An Update of a Theory

Moved from the NIH thread:

Perhaps it is time to re-consider the evidence on the influence of sex and other factors in the causation of ME/CFS.

This is very long but comes in parts.

Some facts and theories.
Autoimmune diseases are more common in women.
Autoimmune diseases are mediated by errors in antibody production by B cells.
Autoimmune diseases appear at random, suggesting they start with random events in B cells - which makes sense since all new antibodies are generated through random events.
Women make antibodies for themselves and for their babies. The control of antibody production includes receptors for female sex hormones, including an effect on extra follicular B cell survival. The implication of that is not clear but it may be that in women a wider range of antibodies is made in contrast to men who focus on making very specific antibodies (in follicles). This would make sense if the mother wanted to give the baby a wide range of 'starter' antibodies to help make their own.
RA gets better in pregnancy and lupus gets worse, so depending in the initial antibody mistake the problem may be further compounded or alleviated by shifts in control from sex steroids.

T cell inflammatory diseases tend not to be 'autoimmune' in the sense of finding specific anti-self T cells. (The exception is the AIRE syndrome.) The T cells just seem to be 'too busy'.
Most are associated with MHC Class I so probably CD8 T cell related.
Most have a fairly equal sex ratio, but one, ankylosing spondylitis, is more severe in men even if possibly similar in frequency.
Tissue targeting in immune disease is different in men and women. For instance rheumatic fever affects the mitral valve in women and the aortic in men. Severity in ank spond may relate to this.

ME/CFS
ME/CFS is pretty strongly related to immune stimuli from intracellular organisms - viruses and some bigger things like Q fever. Autoimmune B cell diseases are not. T cell inflammatory diseases tend to relate to infection with intracellular bacteria. All intracellular infections tend to trigger a CD8 response but also some more innate T cells like NK and CD-1/ MAIT. ME/CFS is not linked to Class I genes. So there are reasons to think ME/CS might be triggered by an innate T cell response that is not Class I restricted.

In EBV infection the gradual recovery process over weeks is associated with a strong CD8 T cell response to EBV infected B cells but probably also more innate CD56/CD57+ NK or T cell responses.

Cells that use CD56 and CD57 also use CD16, which 'borrows' antibodies made elsewhere and uses them to guide cytotoxicity.

My thought in 2018 was that a final common pathway in ME/CFS might draw on both B cell initiated autoimmunity and T cell overenthusiastic processes. But the role of infection seems to be the same for females and males with ME so that idea is weak on that point. Maybe it is more likely that true B cell random-based autoimmunity is not relevant to ME/CFS.

However, if the starting point is a T cell response and the cells involved can borrow antibodies for effector function then the more diverse pattern of female antibody production might still make women more likely to run into severe disease. This would be a bit like the reverse of ankylosing spondylitis where the male tissue response was the main factor in disease severity.

And of course it would allow for something looking rather like ME/CFS to occur in autoimmune diseases where antibody production is generally uncontrolled - which means lupus and Sjogren's specifically. In that situation the T cell regulation may be OK but misbehaviour is driven by the presence of a blur of unhelpful antibodies being picked up by CD16.

The next bit of the puzzle is PEM and crashes. These seem to be salient if not unique in ME/CFS. Psoriasis can wax and wane with stimuli but not in the same way and most other T cell diseases don't much. Maybe exertion stimulates an outpouring of CD-1 or MAIT T cells over a period of days - that would be perfectly reasonable, as a response to muscle and other tissue use requiring increased patrolling and tissue repair. Maybe not so much an outpouring as a waking up of certain interactions in extra follicular lymph mode areas - producing sore nodes and sore throat. The hypothalamus would very likely be involved in 'counting' the exertion, just as it counts how much you eat at lunch, and sending out signals to the lymph nodes.

In this model, the female emphasis on wide spectrum antibody production would explain the sex ratio but have nothing to do with the specific random errors of autoimmunity. An overenthusiastic T cell response might occur in both sexes equally but if men have a less varied antibody spectrum there may be less chance of CD16 picking up antibody that can engage in signal production.

