Catalytic Antibodies May Contribute to Demyelination in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

[Osaca]

I was wondering that too. There are commercial tests available for anti-myelin antibodies, but they must not be the same type of antibodies that Ron was looking at (catalytic), since he had to develop his own test. And the way he explains catalytic antibodies is they WILL cause demyelination if present in large enough quantities and in the right locations. Whether this will be full blown MS or not is not really relevant. They will likely cause symptoms.

There’s no such thing as “MS antibodies” so in particular there can’t be something such as “catalytic MS antibodies”. The closest to a blood test in MS is testing for neurofilament light chain and that is very far off from being a blood test for MS. If these catalytic antibodies would play a role in MS they would automatically also show up on antibody assay looking at MPB antibodies. And thus far antibodies against MBP are not known to really play a big role in MS. From what I can tell MS research has largely moved away from antibodies against MBP and catalytic+MBP+MS also won't get you any interesting hits on PudMed.

"Whether this will be full blown MS or not is not really relevant." It probably is if you make statements such as "half of people with ME might have MS". It's also relevant if these antibodies actually play hardly any role in MS, which is the basis of your whole statement. I agree it would be less relevant if you think there might just be some overlaps between the diseases or symptomology, but if your basis of assumption is "ME is similar to MS, because we found the antibodies" and these antibodies seem to be rather unimportant in MS then your whole statement doesn't make sense. In that case it would be sufficient to just run a larger study of these antibodies in pwME and HC and if there's a difference you have a biomarker for pwME.

Furthermore, as far as is possible today, research has been able to show people with ME don’t have any demyelination and apart from studies looking at this, most of us will have had MRIs showing exactly that (of course within the natural limitations of imaging techniques).

I’m afraid MS researchers wouldn’t take any of this stuff serious (I’m guessing that’s why it ended up in a seemingly low quality journal). Perhaps someone can ask some of the MS researchers that study MS and ME/CFS (I know Jeroen den Dunnen is one of those, maybe there are more?) to clarify this.

 

[Oliver3]

There’s no such thing as “MS antibodies” so in particular there can’t be something such as “catalytic MS antibodies”. The closest to a blood test in MS is testing for neurofilament light chain and that is very far off from being a blood test for MS. If these catalytic antibodies would play a role in MS they would automatically also show up on antibody assay looking at MPB antibodies. And thus far antibodies against MBP are not known to really play a big role in MS. From what I can tell MS research has largely moved away from antibodies against MBP and catalytic+MBP+MS also won't get you any interesting hits on PudMed.

"Whether this will be full blown MS or not is not really relevant." It probably is if you make statements such as "half of people with ME might have MS". It's also relevant if these antibodies actually play hardly any role in MS, which is the basis of your whole statement. I agree it would be less relevant if you think there might just be some overlaps between the diseases or symptomology, but if your basis of assumption is "ME is similar to MS, because we found the antibodies" and these antibodies seem to be rather unimportant in MS then your whole statement doesn't make sense. In that case it would be sufficient to just run a larger study of these antibodies in pwME and HC and if there's a difference you have a biomarker for pwME.

Furthermore, as far as is possible today, research has been able to show people with ME don’t have any demyelination and apart from studies looking at this, most of us will have had MRIs showing exactly that (of course within the natural limitations of imaging techniques).

I’m afraid MS researchers wouldn’t take any of this stuff serious (I’m guessing that’s why it ended up in a seemingly low quality journal). Perhaps someone can ask some of the MS researchers that study MS and ME/CFS (I know Jeroen den Dunnen is one of those, maybe there are more?) to clarify this.

But you don't know what Ron knows. And researchers of specific illnesses can get stuck in group think.
Ron is definitely saying there is a crossover and as of yet normal paradigms of understanding wouldn't necessarily tally with his assertions.
But Ron did say this in a previous lecture and he reasserts it here. Whether it's correct is another question but he's definitely saying they are linked

 

[Vlad83]

There’s no such thing as “MS antibodies” so in particular there can’t be something such as “catalytic MS antibodies”. The closest to a blood test in MS is testing for neurofilament light chain and that is very far off from being a blood test for MS. If these catalytic antibodies would play a role in MS they would automatically also show up on antibody assay looking at MPB antibodies. And thus far antibodies against MBP are not known to really play a big role in MS. From what I can tell MS research has largely moved away from antibodies against MBP and catalytic+MBP+MS also won't get you any interesting hits on PudMed.

