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

Bafflingly fleeting enlargement, too; my neck glands will swell up until for as little as an hour, before subsiding again. A gift of Christmas mince pies last month reminded me that I can often trigger the swelling simply by eating sweet foods.

Am not keeping up with posts very well because my glasses have broken and I can't find the spare pair, but I have enjoyed this thread.

 

My onset wasn’t like that. Right from the triggering viral infection my immune system went into maximum overdrive. I had very swollen hard lymph nodes all over my neck and groin. Heart arrhythmia, random nausea and vomiting, fever and night sweats, and many more symptoms of immune system fighting an infection that lasted months.

I felt the most flu-like sick during the beginning and it stayed in overdrive for many months and then slowly reduced over a couple years.

After those first few years my ME doesn’t feel so “immune” or “flu-like” anymore, the illness and debilitating symptoms now feel like the result of the damage done by that chronic immune overdrive or fighting that initial infection or whatever that happened in the beginning. Or that my body is stuck somehow in a very bad state because of what happened in the beginning.

Do others have the same experience where the immune-related, viral/infectious, and flu-like symptoms are pretty much gone and now your body is in a more severe state where your most prominent and debilitating ME symptoms feel almost entirely neurological and energy related?

 

I had months of joint pain mostly in my hands, wrists and ankles following my initial parvovirus infection which i credit to being the start of my loss of good health. I have also had a number of episodes of uveitis - with no apparent cause... and frozen shoulders and hips...both of which I had before parvovirus... I don’t know if that means anything or not!

 

Q fever used to be included in rickettsia but as I suspected has been moved slightly sideways! So I was making the post that ordinary bacteria do not seem to trigger ME, only the rickettsia-like ones that probably have less in the way of innate immune triggers in their cell wall like peptidoglycan.

It may seem vague but it isn't quite as vague as might seem just from reading the books. A rheumatologist becomes competent at diagnosing Reiter's once they have seen a few cases that are and a few cases that might at first seem to be but are not.

The rashes in Reiter's are quite unique. Keratoderma blenorrhagica or palmar keratosis are a bit like Groucho Marx and Margaret Thatcher - once you can recognise them you are very unlikely to mistake them for something else.

The arthropathy can be non-specific if, for instance, just a single knee synovitis, but in most cases there are telltale signs like asymmetrical finger tenosynovitis. Again, once you have seen a few it becomes fairly clearcut what is and what is not. So reactive arthritis is a very specific pattern, if used to mean a form of seronegative spondarthropathy. It does not look anything like parvovirus arthropathy for instance.

The real give away for the seronegative group are the nail changes - which come in several forms but all pretty unique to the disease.

Behcet's is so uncommon in the UK that few UK rheumatologists see enough cases to get good at identifying it. Of all the patients I have seen with a Behcet's diagnosis I suspect maybe only two actually had the condition. I have a Turkish friend, a really amiable and hugely clever guy called Murat Inanc, who knows Behcet's properly. I suspect he would say the same about Behcet's as I have said about Reiter's. The problem is that these sorts of condition tend to get over diagnosed by 'collector' clinicians.

 

That is right. All you need is one diagnostic sign. Maybe keratoderma or maybe a nail dystrophy. If the signs are less unique in pattern then the diagnosis becomes more a matter of probability but that is standard in medicine, we often work with probables as much as definite.

I think it is reasonable to be confident that we are identifying a specific Reiter process when we see the unique rash or nail abnormality, just as it is reasonable to identify a plant if you just have a very typical flower or leaf.

We don't exclude the people who don't have the rash or nails, we just widen the range of possibilities that need considering. So someone with a single knee synovitis at the age of 20 is quite likely to have the Reiter's process but also reasonably likely to have RA. We manage them as if they might have both.

There are times when the distinction does not matter - if wanting to offer a TNF inhibitor, which works for both. If rituximab is an option then it is important to weigh up as carefully as possible the likelihood of one or the other because Reiter's is not B cell related.

If people had odd collections of symptoms and signs I would follow them as having uncertain diagnosis but offer them anything that was a reasonable risk/benefit choice for the possible diagnostic options - and that would include generalised diagnoses like inflammatory synovitis not otherwise specified. I don't recall closed mindedness amongst my colleagues on this. We all thought we were inching our way forward in semidarkness trying to understand how to categorise in a way that optimised treatment. We all recognised OOTT - one of those things - the illness that did not fit but still needed managing. I got a lot of such cases referred to me in the hope that I might think rituximab would work when the physician had run out of ideas.

And colleagues were always keen to be the first to get on to some new proposed syndrome of a new pattern of association like post-parvovirus arthropathy or Lyme. People were constantly speculating on new micro-syndromes they thought they had picked out.

I realise that I was working in an academic department and one with a number of leading people in the field going through but I don't actually think we were so unusual. In fact the department had so many trainees in the 1980s (12 registrars and 12 senior registrars where most departments had none) that a good proportion of rheumatologists in the UK were trained there.

