Could Phospholipid Dysregulation Contribute to ME/CFS?

[Violeta]

Dynamic phospholipid signaling by G protein-coupled receptors​

Dynamic phospholipid signaling by G protein-coupled receptors - PubMed

G protein-coupled receptors (GPCRs) control a variety of fundamental cellular processes by regulating phospholipid signaling pathways. Essential for signaling by a large number of receptors is the hydrolysis of the membrane phosphoinositide PIP(2) by phospholipase C (PLC) into the second...

pubmed.ncbi.nlm.nih.gov

"G protein-coupled receptors (GPCRs) control a variety of fundamental cellular processes by regulating phospholipid signaling pathways. Essential for signaling by a large number of receptors is the hydrolysis of the membrane phosphoinositide PIP(2) by phospholipase C (PLC) into the second messengers IP(3) and DAG."


GPCR autoantibodies are self-reactive immune proteins that mistakenly target G protein-coupled receptors (GPCRs). Instead of passively binding, many act as "functional autoantibodies" that lock into the receptor—mimicking or blocking natural signals. This continuous overstimulation or blockade drives chronic inflammation and cellular dysfunction in complex disorders.

 

[Verity]

See the following : https://pmc.ncbi.nlm.nih.gov/articles/PMC9231045/

I’ve recently been looking at the few papers on this because I have antiphospholipid antibodies, and I haven’t been convinced. Isn’t this something we’d expect to have turned up more if it was real? Having antiphospholipid antibodies is not really something that stays silent. We should see a high number of clotting events, especially in patients as sedentary as ME/CFS patients.

Perhaps @Jonathan Edwards can correct me if I’m wrong about that—I don’t know if there is some condition under which a patient population might have these antibodies but no increased clotting risk—but I did not think it was probable.

 

[rainy]

I also have antiphospholipid antibodies, and one of the few other ME patients in my life also has this.

But I was excluded from the rituximab trial because I had these antibodies, so if it really was that common, wouldn’t they have noticed the huge amount of patients they had to exclude because of these antibodies?

 

[rainy]

Having antiphospholipid antibodies is not really something that stays silent

I’ve been told by doctors that a percentage of the population will have these with no issues. I was tested only because I was going to be in the rituximab trial. When my GP wanted to test me again, the specialist doctors were surprised why my GP was even testing when I had never had blood clots.

 

[Jonathan Edwards]

Perhaps @Jonathan Edwards can correct me if I’m wrong about that—I don’t know if there is some condition under which a patient population might have these antibodies but no increased clotting risk—but I did not think it was probable.

Patrick Venables said that he noted more antiphospholipid antibodies in people with CFS maybe in the 1990s. I think I looked for a publication and did not find it. Otherwise I don't think studies have picked anything up. I very much doubt there is a significant association. And as I mentioned, antiphospholipid antibodies go with fatiguing illnesses anyway (lupus spectrum) so it is probably a red herring.

Antiphospholipid antibodies are complicated. They are known to be associated with clotting, but only if they are of a certain specificity that involves interaction with a protein (I think it is beta 2 glycoprotein). Otherwise just testing for antibodies to phospholipid tends to give unhelpful results which I think vary over a spectrum of levels with no very good correlation with disease. Tests like this give a result in everyone. A 'positive' is defined arbitrarily as above a certain level - usually because above that level there is a strong statistical link to a clinical disease, not because it falls outside 2 standard deviations.

I am not sure that APL have anything to do with general phospholipid 'dysregulation' anyway.

 

[Colin]

PIP2 corrects an endothelial Piezo1 channelopathy

Open Access: https://www.pnas.org/doi/10.1073/pnas.2522750122


New evidence points to potential treatment for vascular dementia

Boosting a specific phospholipid in brain cell membranes could become a new treatment strategy to restore normal blood flow and enhance brain function.

Embargoed: New evidence points to potential treatment for vascular dementia

Findings published December 22 in Proceedings of the National Academy of Sciences, suggest that adding a missing phospholipid back into a person’s circulatory system could restore normal brain blood flow and reduce symptoms of dementia.

www.eurekalert.org

 

[Violeta]

PIP2 corrects an endothelial Piezo1 channelopathy

Open Access: https://www.pnas.org/doi/10.1073/pnas.2522750122


New evidence points to potential treatment for vascular dementia

Boosting a specific phospholipid in brain cell membranes could become a new treatment strategy to restore normal blood flow and enhance brain function.

Embargoed: New evidence points to potential treatment for vascular dementia

Findings published December 22 in Proceedings of the National Academy of Sciences, suggest that adding a missing phospholipid back into a person’s circulatory system could restore normal brain blood flow and reduce symptoms of dementia.

www.eurekalert.org

Wow, phosphoinositide for the save!

"In summary, our current results provide insights into the mechanisms underlying Piezo1 regulation in the brain endothelium.

Specifically, we show that endothelial GqPCR signaling enhances Piezo1 channel function by depleting the inhibitor phosphoinositide PIP2.

We further demonstrate that changes in endothelial PIP2 levels in different pathological conditions are associated with a Piezo1 channelopathy. Engineered mice carrying mutant endothelial Piezo1 channels suffered hyperemia deficits (5), and here we provide proof of concept that PIP2 injection corrects this impairment.

Despite the weaker inhibition of mutant Piezo1 by PIP2, compared with wild-type channel, systemic treatment of mutant mice corrected blood flow defects. These data collectively suggest a potential therapeutic strategy in which the use of PIP2 could be a strategy to restore normal channel function and enhance brain blood flow.

These findings establish the foundation for a therapeutic approach for improving CBF in conditions where Piezo1 activity is altered and could have impacts beyond brain blood flow control."

 

[mariovitali]

We have one more study with reference to phospholipids :

The observed pattern supported pathway-level convergence with prior ME/CFS metabolomics literature, including carnitine shuttle, fatty-acid beta-oxidation, TCA cycle, redox-thiol, urea cycle, glycerophospholipid and tryptophan-kynurenine axes. In contrast, the hypothesis-free 15 min screen produced high-AUC features that mapped predominantly to environmental or technical signals, including pesticide, industrial-amine and mobile-phase artifact annotations; only one of eight top leads, a truncated oxidised phospholipid, was biologically plausible, and none had tandem-MS support.

Conclusions
In this large community cohort, a literature-curated DBS metabolomic panel captured pathway-level biology associated with a questionnaire-derived PEM-like fatigue phenotype, showed directional concordance across LC gradients, scaled with symptom severity and remained robust to key demographic, anthropometric and anti-leak questionnaire baselines.

The thread of the study can be found here : https://s4me.info/threads/explorato...-a-self-reported-pem-like-2026-hauguel.50641/