"Whether this will be full blown MS or not is not really relevant." It probably is if you make statements such as "half of people with ME might have MS". It's also relevant if these antibodies actually play hardly any role in MS, which is the basis of your whole statement. I agree it would be less relevant if you think there might just be some overlaps between the diseases or symptomology, but if your basis of assumption is "ME is similar to MS, because we found the antibodies" and these antibodies seem to be rather unimportant in MS then your whole statement doesn't make sense. In that case it would be sufficient to just run a larger study of these antibodies in pwME and HC and if there's a difference you have a biomarker for pwME.

Furthermore, as far as is possible today, research has been able to show people with ME don’t have any demyelination and apart from studies looking at this, most of us will have had MRIs showing exactly that (of course within the natural limitations of imaging techniques).

I’m afraid MS researchers wouldn’t take any of this stuff serious (I’m guessing that’s why it ended up in a seemingly low quality journal). Perhaps someone can ask some of the MS researchers that study MS and ME/CFS (I know Jeroen den Dunnen is one of those, maybe there are more?) to clarify this.

The fact that they had to develop their own test for catalytic anti-MBP antibodies probably means no such test is available commercially. I have seen research studying these antibodies in MS. Maybe it's not part of the official diagnosis, but at least some MS patients have it.

Also, I think the whole MS label is besides the point. They still haven't definitively figured out what causes it. And maybe there's multiple causes and maybe it's a spectrum.

What's important, I think is that Ron found these antibodies in MECFS, and they are catalytic antibodies and WILL likely cause demyelination and symptoms.

 

[Osaca]

The fact that they had to develop their own test for catalytic anti-MBP antibodies probably means no such test is available commercially. I have seen research studying these antibodies in MS. Maybe it's not part of the official diagnosis, but at least some MS patients have it.

It's not "maybe not part of the official diagnosis" it's 100% not ever been part of any diagnosis ever. Catalytic antbodies show up on anti-MBP assays as well, because they bind to the antigen. Healthy controls have roughly the same amount of anti-MBP-antibodies as patients with MS https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2753924/ and they are also present in other diseases https://pubmed.ncbi.nlm.nih.gov/1282691/ (this is research from the 1990s). Initially, they were believed to play a larger role but research has moved on. That doesn't mean they don't play a role at all, but that the role is insufficient to establish causality, see also this reference https://link.springer.com/article/10.1007/s00726-021-03111-7 for the complexity on this subject.

MS research receives a far larger amount of research funding compared to ME/CFS research. MS researchers have used millions of dollars just dedicated to look for antibodies alone. Thus far the very strong conclusion would be that such antibodies cannot be used to conclude anything about whether someone has a disease or not. So saying "I found these antibodies in half of ME/CFS patients, meaning half of them could have MS" is not backed by any evidence. That's the point. That is also why this statement cannot be found in the paper itself, since it isn't backed by evidence.

antibodies in MECFS, and they are catalytic antibodies and WILL likely cause demyelination and symptoms.

That isn't based on any evidence. That's simply a belief without data to support this belief.

Also, I think the whole MS label is besides the point. They still haven't definitively figured out what causes it. And maybe there's multiple causes and maybe it's a spectrum.

Indeed, that's definitely the case, however that's completely independent of this paper as well as Ron's statements.

But you don't know what Ron knows. And researchers of specific illnesses can get stuck in group think.

I suggest that anybody interested in this research contact MS researchers to ask them on their opinion of this research. Ron might know a tremendous amount on a whole range of subjects but he obviously doesn't know anything about MS that leading MS researcher don't know about MS, he is a biochemist after all.

