Catalytic Antibodies May Contribute to Demyelination in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2023, Jensen, Davis et al

Here we report preliminary data demonstrating that some patients with myalgic encephalomyelitis/chronic fatiguesyndrome (ME/CFS) may have catalytic autoantibodies that cause the breakdown of myelin basic protein (MBP). We propose that these MBP-degradative antibodies are important to the pathophysiology of ME/CFS, particularly in the occurrence of white matter disease/demyelination. This is supported by magnetic resonance imagining studies that show these findings in patients with ME/CFS and could explain symptoms of nerve pain and muscle weakness.

In this work, we performed a series of experiments on patient plasma samples where we isolated and characterized substrate-specific antibodies that digest MBP. We also tested glatiramer acetate (copaxone), an FDA approved immunomodulator to treat multiple sclerosis, and found that it inhibits ME/CFS antibody digestion of MBP. Furthermore, we found that aprotinin, which is a specific serine protease inhibitor, specifically prevents breakdown of MBP while the other classes of protease inhibitors had no effect. This coincides with the published literature describing catalytic antibodies as having serine protease-like activity. Postpandemic research has also provided several reports of demyelination in COVID-19. Because COVID-19 has been described as a trigger for ME/CFS, demyelination could play a bigger role in patient symptoms for those recently diagnosed with ME/CFS. Therefore, by studying proteolytic antibodies in ME/CFS, their target substrates, and inhibitors, a new mechanism of action could lead to better treatment and a possible cure for the disease.

Open access, https://pubs.acs.org/doi/10.1021/acs.biochem.3c00433

 

A nesting doll of theories within theories, but cool, regardless.

 

I also noticed that a contributor was Miranda Lee Dafoe - not sure of her relationship with Janet or Whitney.

 

I'll have to have a look through these references but from what I've seen up til now I don't think the level of brain changes seen in ME/CFS is anywhere near that typically seen in MS. I think usually the MRI is reported as normal or "non-specific small white matter hyperintensities" (WMH). Of course the WMH might represent demyelination; and myelin damage in MS can be below detection threshold on standard clinical imaging (hence the term "normal appearing white matter" - NAWM) — see threads [1] [2].

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Refs 19-25, only a few of which have threads —

Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome (1999, Journal of the Neurological Sciences)

Chronic Fatigue Syndrome and the Central Nervous System (2008, Journal of International Medical Research)

Intra brainstem connectivity is impaired in chronic fatigue syndrome (2019, NeuroImage: Clinical)

Brain abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome: Evaluation by diffusional kurtosis imaging and neurite orientation dispersion and density imaging (2019, Journal of Magnetic Resonance Imaging)

Neuroimaging characteristics of myalgic encephalomyelitis/chronic fatigue syndrome ME/CFS: a systematic review (2020, Journal of Translational Medicine)

Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study (2016, Journal of Magnetic Resonance Imaging)

Regional grey and white matter volumetric changes in myalgic encephalomyelitis chronic fatigue syndrome: a voxel-based morphometry 3 T MRI study (2014, The British Journal of Radiology)

 

I seem to recall that the groundbreaking (recent) paper linking MS with EBV was based on an MS (blood) biomarker. That (biomarker) makes me wonder why it appears that MS diagnosis is so problematic. But yes, you'd like to think they screened out MS.

 

I'm guessing you're talking about the Ascherio paper. The diagnosis isn't blood based (and never is for MS afaik), but they could link the "Serum levels of neurofilament light chain, a biomarker of neuroaxonal degeneration to seroconversion of EBV".

I haven't had a more detailed look at what Davis et al have done here and probably wouldn't understand it anyways, but it appears that autoantibodies to myelin basic protein can be quite common in healthy controls as well https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2753924/.

 

There are an awful lot of not quite connections in this paper's rationale.

Do PWME have demyelination? Not as far a we know.

Why would an antibody specifically digest myelin basic protein? Generally speaking enzymes that cleave structural proteins cleave a whole range. There are very special enzymes that cleave specific proteins in signalling cascades like complement but autoantibodies arise by random mutation and are very unlikely to be exactly shaped right to digest one protein - and just right across a range of PWME.

Moreover, if these antibodies existed they should show upon an anti-MBP assay and I don't think we have any evidence for that being a consistent finding even in MS.

Immunology is a lot more complicated than biochemists tend to think.

 

So "Serum levels of neurofilament light chain" is a biomarker for MS but not a diagnostic test?

 

"Immunology is a lot more complicated than biochemists tend to think."

 

Can someone put together a summary of what I am missing for my brain-fogged self? I have eventually got through most of the abstract.
How many patients are likely to have this?
How much symptom improvement did copaxone given in those who tried it?

What I have so far:

* some ME/CFS patients have catalytic autoantibodies that breakdown MBP
* without MBP you get demyelination- which is where nerves from brain and spinal cord don't have the protective fatty layers (M.S. does this)
* Demyelination could explain nerve pain and muscle weakness

*The drug Copaxone (licensed for MS) has been tried and helps stop demyelination
*This may be particularly relevant for ME/CFS from Covid

*Diminished nerve function in ME/CFS study:
Inglese, M. Multiple sclerosis: new insights and trends. AJNR Am. J. Neuroradiol. 2006, 27, 954– 957
18
Multiple sclerosis: new insights and trends
Inglese M
AJNR. American journal of neuroradiology (2006), 27 (5), 954-7 ISSN:0195-6108.

I am lost at the diagrams.

 

https://twitter.com/user/status/1742381992858272190


Place holder for upcoming explainer video.

 

Here is the video—also posted in the Ron Davis thread.

https://www.youtube.com/watch?v=Hx_FNcLBZF0

 

See also ACE-2-like enzymatic activity is associated with immunoglobulin in COVID-19 patients (2024, mBio)