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Wolfe Hypothesis ~ Key causative processes involved in CFS/CFIDS/M.E.

Does this theory seem plausible?

  • Yes

    Votes: 9 23.7%
  • Didn't read it

    Votes: 5 13.2%
  • Not sure I fully understand it

    Votes: 5 13.2%
  • No

    Votes: 19 50.0%

  • Total voters
    38

John H Wolfe

Senior Member
Messages
220
Location
London
This is bound to attract some criticism - particularly given the nature of some of the sources, and my own fuzzy-logic and non-scientific brain/background - but ideas, constructive discussion/debate, and resultant refinement, can only aid 'the cause'. On that note, if anyone has a good understanding of related science (biological systems) and can explore further the link between D-lactate, mitochondrial dysfunction and cell formation that would be brilliant (what I've put is a bit wooly to say the least)!

I have now added my own interpretation of what could be going on 'under the surface' with CFS/CFIDS/M.E. to my blog page analysing some of the purported processes involved. As detailed in the report, this is not strictly scientific in its basis, or as yet evidenced/evidencible, and indeed there may not be a single aetiology, however that does not, to my mind, preclude there being value in drawing pictures, such as this, which attempt to link and contextualise multiple reported processes within a single theoretical framework:

Updated Information can be found here
 

Enid

Senior Member
Messages
3,309
Location
UK
Very interesting - and on a personal note the "exhaustion of the immune system" rings bells - in my early days of constant sore throats and raised glands I did wonder just how long my immune system could hold out. (non scientist though). It didn't - symptoms of polio and chicken pox followed (latent viruses).
 

ukxmrv

Senior Member
Messages
4,413
Location
London
I have acute onset ME. Was a previously healty adult with no gut problems and no signs of lympathic problems. My symptoms were mainly viral.

ME, as you probably know, appeared in epidemics in the 20 Century. I can't see how your factors could explain the epidemics.

Also can't see how it would explain the why ME is spreading to the in-laws of my family.

There may be some nuggets in your theories and for some people it's going resonate.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
I think some of this might be right, but its likely that its not complete nor fully right, and it will require further studies to investigate. Just today something was announced from several sources about a potential salivary biomarker for CFS: a PRB4 peptide. This is a protein that is produced by saliva (and possibly gut bacteria) that cleaves gluten. Gluten can cause celiac disease but also non-celiac wheat sensitivity (for which I think a paper was published recently showing this). The PRBs (there are at least 4) also bind dietary tannins, which are toxic. The biomarker was a fragment of PRB4, I am looking for a full molecular weight of PRB4 but it is proving hard to find a good reference. If its being cleaved in CFS, then the pieces will be less effective. Less effective PRB will result in more tannins and gluten reaching the gut and causing damage.

If on the other hand the PRBs are full length, then they will decrease tannins and gluten reaching the gut as we have too much of it ... so I think this interpretation is unlikely. The fragment they found was 2.6 kDa, which is a weight. One source refers to 27 kd for PRB4 which might also be a weigth ... so the peptide fragment is 10% or so and indicates cleavage or malformation of the parent PRB4.

This may be very important. It might lead to not just a diagnostic test but treatments. What I would like to see is a test assaying the function of our PRB4 in saliva, versus controls. This could tell us a lot.

http://www.aacc.org/events/annualmtgdirectory/Documents/AACC_12_Abstracts_E140-E208.pdf
(Scroll down to E-185)

Could you imagine causing a full CFS reversal by just popping an enzyme pill every time you eat? Awesome.

It is worth noting that elastase can cleave PRB4, though I don't know if it produces a 2.6 kDa fragment. High elastase is associated with high lmw RNaseL in CFS, and together are a potential biomarker.

I think the model presented here might be well served by examining it in light of recent work by Maes on autoantibodies, and also some stuff I am slowly assembling on secondary effects of LPS from the gut, including translocation of gamma delta T cells.

I can't cast a vote as my opinion is this model is mostly plausible, but I am not sure its fully plausible, and don't have the time to really investigate or make detailed commentary.

Bye, Alex

PS Correction: I had protein cleaving on my brain, doh, PRB4 might not cleave to gluten but bind to it, its a binding protein not a protease I think. I am not sure though: too much is not known about PRB4.
 

justy

Donate Advocate Demonstrate
Messages
5,524
Location
U.K
I'm confused, what was the study and where's the paper?
Hi Holmsey - this is John's theory or hypothesis as to the causes of M.E based on his readings etc. It is not a new paper or study.
Justy
 

Enid

Senior Member
Messages
3,309
Location
UK
Theories are theories of which much abound depending on the particular investgations and findings of particular researchers - all to the good in a complex illness pathogenesis (spelling ?) will be the big one.
 

