The true nature of an autoimmune disease, Leisk and Nocon 2021

@joshua leisk,

I realise that my comments may sound unduly critical. I don't doubt that you would like to help PWME but the field is so overburdened with bad science from people who should know better it is hard not to get exasperated.

I think a general point may be worth making.

When I talk about pseudoscience I am including about 90% of papers in this sort of biomedical field now appearing in journals. Whereas a volume of Annals of Rheumatic Diseases from 1966 might contain ten papers, six of which are still regarded as foundational to the field, the average journal volume from 2020 will contain nothing that will be of any consequence in five years time. We are awash with garbage, and you can tell it is garbage easily enough. Most papers serve to bring in salaries, not to advance science.

I think that is likely to be a major problem if you are wanting to take an information technology approach because you will get garbage in garbage out. Even within fields like immunology the main problem is that researchers do not have a wide enough experience of the practical realities of the things they study in the lab so they are making false connections.

As an example, you quote the production of some monoclonal antibodies by a Japanese team from PBC patients. Looking at the abstract of citation 3 they say that they produced these using EBV transformation of patient B cells. In this situation the EBV has nothing whatever to do with the pathology. It is just a lab trick for making B cells clone in vitro. The antibodies involved have no relation to EBV. These days the antibodies would be pulled out using PCR from RNA without going anywhere near herpesvirus.

The other things that a single monoclonal antibody from a patient tells us very little because will be just one of millions of clones any of which may cross react with anything else. This sort of experiment was popular in the early 1990s because monoclonal antibodies were a new probe, but by 2000 it became clear that it told us little or nothing. We have gone back to measuring functional effects of polyclonal populations in patients. And PWME, so far, have not shown any clinically significant autoantibody populations.

The recent studies on mitochondria in ME are worth keeping an eye on but it should be remembered that on past experience we can expect a 95+% likelihood that they will not hold up. If a group sets out to study mitochondria it has to find something that looks like a result in order to get another grant in. Forty years ago you could afford to get a negative result and publish. The pressures from competition now are too harsh for that. Also, the observations on tranformed lymphocytes are very hard to interpret. There are maybe three likely explanations fora difference in ME patients. There might be a genetic difference but that would not make sense because it should be operating from birth. There might be an effect on lymphocytes from acquired signals like cytokine production but that should have washed out during the cell culture process. There might be a sampling artefact so that lymphoblasts are being cloned from a different original subset. That is plausible but it would mean that the results do not tell us anything.

 

Thank you, Jon - truly. This is the type of conversation I came here to participate in. Appreciate your comment.

To clarify, in those early paragraphs, I'm aware of the research-use of EBV to transform b-cells for this purpose. Rightly, or wrongly, I was trying to tie Fukushima's work to EBV, or another HHV, via Kojima et al. 1999. (doi:10.1007/s005350050324). I circled back to this later by saying:

Now, I don't think we really know which virus is creating specific antigens at this time, only that they exist. EBV is an easy one to finger because of the 90+ known antigens which it expresses. There's a long list of targets. The other HHV family members aren't much better, from my understanding.
Nilsson et al. 2020 (doi:10.3389/fmed.2020.00108) compiled a nice list derived from other papers, listing some antigens commonly found in CFS/ME.



So these were used in the paper as an example of potential inputs to creating this looped state.

Whether or not the antibodies to PDC or α-ketoglutarate dehydrogenase complex exist in CFS/ME patients becomes less relevant, only that their existence would trigger this loop.
I then went on to demonstrate a number of other ways / entry points to trigger this loop state.. excess ROS (particularly H2O2, HNE) triggering α-KGDH depletion, NAD+ depletion via IDO biosynthesis impairments (Khasi, Davis - doi:10.3390/diagnostics9030082), same again for mitochondrial membrane damage from eg. salicylates, hypoxia or other induced PDH deficiencies(Fluge et al.) and GDH excess (or insufficiency) triggering a-KG elevation and then α-KGDH depletion. Tretter (doi:10.1098/rstb.2005.1764) had a lot to say about the duality of a-KGDH - how sensitive it is and how much it controls TCA efficiency.

Now, in the n=2 I showed later, a lytic EBV or CMV phase wasn't the cause of CFS/ME in those two cases - zeros on PCR tests, post-aldactone. They'd already temporarily 'patched' these 3 hotspots I mentioned, so they had normal daily lives again, however it was dose dependent, even without a lytic phase.

This seems to leave just the latent cell behaviour... and location.