Nevertheless, it is still possible that antibody regulation loops quite similar to those seen in autoimmunity can contribute even if 'piggy-backed' onto T cell misbehaviour. The analogy would be the antibodies in coeliac disease, which is dependent on a continuing T cell response to gluten in diet.

If this sort of model is right then maybe the signalling pathway that needs blocking is not the 'riot police' fever signal based on TNF and IL-1 but a 'morning after clear up' signal that follows exertion and is normally unnoticed but which can have quite profound effects - as seen for instance after major surgery when nitrogen metabolism shifts and appetite changes.

 

This is way over my head but I just wanted to thank you for thinking so hard about this, @Jonathan Edwards !

 

Need to remove rust from brain….

 

Lemon juice could be good.

 

You can see why Wessely/White/Chalder/the Dutch etc opted for fear avoidance and deconditioning, really. Or should we call it, the "easy task". Because what you've described sounds awfully like a "hard task".

Thank you so much.

 

Way out of my depth here, but Just wanted to pinpoint to this extract from the recent Biopsy study from Rob Wust on Muscle Tissue Biopsy before vs Biopsy I’m PEM 1-day after - in Long Covid patients (ME type) versus healthy controls.

Abundant T-cells in Muscle Tissue at baseline (and directly after exercise for LC ánd HC)

“CD3+ T-cells were absent in healthy controls, but present in patients with long COVID before induction of post-exertional malaise. Exercise resulted in an accumulation of CD3+ T-cells inside skeletal muscle tissue, but this response was blunted in patients experiencing post-exertional malaise. “

https://www.nature.com/articles/s41467-023-44432-3

 

Which bit would be the hard task?
Sorry, I can't quite follow your metaphorical allusion - although I can see where it is coming from.

If the model I am suggesting is right then quite likely the solution is sitting on some biotech shelf just as rituximab was when I worked out it might be useful for RA. A nice small molecular weight CD16 inhibitor maybe - but a little bit more data might be needed in this case, I agree!

 

Yes, that would be consistent but T cells go in to muscle at the drop of a hat and it is hard to be sure whether one can make much more of it. If my model is roughly right most would probably be what in science we call 'fast followers' - moving in where the real culprits have got started.

 

The hard task is coming up with the model you have proposed, that takes it right from the point of infection and explains why patients might feel how they feel, and how the sex differences that have been reported in the literature might make sense, and how to try to identify a treatment that might actually work. The easy task is coming up with a model that just blames patients, though they would say empowers us, with the treatment the ever-ineffective, sometimes harmful "Do more".

So the task is the model. This came out of a crashed brain, so what makes sense to me today may not make sense to others!

If your model ends up having an easy solution, well, you'd have a world-ful of grateful pwME/CFS.

 

Definitely feels like the 'clear up' has major problems. I do everything possible to stay away from very severe ME again.

Thanks for your indepth knowledge and I hope you are closer to what could be going on. I'd love to see the answer to this illness finally.

 

Your hypothesis attempts to account for every feature of ME/CFS, especially PEM, which is sorely missing from most hypotheses. I wonder what experiments could be done to prove or disprove this model. DecodeME might be helpful if it highlights certain immune pathways.

 

This is an interesting updated model, which covers the sex differences and encompasses PEM features. It has an elegant sophistication to my untrained eye, which takes the trying to understand and unravel the causation/continuation of ME to yet another level. Thank you very much for doing this Jonathan.

I can’t help you at all in regards to the details of the workings of the body or the chemical and other process pathways which mediate the patients experience of ME/CFS. I have however observed very closely the effects of ME/CFS on the patient and wonder how much your model can explain the various effects apparent in ME/CFS.

The principle effect of course is what we call ‘effort intolerance’, which in the early months even years, follows a boom and crash pattern unless the patient moderates their activity to a level which prevents or minimises the crash.This might be described as being quick to reach ‘exhaustion’ and slow to ‘recover/replenish (the clear up being an apt term).In many patients this affects their ability to carry out the activities of daily life to varying degrees of severity, from mild to very severe.