Sparrow

Senior Member
Messages
691
Location
Canada
It looks like you've covered a lot of the common elements. And of course, once the ATP production is affected, all kinds of different things can go wrong or not work as well. I'm with you on an autoimmune element as well, for sure.

I currently think it's autoimmune, triggered most often by viral involvement. And it would then be the attacks that are responsible for the wide variety of symptoms. The flare and remit pattern, variety of systems hit, worsening under stress, and many of our symptoms are a lot like MS or other autoimmune conditions in some ways, though I think obviously a different part of our system is under specific attack (and I'm not sure exactly what, though I suspect the CNS is involved). Mass outbreaks would be related to exposure to either specific infections or toxins that are more likely to throw the system out of balance and act as a trigger.

In addition, the pattern of response to Rituximab, and the opinions of both Stanford and PHANU (both of whom I respect) seem to be pointing towards an autoimmune component. I would be surprised if that part didn't turn out to be true.
 

Holmsey

Senior Member
Messages
286
Location
Scotland, UK
Hi Holmsey - this is John's theory or hypothesis as to the causes of M.E based on his readings etc. It is not a new paper or study.
Justy
I can see it's being keenly received and it's not my website, but the headline thread on this forum explicitly states that it is for published research papers.
I'm not trying to be a party pooper, like many others I'm working and so have limited time to scan for new data, I generally come here first and like the idea that anything I'm reading has been validated and published.

Not for me to say, and as I mention I can see the enthusiasm behind this thread but shouldn't it be posted on one of the alternate forums?
 

justy

Donate Advocate Demonstrate
Messages
5,524
Location
U.K
I can see it's being keenly received and it's not my website, but the headline thread on this forum explicitly states that it is for published research papers.
I'm not trying to be a party pooper, like many others I'm working and so have limited time to scan for new data, I generally come here first and like the idea that anything I'm reading has been validated and published.

Not for me to say, and as I mention I can see the enthusiasm behind this thread but shouldn't it be posted on one of the alternate forums?

I hadn't noticed which forum this was in - you are quite right that this is not the right forum for this thread. Perhaps you could report it to the mods and they can move it?
On second thoughts,as i have more time than you i will ask them now to move it.
All the best, Justy.
 

justy

Donate Advocate Demonstrate
Messages
5,524
Location
U.K
I have just noticed that you have a copyright sign at the bottom of your first post. Have you copyrighted the ideas put forward here? Wouldn't that imply it was an original idea, rather than a pulling together of other peoples work?

Justy
 

user9876

Senior Member
Messages
4,556
I have just noticed that you have a copyright sign at the bottom of your first post. Have you copyrighted the ideas put forward here? Wouldn't that imply it was an original idea, rather than a pulling together of other peoples work?

Justy
You can only copyright text and not ideas.
 
Messages
2,562
Location
US
I voted yes. I only read the post and not the link. I don't have the energy to fully understand it.

I think my GI problems involved antibiotics but also general poor nutrition. Also for your section on lymphatic system, mine were partly due to my chronic dehydration IMO.
 
Messages
445
Location
Georgia
Yes, your theory seems highly plausible. Seventy percent of immune activity occurs in the gut. So a chronic, hard to detect illness being kicked off by something as innocuous as weak mucosal barrier makes sense. Also, many more women get cfs, ms, lupus, than men. They are the fairer sex and their gut lining is more fragile than most men's. Women are more susceptible to idiopathic IBS. Women, I'm guessing, have a weaker BBB than men, allowing more HPA interference than in men, in addition to the usual cognitive symptoms most CFS patients get. It comes down to ruggedness of tissue barriers scattered about the body. I point out also that even among strong healthy girl athletes the rate of concussion, as well as tearing of joint ligaments is much higher than in guys. I have always felt CFS should be informally renamed the "weak borders and barriers" disease. Btw Dr Rowe made his important observation that CFS patients have more hyper mobility in joints. This was extremely important. The "pathogen searchers" are off base. That flu, mono, stressful situation you had just weakened your body's mucuousal barriers enough to get thing started. The pathogens jumped in after the fact. Sorry to go on so long. This is just MHO.
 