This paper can serve as a hypothesis paper with a lot of conjectures, so that others researchers can work out the details. Which is interesting and good. But it's important to understand for patients that thus far there isn't any evidence for these conjectures. It seems the paper might have been motivated by the one patient that improved on copaxone.

 

[Rufous McKinney]

and in the right locations.

perhaps something regarding WHERE potential demylenization is occuring...might matter and lead to differing symptoms and diagnoses.

 

[Oliver3]

It's not "maybe not part of the official diagnosis" it's 100% not ever been part of any diagnosis ever. Catalytic antbodies show up on anti-MBP assays as well, because they bind to the antigen. Healthy controls have roughly the same amount of anti-MBP-antibodies as patients with MS https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2753924/ and they are also present in other diseases https://pubmed.ncbi.nlm.nih.gov/1282691/ (this is research from the 1990s). Initially, they were believed to play a larger role but research has moved on. That doesn't mean they don't play a role at all, but that the role is insufficient to establish causality, see also this reference https://link.springer.com/article/10.1007/s00726-021-03111-7 for the complexity on this subject.

MS research receives a far larger amount of research funding compared to ME/CFS research. MS researchers have used millions of dollars just dedicated to look for antibodies alone. Thus far the very strong conclusion would be that such antibodies cannot be used to conclude anything about whether someone has a disease or not. So saying "I found these antibodies in half of ME/CFS patients, meaning half of them could have MS" is not backed by any evidence. That's the point. That is also why this statement cannot be found in the paper itself, since it isn't backed by evidence.

That isn't based on any evidence. That's simply a belief without data to support this belief.

Indeed, that's definitely the case, however that's completely independent of this paper as well as Ron's statements.

I suggest that anybody interested in this research contact MS researchers to ask them on their opinion of this research. Ron might know a tremendous amount on a whole range of subjects but he obviously doesn't know anything about MS that leading MS researcher don't know about MS, he is a biochemist after all.

This paper can serve as a hypothesis paper with a lot of conjectures, so that others researchers can work out the details. Which is interesting and good. But it's important to understand for patients that thus far there isn't any evidence for these conjectures. It seems the paper might have been motivated by the one patient that improved on copaxone.

Whilst, that may be, my assertion was Ron said this, which you denied and he's said it again.
Nothing wrong with conjecturres and putting ideas out there.
Neither you or I know what Ron knows and what he's is or is not privy to.
Let's face it, he knows more than us.
Let's see. I knew he'd said this previously. It's a bug bear of mine...always being told you got it wrong medically...I knew I'd heard it right.
So now we have to wait and see if it pans out

 

[Oliver3]

It's not "maybe not part of the official diagnosis" it's 100% not ever been part of any diagnosis ever. Catalytic antbodies show up on anti-MBP assays as well, because they bind to the antigen. Healthy controls have roughly the same amount of anti-MBP-antibodies as patients with MS https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2753924/ and they are also present in other diseases https://pubmed.ncbi.nlm.nih.gov/1282691/ (this is research from the 1990s). Initially, they were believed to play a larger role but research has moved on. That doesn't mean they don't play a role at all, but that the role is insufficient to establish causality, see also this reference https://link.springer.com/article/10.1007/s00726-021-03111-7 for the complexity on this subject.

MS research receives a far larger amount of research funding compared to ME/CFS research. MS researchers have used millions of dollars just dedicated to look for antibodies alone. Thus far the very strong conclusion would be that such antibodies cannot be used to conclude anything about whether someone has a disease or not. So saying "I found these antibodies in half of ME/CFS patients, meaning half of them could have MS" is not backed by any evidence. That's the point. That is also why this statement cannot be found in the paper itself, since it isn't backed by evidence.

That isn't based on any evidence. That's simply a belief without data to support this belief.

Indeed, that's definitely the case, however that's completely independent of this paper as well as Ron's statements.

I suggest that anybody interested in this research contact MS researchers to ask them on their opinion of this research. Ron might know a tremendous amount on a whole range of subjects but he obviously doesn't know anything about MS that leading MS researcher don't know about MS, he is a biochemist after all.