Each of these severity levels comes with its own answer as to how much the patient can do ‘repeatedly’ and ‘safely’. For some ME patients, this question of how much ‘repeatedly and safely’ they can tolerate activities spreads to all their interactions with the environment both external to them and internally. They develop disruptions in other body systems/activities, with the same pattern of having to find the safe level, if possible of repeatability of the actions like eating the same food or taking the same medication. These are questions around sensitising to frequently eaten foods or frequently used fragrances and other chemicals. ME patients seem to develop body system activity, replenishment and safely repeatable levels below that of a well person across many bodily processes the rest of us take for granted.

I have probably explained this very badly, but wondered whether your model accommodates these features of the illness and whether there might be a proclivity towards rapid exhaustion across many body systems coupled with a poor or exhausted ‘clear up’ operation. I can see why resting/pacing/avoiding foods/chemicals etc improves the patients symptoms ie avoids complete immune system exhaustion but am less clear about how helping with the ‘clear up’ will answer the underlying problem of rapid exhaustion, if indeed that does exist as a separate concern.

In many ways it seems to me that ME\CFS comes to look like running on empty most of the time with inadequate uptake or use of the fuel being put in and/or adequate ‘clear up’ of what is used and that which has not been processed quickly enough by the body.

I hope you can see your way to testing the validity of the model, which you seem to suggest might be done without too much difficulty.

 

My ME seemed to start as a type IV food sensitivity, first to oranges, then to most foods. It also had two abrupt changes in delay, from a very precise and consistent 48 hr delay, to 17.5 hrs, then 23.6 hrs. Then the type IV reaction abruptly ended (after food poisoning), but the symptoms persisted, eventually recognized as ME. Would that fit your model?

 

I think the problem is that it is very hard to tell quite what is going on with food intolerances. They might reflect a pre-exiting viral or intracellular bacterial colonisation affecting gut making it sensitive. I doubt Robin Coombs would have recognised his 'type IV' in this context to be honest. It was mostly defined as a skin reaction and we now know skin and gut immune responses are very different.

Acute enteritis is of course a standard way to get started with a post-infective response as in Reiter's.

In the model I am thinking of the initial trigger event need not necessarily be inactive though, it might just be that intracellular organisms are the best stimulus for getting a persistent aberrant T cell response going. In psoriasis very often there is no clear trigger.

 

Maybe it would help elucidate your model to study anecdotes of medication triggering ME/CFS, and seeing if the known drug pathways could potentially mesh with your theory in their effects on the immune or other body systems.

For example, with me, marijuana and clozapine (dopamine antagonist), separately, both caused ME/CFS.

As another example, from Reddit (the original post they are replying to is me):

Another:

I was searching for cases of dopamine antagonists specifically though, so I do not know which other drugs have been reported to cause ME/CFS.

 

I'm wondering if there are/ay be clues from GWAS [DecodeME] e.g. are there well known diseases [with/without T-cell involvement] where GWAS tells you where to focus research effort?

 

Yes, the cluster of diseases around seronegative arthropathy - psoriasis, Crohn's, UC, Ank Spend, Reiter's etc all show linkages to signalling proteins involved in T cell interaction.

The most obvious are the MHC Class I genes, which has not shown up for ME/CFS.
But an important point is that other genes have shown up - including cytokine receptor genes and genes involved in innate signals relating to inflammasomes.

What would be quite a good test of a theory involving T cells or non-B, non-T lymphocytes related to T cells such as NK, would be the prediction that at least some signalling thresholds should carry genetic risks. ME/CFS ought to be genetically linked to some sort of leucocyte signalling gene.

The argument against that is that the risk genes so far identified feed in to classical inflammatory pathways - IL-17 receptor, macrophage clearance or whatever. In ME/CFS these pathways do not seem to be involved. Maybe an interferon-related gene would be more likely to show up.