So taking the known behaviour of both CMV (Chambers - 10.1128/JVI.02123-09) and EBV (Krisna - doi:10.3390/v12080811), where over-expression of KGA, GLS1, GLUD1 & GLUD2 causes the cells to prefer glutaminolysis, we'd see the same behaviour as various cancer cells. This of course means lactate, ammonia and hypoxia and has been shown to influence neighbouring cells. Some organs.. and one in particular.. have some key roles around lactate metabolism and energy production, etc.

Happily, their current therapeutic interventions are also reducing their viral burden.

EBNA IgG from 297 > 229 U/mL. VCA unknown as both exceed the report ranges.
For these 2 people, it'll be interesting to follow up later this year and see how this progresses.
Importantly, if the titres being reduced correlate with any changes in untreated symptoms.

In the meantime, we'll continue to run some limited case studies and I should have an answer next week about the pilot.

I'd happily take input for the pilot design, if anyone has suggestions of what they'd want to see incorporated into the pilot study.

 

I don't understand what you are trying to mean here. Each virus encodes a series of its own proteins which are the antigens for the host antibody response to virus. (I don't understand what you meanly long list of targets.) As far as we know that has nothing to do with autoantibodies except conceivably in Guillain Barré syndrome although I am increasingly doubtful about the meaning of Willison's work even in that case.

There is an old idea from the 1960s that antibodies to viral or bacterial proteins cross-react with host proteins in autoimmune disease but there was never any evidence for this at the time and pretty much none since. The idea should have been buried and forgotten long ago.

The antibodies described by Nilsson are found at much the same levels in normal people so they mean nothing. Tables like that are totally misleading.

I am finding it quite hard to see how you are making any sort of connection here to ME/CFS. It almost sounds as if you are confusing viral antigens with host antigens but I find that hard to believe.

Theories based on what I think you are invoking, which is called molecular mimicry, have been around for fifty years and consistently have been found to go nowhere. The fact that people still raise these ideas seems to indicate that a lot of people in immunology are not able to distinguish a theory that works from one that goes nowhere but sounds superficially as if it should work (molecular mimicry doesn't actually make sense as a model on close inspection even if at first it does). Sadly, that was the conclusion I came to over the years. A handful of my colleagues understood what they were talking about but the majority just seemed to follow fashion.

The remainder I do not follow at all. Loops are an essential part of a systems analysis but I find it hard to believe they occur in basic metabolism. This sounds like the 'metabolic trap' idea that I suspect has no basis. The rest sounds like free floating systems theory detached from any relevance to a real illness. Systems analysis is essential to understanding long term biological dysregulation but each step needs to be firmly grounded otherwise you rapidly float off into fairyland.

Building theories like this is extremely hard for any one person to do. I know from experience working on the role of B cells in autoimmunity. I had a group of about six people at any one time and theories were built by hours of dialogue, with each person with their particular expertise contributing. Much the greatest amount time was devoted to working out why one person's suggestion couldn't work based on another's expertise.

To put it another way, I don't think any of the building blocks you have chosen will act a well-fired brick. They are still blocks of soft mud. A viable theory needs every one to be solid. Medical research is for real. It has to get things right, just as Boeing has to make sure its planes don't crash. In ME we have seen vast numbers of people exposed potentially harmful treatments because medical academics have not bothered to get things right - whether BPS or virus theories - it is the same.
We need people to check ideas make sense.

 

It’s very much like the “metabolic trap” and explains a lot of Fluge’s work.

Essentially, both of those papers bolt directly into this disease model without any alteration and directly extend it.

For the purposes of being responsible to the wider community, we intentionally did not spell out the treatment / model testing protocol in the paper, however we will happily share it privately with any researcher who wants to explore it further and assess any potential risk factors.

 

Sounds sensible and efficient.

With the case reports, we’re currently just using consumer grade wearable fitness trackers. eg.

Spoiler: image of activity tracker readout

 

The activity monitor shouldn’t be a Fitbit or similar casual use device. I used one and it did sort of work, but not well enough for a scientific study. It’s also not waterproof, at least not washing machine proof. Oops.

 

Hi Trish,

The paper was submitted for peer review on the same day as the preprint.



It was apparently too long for that publication, so has been resubmitted.

I’ve considered your other points and decided to respectfully disagree, but appreciate you taking the time to make them.

The approach I’ve taken my entire life served me well. I see no reason to change my methods at this time.

I’m happy for guidance on specific technical details if/when I make an error or am aware of a knowledge gap. I have no plans to change the direction of this journey at all.

As it stands, I have a number of clients, including some who have been previously bedridden, for over a decade, now mobile and living normal lives.