I actually think the problem here is something a bit different. The way we manage people is probably more dependent on the evidence for a local process that we think we can alter than on a diagnosis. If people have synovitis, which is evidenced by clear physical signs, then we know that we may well help that with steroid injections or TNF inhibitors. But where there is joint pain and no signs of synovitis it is more difficult. Even if I diagnosed Reiter's I would not want to inject steroid into a joint if there was no evidence of inflammation or use a TNF inhibitor.

Other physicians often explain what they do in a different way from me - which is probably why I was invited to give lectures on my slightly unusual ideas about diagnostic categories. But I think this has more to do with the way people talk than how they actually act. There was much less disagreement amongst us what we would do in particular situations.

Of course the bottom line in all this is the raw deal that the person with a problem that we do not know how to fix gets. So pain without synovitis gets a raw deal. The BPS people think they can conjure up some stories to wade in. People like me who need some biological clue to work from are stuck, so I never got anywhere with problems of that sort. As I have said before, I think this is probably the biggest reason why PWME get a raw deal.

 

Curiously, Coxiella burnetti utilise receptor mediated entry into cells somewhat similar to viruses. The known entry receptors are αMβ2 Integrin or αvβ3 & Integrin Associated protein. Notably, it can survive for some time in the lysosomal-like compartment after internalisation.

How bacterial pathogens colonize their hosts and invade deeper tissues
https://pubmed.ncbi.nlm.nih.gov/25637951/

Note that other viruses associated with ME/CFS also have interactions with Integrins. (note that SARS-CoV-2 has a RGD domain)
Beyond RGD: virus interactions with integrins
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086847/

 

I still don't understand what sort of longer-range signalling would be involved such that symptoms appear in other parts of the body? I do realise that all of this is speculative.

I'm trying to tie in how such a hypothesis would lead to stimulation or sensitisation of chemosensitive type III/IV muscle afferents, for example. (either directly, or several steps indirectly)

 

Yes, this is the problem for pretty much any theory we have so far as far as I can see. Cross out all the known cytokines and then what?

I guess one possibility is that CD8 T cells directly annoy the nerve endings in lymphoid tissues through short-range cytokine action (membrane bound?) or even granzymes. This might be a regular job they do to signal to central control that virus is about.

They might also prime monocytes or dendritic cell precursors trafficking through lymphoid tissue which then emigrate into muscle during exercise (we know that monocytes do that) and give a signal to say:

"hang on, you are exercising while there is a pandemic going on and you really ought to stay at home so have a dose of this nerve sensitising membrane bound signal to keep you there".

Maybe we are expecting everything to be done over the internet with cytokine bank drafts and forget that the body still has the option of sending a cheque sealed in envelope by post via various policing cells.

How about that for an imaginative answer?

 

And that could be integrin turtles all the way down.

 

As @Snow Leopard said, I know this is speculative but I wonder what sort of clue/biomarkers would indicate this sort of problem?

 

The ones nobody has thought of yet.
I will have to try and think.

 

Lets remember there are several research groups looking at T-cells in ME. I hope they find some interesting clues.....
* Jackson Group
* Anna Selin via Ramsay award
* Mark Davis
* UK ME Biobank / LSHTM (published)
* Chris Ponting

Here is an excerpt from NIH Reporter on the work Mark Davis's team is doing in ME/CFS that relates to this thread.

Source : https://projectreporter.nih.gov/pro...dvalue=&ddsub=&cr=2&csb=default&cs=ASC&pball=

As an aside, Mark Davis has a new 2020 award to look at how B and T-cells change with COVID infection in a large cohort. He has been studying influenza for a long time (Reporter shows 17+ years) but I imagine COVID has given him access to many more patients to study what happens to the immune system with infection.

Source : https://projectreporter.nih.gov/pro...dvalue=&ddsub=&cr=5&csb=default&cs=ASC&MMOpt=
(If you click on his name in this link it will show all his active projects - note, his ME one has Ron Davis as PI).

This would place Mark Davis and colleagues in a great position to study what happens to B and T cells during long COVID.

 

Well put, thought the same thing after reading about all these theories over the years.

 

Love the analogy

 

That sounds closer to my onset experience. 8 weeks with intense flu like symptoms that gradually became something less intense but very reactive. For the next six months I would sweat so much at night I had to wear full length cotton pjs that I could change for fresh ones once or twice every night to soak up the worst of it, among other things. I spent most of those six months in bed feeling distinctly sick. After that everything calmed down gradually and I was left with severe going on moderate ME.

 

I was wondering who the leading research groups are re T-cells - Jo Cambridge (UCL)?
@Michiel Tack

 

I listed some of the groups above that are studying T-cells in ME/CFS. Each have different strengths so it is not possible to say which is the leading group.
* Some use a standard research tool called flow cytometry to characterise T-cells in large numbers of patients.
* Others are looking at T-cells in ME with a clinical experience focus
* Some using new genetic techniques to characterise what T-cells are targeting,
* Many (not listed) are using the standard Seahorse energy test using the Agilent test script for T-cells and have published or not published
* A few are looking at rare T-cells types to see if they play a role in a subset of patients.
* One is performing basic research into B and T cells in the immune system and is including ME/CFS samples in that work.