This paper can serve as a hypothesis paper with a lot of conjectures, so that others researchers can work out the details. Which is interesting and good. But it's important to understand for patients that thus far there isn't any evidence for these conjectures. It seems the paper might have been motivated by the one patient that improved on copaxone.

Your final sentence is also conjecture. Let's see eh

 

[datadragon]

Multiple sclerosis is a disease in which the immune system attacks the myelin sheath, the protective covering of nerve cells causing communication problems between the brain and the rest of the body. MS is driven by immune cells attacking oligodendrocytes and the myelin they produce, which is an insulating layer ensheathing nerve cells. https://www.sciencedaily.com/releases/2022/01/220128141316.htm

The formation of myelin is a complex process during which the Oligodendrocytes (OL) precursor cells (OPCs, also known as NG2-glia) become mature Oligodendrocytes through a highly regulated program of differentiation. Oligondendrocytes have immune-inflammatory functions beyond myelination as well https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9165378/

Butyrate suppresses demyelination and enhances remyelination and Butyrate is also lower at the same time as a downstream effect of the gut dysbiosis. Butyrate may affect oligodendrocytes directly. Butyrate treatment facilitated the differentiation of immature oligodendrocytes https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688239/

a reduction in bacteria belonging to Clostridia clusters IV and XIVa, which produce short-chain fatty acids (SCFAs) in MS patients https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569432/

In ME/CFS there is also low confirmed butyrate by the NIH https://forums.phoenixrising.me/thr...s-chronic-fatigue-syndrome.90582/post-2443638

When I looked briefly into autoantibodies, I was surprised that butyrate was also a main player and this also happens to be another downstream effect (low butyrate) of the lowered zinc availability during inflammation/infection states. Short chain fatty acids including butyrate exert modulatory effects on intrinsic B cell functions even at moderate concentrations, thereby is what shapes normal and effective antibody and autoantibody responses. Autoantibodies are found in healthy individuals, they arent all 'bad' but are being dysregulated in certain cases. So that means that when butyrate is low it can cause dysregulated antibody responses leading to generation or dysregulation of autoantibodies. https://forums.phoenixrising.me/threads/bc007-what-are-your-thoughts.87520/post-2441668

This research had mentioned that the 4EPS (4-ethylphenyl sulfate) metabolite, produced by bacteria that reside in the mouse gut, can travel to the brain and alter the function of brain oligodendrocytes cells which were altered. These cells are important in part because they produce a protein called myelin, which acts as a protective coating around neurons and nerve fibers called axons, like insulation around an electrical wire. The team found that in the presence of 4EPS, oligodendrocytes are less mature and consequently produce less myelin and also anxiety https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9170029/ I mentioned previously here. https://forums.phoenixrising.me/threads/bc007-what-are-your-thoughts.87520/post-2442283

The myelin sheath is made of phospholipids whose synthesis depends on cytochrome c oxidase activity. Cytochrome c oxidase, the terminal oxidase in the electron transport chain, is copper dependent. They used a copper reducer to induce demyelination and this goes back to ceruloplasmin production needed to make copper and iron usable (bio available) which requires zinc, Vitamin A and magnesium that would be impacted from prolonged inflammation/infection. https://forums.phoenixrising.me/thr...-anyone-tried-it-on-me-cfs.90877/post-2444770

The active form of Vitamin B6 (PLP) also serves as a cofactor in sphingolipid synthesis and is thereby important for myelin formation which also is affected by zinc status. Sphingomyelin is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons. https://pubmed.ncbi.nlm.nih.gov/17260529 https://pubmed.ncbi.nlm.nih.gov/12686137 https://pubmed.ncbi.nlm.nih.gov/6342384

Another interesting research showed a biochemical pathway that dendritic cells use to stop other immune cells from attacking the body and this pathway can be activated with lactate. https://medicalxpress.com/news/2023-08-probiotic-multiple-sclerosis.html gut microbes can utilize lactate and convert it to propionate, butyrate or acetate. https://www.cambridge.org/core/jour...t-microbiome/70FFDA0D826775206007393EB4E21FE2 Oligodendrocytes can generate lactate, which can then be transferred to axons to generate metabolic energy in the form of ATP. Indeed, a number of glycolytic and Krebs cycle enzymes such as succinate dehydrogenase and fumarase are expressed in the myelin sheath, which contribute to glucose catabolism and ATP production https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912544/

 

[SWAlexander]

datadragon great job​

I'll read it all, after my appointment, but it will take some time. Thanks.