John H Wolfe

Senior Member
Messages
220
Location
London
I have acute onset ME. Was a previously healty adult with no gut problems and no signs of lympathic problems. My symptoms were mainly viral
I was exactly the same, although I’ve retrospectively realised that my energy levels weren’t what they might have been for a reason e.g. when I really pushed myself at sport I couldn’t quite keep up with others (tennis squad – 6 hours tennis a week proved too much)

ME, as you probably know, appeared in epidemics in the 20 Century. I can't see how your factors could explain the epidemics
It’s also been associated with the American civil war, WWI, and the 1st Gulf War, all three of which involved toxic agents. If Perrin is correct, and my theory feeds off his theory, then toxic stress can be a cause of the persistence of CFS/M.E. type symptoms

To put it in the context of epidemics - if there is a failure of the lymphatics to adequately deal with sudden and pronounced action on the system (all sorts of immune-response-linked bits and bobs e.g. used white blood cells go into the lymphatics to be broken down), plus the aggravating factor of inflammation (may be intrinsic and/or extrinsic), then there is a risk of fundamental breakdown of the proper drainage mechanisms due to thoracic duct varicosity, leading to ’backflow’:



Perrin theorises that the propensity for a failure to deal with such an influx relates to postural defects, commonly found in PWME (myself, and the friends I’ve examined, included):


Also can't see how it would explain the why ME is spreading to the in-laws of my family
I can’t comment on such things without detailed knowledge of individual PWME

I think some of this might be right, but its likely that its not complete nor fully right, and it will require further studies to investigate
That’s my position too, virtually none of the pieces of the puzzle have been fully/rigorously investigated, but there are compelling signs here there and everywhere that the various constituent parts of my theory ought to be investigated, both in isolation, as well as as part of an integral investigative approach

Gluten can cause celiac disease but also non-celiac wheat sensitivity (for which I think a paper was published recently showing this)
I have non-Coeliac wheat sensitivity, and my grandfather had Coeliac disease, many of the PWME I have spoken to have similar intolerances ~ this feeds into the Metabolic Acidosis/Candidiasis part of the picture

The PRBs (there are at least 4) also bind dietary tannins, which are toxic
Thanks for the info, very interesting - will definitely look into this

High elastase is associated with high lmw RNaseL in CFS, and together are a potential biomarker
I’m not too sure about this stuff (my brain isn’t the best atm due to a cold, and my scientific mind is fairly infantile anyway, but I did stumble across RNaseL and included a bit about it on my page yesterday)

I think the model presented here might be well served by examining it in light of recent work by Maes on autoantibodies, and also some stuff I am slowly assembling on secondary effects of LPS from the gut, including translocation of gamma delta T cells
Thanks, any further input/critical analysis would be wonderful

I'm confused, what was the study and where's the paper?
It’s a literature review based quasi-thesis rather than an academic experimental research paper

Mass outbreaks would be related to exposure to either specific infections or toxins that are more likely to throw the system out of balance and act as a trigger
Agreed

I can see it's being keenly received and it's not my website, but the headline thread on this forum explicitly states that it is for published research papers
My article falls under “abstracts … of published research”, and discussion of them – it’s a discussion of contemporary research (inc. various papers referenced directly by way of web-links)

I have just noticed that you have a copyright sign at the bottom of your first post. Have you copyrighted the ideas put forward here? Wouldn't that imply it was an original idea, rather than a pulling together of other peoples work?
The component processes are not, for the large part, original ideas ~ however the theory/thesis as a whole, is, to my knowledge, unique

They are the fairer sex and their gut lining is more fragile than most men's
This I did not know!

Women, I'm guessing, have a weaker BBB than men, allowing more HPA interference than in men
Hmm, wonder if that’s true(?)

Thanks for your comments all :)
 

user9876

Senior Member
Messages
4,556
Yes, your theory seems highly plausible. Seventy percent of immune activity occurs in the gut. So a chronic, hard to detect illness being kicked off by something as innocuous as weak mucosal barrier makes sense. Also, many more women get cfs, ms, lupus, than men. They are the fairer sex and their gut lining is more fragile than most men's. Women are more susceptible to idiopathic IBS. Women, I'm guessing, have a weaker BBB than men, allowing more HPA interference than in men, in addition to the usual cognitive symptoms most CFS patients get. It comes down to ruggedness of tissue barriers scattered about the body. I point out also that even among strong healthy girl athletes the rate of concussion, as well as tearing of joint ligaments is much higher than in guys. I have always felt CFS should be informally renamed the "weak borders and barriers" disease. Btw Dr Rowe made his important observation that CFS patients have more hyper mobility in joints. This was extremely important. The "pathogen searchers" are off base. That flu, mono, stressful situation you had just weakened your body's mucuousal barriers enough to get thing started. The pathogens jumped in after the fact. Sorry to go on so long. This is just MHO.

