On the other hand, the lack of adequate antigen loading in the childhood may delay Treg maturation. Allergy and asthma manifestations may be a consequence of such Treg insufficiency. Thus, both excess and deficiency of Tregs may be at the bottom of morbid conditions. The advances in modern pharmacology open up opportunities for developing new methods to control the Treg level.

PMID:21950132

 

[Jonathan Edwards]

That looks like a complete load of fairy tales, Adreno. I cannot see why extra T regs would produce 'functional somatic syndromes' whatever they might be! If T regs prevent inflammation then shouldn't one get the opposite? And you do not get CFS with ageing. I cannot make any sense of it , can you?

 

[adreno]

That looks like a complete load of fairy tales, Adreno. I cannot see why extra T regs would produce 'functional somatic syndromes' whatever they might be! If T regs prevent inflammation then shouldn't one get the opposite? And you do not get CFS with ageing. I cannot make any sense of it , can you?

Well, I'm not the expert here, but I have seen several comparisons of CFS with accelerated ageing. Lastly, Hornig compared CFS to immunosenescence.

I'm not sure what functional somatic disorders are either, and the article is unfortunately in Russian. However, could the main premise that a hypoactive HPA axis leads to accumulation of Tregs be true?

Several studies have, as you know, found both hypoactive HPA and increased Tregs in CFS.

 

[adreno]

There is another article by the same authors, that might help make the picture clearer:

J Neuroimmunol. 2008 May 30;196(1-2):133-8. doi: 10.1016/j.jneuroim.2008.02.003. Epub 2008 Apr 16.

HPA axis exhaustion and regulatory T cell accumulation in patients with a functional somatic syndrome: recent view on the problem of Gulf War veterans.

Pukhalsky AL1, Shmarina GV, Alioshkin VA, Sabelnikov A.

Abstract

The authors proceeded from the assumption that physical and mental symptoms of functional somatic syndromes (including those observed in Gulf War veterans) are based on both underactivity of hypothalamic-pituitary-adrenal (HPA) axis and excessive accumulation of regulatory T cells (Tregs). Permanent psychogenic stress coupled with high antigen loading leads to gradual depletion of HPA axis, which is manifested by the reduction of stress-induced cortisol response. Under stress hormone deficiency, Tregs begin to play a principal role in anti-inflammatory mechanisms and each new pro-inflammatory stimulus increases their number. Superfluous accumulation of active Tregs results in malfunction of Th1 cells in the brain that leads to the appearance of neurodegeneration foci, which seems to be an anatomic substance for various cognitive and psychological symptoms. New approaches to the treatment of such conditions are also discussed.

PMID:18420283

 

[adreno]

And:

Vestn Ross Akad Med Nauk. 2014;(7-8):30-7.

[Immune dysfunction and cognitive deficit in stress and physiological aging. Part II: New approaches to cognitive disorder prevention and treatment ].

Pukhal'skiĭ AL, Shmarina GV, Aleshkin VA.

Abstract

Long-term stress as well as physiological aging result in similar immunological and hormonal disturbances including hypothalamic-pituitary-adrenal) axis depletion, aberrant immune response (regulatory T-cells, Tregs, and T(h17)-lymphocyte accumulation) and decreased dehydroepiandrosterone synthesis both in the brain and in the adrenal glands.

Since the main mechanisms of inflammation control, "prompt" (stress hormones) and "delayed" (Tregs), are broken, serum cytokine levels increase and become sufficient for blood-brain-barrier disruption. As a result peripheral cytokines penetrate into the brain where they begin to perform new functions. Structural and functional alterations of blood-brain-barrier as well as stress- (or age-) induced neuroinflammation promote influx of bone marrow derived dendritic cells and lymphocyte effectors into the brain parenchyma. Thereafter, mass intrusion of pro-inflammatory mediators and immune cells having a lot of specific targets alters the brain work that we can observe both in humans and in animal experiments.

The concept of stressful cognitive dysfunction, which is under consideration in this review, allows picking out several therapeutic targets: 1) reduction of excessive Treg accumulation; 2) supporting hypothalamic-pituitary-adrenal axis and inflammatory reaction attenuation; 3) recovery of dehydroepiandrosterone level; 4) improvement of blood-brain-barrier function.

PMID:25563002

Is it all nonsense?

 

[nandixon]

Cyclophosphamide, which the Norwegians are wanting to trial, reduces Tregs. I'm not sure how effectively.

I wonder if Tregs are elevated in a subset of ME/CFS due to unresponsive B cells?

Perhaps somewhat analogous to the finding in this work (assuming it has merit)?:

B cell resistance to Fas-mediated apoptosis contributes to their ineffective control by regulatory T cells in rheumatoid arthritis

 

[adreno]

I wonder if Tregs are elevated in a subset of ME/CFS due to unresponsive B cells?

Yes, the elevation of Tregs might be adaptive.

However, rituximab seems to upregulate Tregs.