 

[Rufous McKinney]

@datadragon great job

ditto

but it will take some time.

double ditto

 

[datadragon]

This study suggests that gut microbiota, microbes-derived metabolites and short chain fatty acids SCFAs may be involved in the beneficial effects of (R)-ketamine. https://www.sciencedirect.com/science/article/abs/pii/S0028390822001988

Ketamine exhibits rapid and sustained antidepressant effects. As decreased myelination has been linked to depression pathology, changes in myelination may be a pivotal mechanism underlying ketamine’s long-lasting antidepressant effects. Although ketamine has a long-lasting facilitating effect on myelination, the precise roles of myelination in ketamine’s sustained antidepressant effects remain unknown. Ketamine’s ability to restore impaired myelination in the brain by promoting the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes was demonstrated. Moreover, we showed that inhibiting the expression of myelin-associated oligodendrocytic basic protein (Mobp) blocked ketamine’s long-lasting antidepressant effects. We also illustrated that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) signaling mediated ketamine’s facilitation on myelination. In addition, we found that the (R)-stereoisomer of ketamine showed stronger effects on myelination than (S)-ketamine, which may explain its longer-lasting antidepressant effects. These findings reveal novel mechanisms underlying the sustained antidepressant effects of ketamine and the differences in antidepressant effects between (R)-ketamine and (S)-ketamine, providing new insights into the role of myelination in antidepressant mechanisms. https://www.nature.com/articles/s41380-023-02288-5 The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is an ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system.

 

[SWAlexander]

Butyrate suppresses demyelination and enhances remyelination and Butyrate is also lower at the same time as a downstream effect of the gut dysbiosis.

Having APS prevention will no longer help me. How many people with leaky gut are tested for APS?

Butyrate is known to feed the cells lining the colon, promote a healthy gut barrier, and prevent “leaky gut”.
https://newsroom.uw.edu/blog/butyrate-microbiome-abates-host-ills-studies-find

"The role of the intestinal microbiome in antiphospholipid syndrome"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9732728/

"Butyrate: A Double-Edged Sword for Health?"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333934/

 

[Methyl90]

Is there a difference between using a butyrate-based solution intra rectally (enema) compared to the classic oral route?

 

[jaybee00]

Can we please keep posts relevant to the Jensen/Davis study/article—thanks.

 

[datadragon]

VITAMIN D and Myelination:

Oligodendrocytes are the specialized cells that create the myelin sheath; these cells, in turn, are formed from precursor cells called oligodendrocyte progenitor cells (OPC). Blocking vitamin D receptors on OPCs would affect the maturation of OPCs into myelin-forming oligodendrocytes and, consequently, lead to impaired remyelination. When the authors of one study blocked vitamin D receptors from binding vitamin D and functioning correctly, this prevented OPCs from maturing properly into myelin-forming oligodendrocytes.

The active form of Vitamin D 1,25-Dihydroxyvitamin D3 enhances neural stem cell proliferation and oligodendrocyte differentiation. Neural stem cells are one type of stem cell in the body that can multiply themselves and transform, or differentiate, into mature types of cells of the nervous system, including oligodendrocytes, which are myelin-forming cells. When they added the active form of vitamin D to the cell culture plates, the neural stem cells increased their numbers significantly after one week, demonstrating that vitamin D triggers neural stem cells to activate and multiply. Importantly, vitamin D stimulated the neural stem cells to mature into both neurons and myelin-forming oligodendrocytes, but not astrocytes. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400846/

Vitamin D receptor–retinoid X receptor heterodimer signaling regulates oligodendrocyte progenitor cell differentiation- Note that RXR are Vitamin A receptors which require zinc in Vitamin A metabolism and vice versa, and Vitamin D increases OPC differentiation through VDR signaling which also requires Vitamin A and Zinc for the VDR functions of to function properly. I covered a part of that here https://forums.phoenixrising.me/threads/dang-those-vitamin-d3-levels.91152/post-2450071 Under inflammation/infection that is yet another area that would be impacted negatively.