I thought the argument was that women had a stronger immune system. I found this review article where they talk of autoimmunity and address the difference between men and women:
http://wwwnc.cdc.gov/eid/article/10/11/04-0367_article.htm

Even though women’s greater susceptibility to autoimmune diseases has been recognized for more than 100 years, only recently has attention focused on this topic (5). For some time, the basic immune response between men and women has been known to differ, with women producing a more vigorous immune response and increased antibody production (5,38). However, autoimmune diseases that develop in men often are more severe (39). Most of our understanding of sex differences in the immune response comes from work done in animal models. Many animal models of autoimmune disease have shown a similar sex bias, with a higher incidence of disease in women. Sex hormones, such as estrogen, testosterone, and progesterone, may mediate most of the sex-biased differences in the immune response (39). Recently, estrogens and androgens have been found to directly influence whether a Th1- or Th2-type immune response develops by interacting with hormone receptors on immune cells (38). Not only are a variety of sex hormone receptors found on immune cells, but cytokine receptors (e.g., IL-1R, IL-18R) have likewise been discovered on hormone-producing tissues, which suggests bidirectional regulation of the immune response. Furthermore, proinflammatory cytokines such as TNF-α and IL-1β stimulate the release of glucocorticoids from the hypothalamus-pituitary-adrenal axis, which regulates the inflammatory process, along with androgens and estrogens (40).
 

Shell

Senior Member
Messages
477
Location
England
John, that interesting. I've just been reading how fibro and cfs/ME is most likely autonomic in root, but that leaves the question of what made the autonomic system dysfunctional? It also leaves open the question of how the immune system is related - something Perrin seems to explain his hyppthesis. Extermal toxins does seem an Occam's answer, particularly in light of the cluster outbreaks and the family and friends spreading of it.
Does the autonomic-toxin hypothesis explain mitochondrial dysfunction I wonder?
 

John H Wolfe

Senior Member
Messages
220
Location
London
John, that interesting. I've just been reading how fibro and cfs/ME is most likely autonomic in root, but that leaves the question of what made the autonomic system dysfunctional?
I describe how I think the ANS becomes out of kilter in the piece as possibly relating to the following purported effects:

1) Toxic disturbance, via the Cerebrospinal Fluid/blood brain barrier, specifically of the Basal Ganglia > Hypothalamus (Perrin)

2) Disturbance of the Hypothalamic-Pituitary-Adrenal (HPA) Axis (could be toxic, viral, neurological..) > sub-optimal levels of Anti-diuretic Hormone (ADH) > what ADH signals there are, become jumbled/misinterpreted > Adrenal Insufficiency

2) Toxic disturbance of the Sensory Nervous System Dorsal Ganglia (function of local infection and related inflammation, among other sources of toxicity)

It also leaves open the question of how the immune system is related - something Perrin seems to explain his hyppthesis
My understanding is that the following processes apply for M.E.

1. Trigger: Things like Herpesvirus like EBV, or perhaps a Retrovirus, or acute infection/toxic overload

2. Propagation: An latent immunodeficiency e.g. impaired lymphatic drainage ~ caused by dorsal defects/trauma; supposing the trigger itself isn't severe enough enough to nuke the system for some considerable time in a normal individual e.g. gulf war syndrome/certain epidemics

3. Prolongation: Immune depressors like Candidasis, autoimmune disease, or metabolic acidosis induced autoimmunity

Does the autonomic-toxin hypothesis explain mitochondrial dysfunction I wonder?
Yes, through the autonomic disturbance > HPA Axis > Adrenal Insufficiency > Hypoaldosteronism chain of effects ~ causing cation [electrolyte] imbalance in the Sodium (Na+)/Potassium (K+)-ATPase Pump > Depolarisation of resting membrane potential of cells (their ‘battery’ charge is directly destabilised + Metabolic acidosis (which proves an impediment to mitochondrial energy in a number of ways, touched on in my page: Section 2)

I should say that I've yet to finish reading up on ATP/mitochondrial dysfunction e.g. getting my head around L-Lactate vs D-Lactate and what Myhill has to say about the ATP vs AMP / ADP situation
 

John H Wolfe

Senior Member
Messages
220
Location
London
Latest incarnation of this hypothesis:

1) Differential Presentation of Autoimmune Disorders Involved in ME/CFS:
PWME have a disorder related to at least one of the key regions implicated in our discussion:
Gastrointestinal Disturbance (GID)
Cerebrospinal Disturbance (CSD)
a) 'Myalgic Encephalomyelitis Gastrointestinal Autoimmune Disorder' (MEGIDAD)
Slow Onset CFS/ME with chronic GID:
  • GID is essential
  • CSD does not present as an issue, in terms of signs of osteopathic/chiropractic dorsal/CSF anomalies, but there may very well be (a) complicating disorder(s) distinct from GID involved in perpetuation
Example: ME/CFS patients who suffer with chronic GI infection/disease/inflammation prior to onset
Sudden Onset CFS/ME with acute GID:
  • GID is essential
  • CSD does not present as an issue, in terms of signs of osteopathic/chiropractic dorsal/CSF anomalies, but there ma very well be (a) complicating disorder(s) distinct from GID involved in perpetuation
Example: ME/CFS patients who suffer an GI infection/acute allergy attack shortly before onset
b) 'Myalgic Encephalomyelitis Cerebrospinal Disturbance Autoimmune Disorder' (MECSDAD)
Slow Onset CFS/ME with no GID + signs of osteopathic/chiropractic dorsal/CSF anomalies:
  • GID does not appear an issue but there may well be (a) complicating disorder(s) distinct from CSD involved in perpetuation
  • CSD is essential
Example: Those epidemic outbreak ME/CFS patients that have never encountered GI disturbance and do not recall having had an acute infection shortly before onset
⇒ Sudden Onset CFS/ME with no GID + signs of osteopathic/chiropractic dorsal/CSF anomalies:
  • GID does not appear an issue but there may well be (a) complicating disorder(s) distinct from CSD involved in perpetuation
  • CSD is essential
Example: Gulf War Syndrome patients that have no GI disturbance
c) 'Myalgic Encephalomyelitis Gastrointestinal and Cerebrospinal Disturbance Autoimmune Disorder' (MEGICSDAD)
Slow Onset CFS/ME with GID + signs osteopathic/chiropractic dorsal/CSF anomalies:
  • GID + CSD present and interacting
Sudden Onset CFS/ME with GID + signs osteopathic/chiropractic dorsal/CSF anomalies:
  • GID + CSD present and interacting
MEGICSDAD may well be the dominant modal state among PWME - as distinct from those with CFS without Myalgic Encephalomyelitis, sleep disorders and psychiatric conditions; the mutually regressive interaction between the two regional disorders (touched on below) would certainly help to explain the 'downward spiral' that many PWME experience
Indeed, MEGICSDAD may the the essential modal state for long term ME/CFS - a theory that may not be refuted until we can exclude the possibility of GID and/or CSD with absolute certainty in a statistically significant number of cases
At this stage, which of the two key regions the disorder stems from originally remains very much a 'chicken or the egg' type enigma, however GID may be the root source of disorder e.g:
  1. Prenatal-perinatal-postnatal transmission of toxins (specifically those prevalent in industrialised regions, alcohol or drugs), antigens, and allergens from mother to infant (particularly between mothers with compromised toxin/allergen filtration, processing and drainage systems, and antigenic immune functionality, and particularly concerning first-born infants) via the the placenta/in the breast milk
  2. (A) stochastic/[latent root] GID-linked disorder(s) develop(s)[(is/are] accentuated]
  3. Conditions ideal for the development/[accentuation] of (a) stochastic/[latent root] CSD(s)-linked disorder(s) are created
  4. (A) stochastic/[latent root] CSD-linked disorder(s) develop(s)/[(is/are) accentuated]
3) The MEGICSDAD ME/CFS Subset Road Map:
a) Precursory States:
(1) PrecursorsGID Emergence/Onset: An onset/worsening of (a) (latent) GID-linked disorder(s):
  • Genetics
  • (+) CSD
  • (+) Food allergies e.g. wheat
  • (+) Gluten sensitivity
  • (+) Hypochlorhydria
  • (+) [...]
  • (+) Psychological stress
    • Enhanced potential for GID
(2) PrecursorsCSD Emergence/Onset: An onset/worsening of (a) (latent) CS-linked disorder(s); CS(F) denotes a Cerebrospinal(Fluid)-linked factor:
  • Genetics
  • (+) GID
  • (+) CS(F) (Viral infection x interacting bacteria) + mirror-viral autoantigenic activity
  • (+) CS(F) Bacterial infection
  • (+) CS(F) Drainage & pressure (subject to state of lymphatic system)
  • (+) CS(F) Blood/brain barrier permeability (subject to NO)/peroxynitrate)
  • (+) CS(F) Blood/nerve barrier permeability (subject to NO)/peroxynitrate)
  • (+) CS(F) Toxic action (subject to state of lymphatic system & blood barriers)
  • (+) CS(F) Amyloidosis (subject to state of lymphatic system & blood barriers)