I can understand people’s skepticism, but time and data will demonstrate otherwise.

Thanks,

Joshua

 

Cheers,

I’m quite surprised to hear this..

All the the recent generations are waterproof and we’ve previously tested them to within 5% error margin over a month with DEXA scans, combined with food logging. I was surprised, as the DEXA machine has a tolerance of about 4%.

Was there a particular issue you had that would preclude their use in a study? I’m genuinely curious.

 

I'm not qualified, or competent, to follow/understand many of the posts on this thread, but the following caused some concern.

Really? You talked to 2 pwME for 5-8 hours a day, for many months?

I stopped reading at this point.

For someone who says they had ME/CFS, posting on an ME forum, your posts are incredibly long.

Your description of what you consider typical symptoms does not match my experience, in a couple of cases it is diametrically opposed.

 

Indeed. In fact, I continue to talk with those people and many more. My day is basically talking with people who have ME and helping / listening / understanding.

 

How do you define "normal lives"? Do you mean pre-M.E. life?

 

Yes. A life where they can go out and participate in social activities, have fun, etc.

 

Just skimming through the list of observations from your clients, few of those fit myself. I don't have alopecia, no leukopenia, my leukocytes are elevated but just within reference range. No elevated liver enyzymes or any other abnormality that could be found on routine blood tests. I tested positive against some chronic bacterial infections, but didn't have any improvement following antibiotics. I also briefly trialed valacyclovir, which made me rapidly worse, but at the dosage I took, it likely had nothing to do with its antiviral effects, but maybe due to secondary metabolic effects. I almost never get ill with acute infections despite coming in contact with sick people (this started after I developed ME/CFS symptoms). When I do get sick once every five years, my ME/CFS symptoms improve.

I have never had any eating disorder. I have some seasonal allergies, no food intolerances, eggs are not a problem at all. I have restricted my diet since getting ME/CFS as I noticed lots of carb intake made me feel worse, but it doesn't seem to be related to a specific type of food. I have trialed the ketogenic diet, felt better at first, but after a few days of ketosis became overriden with fatigue and flu-like symptoms. I have trialed lots of supplements, but I wouldn't describe it as a lifestyle or obsession, rather I think it works as form of morale boost for me to trial new things. I find even the supplements that work initially stop working within matter of days or weeks, which suggests they are not really addressing a deficiency, but rather pushing my body and metabolism temporary into some direction where symptoms become less severe. NO booster supplements containing arginine and citrulline produced the same, temporary benefit lasting a couple of days. Over the years I have also noticed a decreased tolerance for any drugs or supplements, which has forced me to entirely stop most supplements.

Comparing my background to your clients, it seems to me there's a big risk you are observing features that are not specific to ME/CFS and that might not have anything to do with the core pathology of ME/CFS. Again that's just based on my own N=1 sample, but your sample size isn't that much bigger.

P.S. Since your paper mentions PDH, have you looked into Victoria Bohne's treatment (link to patent)? This was discussed on ME/CFS forums a couple of years ago, there might be some overalp with your research. Bohne has compounded a mixture of oxalic acid foods that supposedly addresses the PDH deficiency. Similar to your protocol, it's a mix of natural ingredients that needs to be taken several times daily. Bohne claims she has kept herself and some patients healthy with this protocol, but it has all gone very silent and I'm not exactly sure what the latest status is.

 

@joshua leisk


I did a bit of searching on your regimen. So, spironolactone has anti-androgenic properties :


https://en.wikipedia.org/wiki/Spironolactone


Here is where it gets more interesting. Machine Learning identified Apigenin as a proposed target for amelioration of ME symptoms :





Apigenin may be important in clearing EBV :

But, apigenin may have anti-androgenic activity (?):

https://pubmed.ncbi.nlm.nih.gov/12032841/

https://pubmed.ncbi.nlm.nih.gov/28947342/


I wonder whether after taking finasteride and stopping it, i got an EBV reactivation. @Jonathan Edwards does this (EBV clearance from apigenin) seems plausible?

@joshua leisk have you had ME male patients? Has spironolactone affected their androgen levels?

 

That’s very interesting! Arresting lytic phase helps with some of the daily annoyances.

So far no issues at 25mg or 2x25mg/day dosing, over 5+ months. The studies have 30% of males showing symptoms from anti-androgenic behaviour at 100mg, single dose per day. This is even less of an issue with ME, as many people have elevated DHT via adrenal cortex dominance / impaired gonadal synthesis route.

The underlying aldosterone issues most people have with ME also get addressed at the same time as the Complex V issues. (doi: 10.1681/ASN.2010050481)