Oligodendrocytes are the specialized cells that create the myelin sheath; these cells, in turn, are formed from precursor cells called oligodendrocyte progenitor cells (OPC). Previous research has identified a special protein called retinoid X receptor-γ (RXR-γ) that, when activated, helps OPCs rapidly mature into myelin-forming oligodendrocytes. A group of researchers based at the University of Cambridge (UK) noted that RXR-γ only works when it interacts with another protein. This group, together with an international team of collaborators, went on to demonstrate that this unknown protein is the receptor that binds vitamin D.

• blocking vitamin D receptors on OPCs would affect the maturation of OPCs into myelin-forming oligodendrocytes and, consequently, lead to impaired remyelination;. When the authors blocked vitamin D receptors from binding vitamin D and functioning correctly, this prevented OPCs from maturing properly into myelin-forming oligodendrocytes. As expected, this led to impaired remyelination in rats with the MS-like disease. At the other end of the spectrum, activating these receptors with vitamin D led to improved remyelination.
• vitamin D receptors interact with RXR-γ in OPCs and oligodendrocytes grown in cell culture;
• vitamin D receptors are present during remyelination by examining brain tissues from rats in which demyelination was experimentally triggered;

https://rupress.org/jcb/article/211/5/975/38384/Vitamin-D-receptor-retinoid-X-receptor-heterodimer

This combined with other downstream effects of the lowered zinc availability and uptake during inflammation/infection states can lead to the myelination impairment.

 

[SWAlexander]

In my case, white matter damage (diagnosed in 2008)

What lies beneath: White matter microstructure in pediatric myalgic encephalomyelitis/chronic fatigue syndrome using diffusion MRI​

Abstract​

Recent studies in adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suggest that changes in brain white matter microstructural organization may correlate with core ME/CFS symptoms, and represent a potential biomarker of disease. However, this has yet to be investigated in the pediatric ME/CFS population. We examined group differences in macrostructural and microstructural white matter properties, and their relationship with clinical measures, between adolescents recently diagnosed with ME/CFS and healthy controls. Forty-eight adolescents (25 ME/CFS, 23 controls, mean age 16 years) underwent brain diffusion MRI, and a robust multi-analytic approach was used to evaluate white and gray matter volume, regional brain volume, cortical thickness, fractional anisotropy, mean/axial/radial diffusivity, neurite dispersion and density, fiber density, and fiber cross section. From a clinical perspective, adolescents with ME/CFS showed greater fatigue and pain, poorer sleep quality, and poorer performance on cognitive measures of processing speed and sustained attention compared with controls. However, no significant group differences in white matter properties were observed, with the exception of greater white matter fiber cross section of the left inferior longitudinal fasciculus in the ME/CFS group compared with controls, which did not survive correction for intracranial volume. Overall, our findings suggest that white matter abnormalities may not be predominant in pediatric ME/CFS in the early stages following diagnosis. The discrepancy between our null findings and white matter abnormalities identified in the adult ME/CFS literature could suggest that older age and/or longer illness duration influence changes in brain structure and brain–behavior relationships that are not yet established in adolescence.
https://onlinelibrary.wiley.com/doi/10.1002/jnr.25223

 

[SWAlexander]

Female reproductive steroids, estrogen and progesterone and its physiologically active metabolite, allopregnanolone,

Catecholamine (neurotransmitters and hormones) testing for different and additional hormones is usually not available unless you have a keen doctor. Ergo ????
Keep in mind, that there could be an error in Gene gs224 tetrahydrobiopterin.

What about if deficiency is solely related to muscular malfunction like SMN and not neurologically?