Preprint Replicated blood-based biomarkers for Myalgic Encephalomyelitis not explicable by inactivity, 2024, Beentjes, Ponting et al

Some are, some are anti-inflammatory, some have nothing to do with inflammation.

Activation of complement in tissue to generate C3a and C4a is a classical inflammatory pathway.

Activation of complement in plasma to generate C3b attached to immune complexes is a classical anti-inflammatory event - leading to silent clearance of complexes that might otherwise cause inflammation.

Binding of C3dg to complement receptor 2 is an instructive event for B cells but is not in itself inflammatory.

Activation of complement in brains appears to be a non-inflammatory event. C3a may not operate as a chemotactic agent in brain normally or the events may be too local to generate significant C3a levels. C3b appears to engage with neurone in a way that does not lead to MAC formation. And so on.

 

In "Insight into the biological pathways underlying fibromyalgia by a proteomic approach" (J Proteomics, 2018) CFaH is listed as one of the proteins differentially expressed in the plasma of fibromyalgia patients:

 

In this context, what is the difference between an inflammatory and a non-inflammatory event, I’ve always had troubling pinpointing down what “inflammation” means at the smaller level.

Does it mean the other immune cells aren’t “called to arms” and cytoxicity is not triggered?

 

Inflammation is defined as a change in tissue water and cell content due to a change in blood vessel behaviour. The vessels dilate (redness), leak fluid (oedematous swelling) and allow cells to emigrate (infiltrative swelling). The phenomenon was described in detail by Metchnikoff and by Lewis. The very slightest change consist of blood vessel dilatation with leakage of water - urticaria in the skin and transparent oedema in the mesentery. Protein leakage requires a bit more change and cell migration even more and takes longer.

It is important to keep in mind the original definition because it allows one to understand why, for instance, cytokines in the bloodstream are no inflammatory, because to be inflammatory a molecule has to call cells out of the bloodstream into the tissue. Calling white blood cells in the blood into the blood is meaningless. Similarly, bone marrow and spleen do not get inflamed because their blood vessels normally have no well defined walls. The blood goes in and can swim around everywhere in the normal state. So dilating and leaking adds nothing. The brain has unusual vessels with very low protein permeability and that makes inflammation in the brain different. It is hugely sensitive to leakage of water and copes very badly with cells because its lymphatic system is very limited.

If immune complexes are allowed to pass into endothelial basement membranes and fix complement there they will generate inflammation through C3a release. But if they fix complement in blood first and that binds to CR1 on red cells they are whisked away to spleen (which doesn't have inflammation) and all is well.

 

Looking at long COVID studies: in "Post-acute sequelae of SARS-CoV-2 cardiovascular symptoms are associated with trace-level cytokines that affect cardiomyocyte function" (Nature Microbiol, 2024) complement factor H was reported as one of the proteins more abundant in plasma in PASC patients than controls, and in "Proteomic analysis of Post-COVID Condition: Insights from plasma and pellet blood fractions" (J Infect Public Health, 2024), in the supplementary data showing plasma fraction results (Table S4), factor H was reported upregulated (fold change=1.730, p<0.001).

 

Just noting a couple more studies in other conditions with high factor H:

S4ME thread: Evaluation of serum and peritoneal fluid mannose-binding lectin associated serine protease-3, adipsin, properdin, and complement factor-H levels in endometriosis patients, 2025 (Int J Gynecol Obstet)

Prediction Models for Late-Onset Preeclampsia: A Study Based on Logistic Regression, Support Vector Machine, and Extreme Gradient Boosting Models, 2025 (Biomedicines)

 

I haven't the energy to read the whole thread... I read the abstract and I don't really understand. It mentions insulin resistance and liver disease. I wasn't under the impression that these were particularly common in PWME???

 

if I recall correctly this study used the UK biobank which has pretty loose diagnostic criteria for ME that likely include a lot of "chronic fatigue" cases, so it could be that those are mechanisms implicated in chronic fatigue and not ME.
Or perhaps the liver is implicated in ME, who knows?

 

Sometimes its the unexpected things that are most worth thinking over carefully. Chris P has mentioned some further analysis of this study which I think strengthens the data. I cannot give specifics though. I was worried that these might be artefacts of diagnostic ascertainment but I am prepared to take them seriously.

 

I have only been checking this since Covid rampaged through my body and made me worse but measurements of liver function vary quite a bit. Sometimes everything is normal and at other times the standard urine tests shows problems. Its intermittent which would explain why its only seen in some people in a test with ME/CFS. You would have to track it daily/weekly for a year to catch all its coming and going as I have.

If you wanted to do more detail testing you would need the flexibility to do that testing when the patient said the urine test strip showed something was wrong and within 24 hours. Would be very hard to study based on how all the studies currently work.

 

May be worth mentioning: in a recently posted review in the Science Signalling journal it was noted there is some evidence that insulin resistance appears to be mediated by sleep-related variables; given the often profoundly poor-quality sleep that pwME tend to have this may be an additional confounder:

 

Interview with Chris Ponting by David Tuller about this study from Nov 19, 2024:

https://www.youtube.com/watch?v=08qLpdjhu_g

 

I have a somewhat vague question and only have had a quick glimpse over the paper: The analysis accounted for physical activity using some metrics (duration of walks, duration of moderate activity, duration of physical) but seemingly not for some other more possibly indirect metrics of physical activity/fitness/deconditioning (for instance BMI). Since there are significant differences in BMI between the ME/CFS cohort and controls can it be ruled out that certain differences (for instance in relation to some of the insulin resistance findings that have been discussed) aren’t simply due to BMI differences? (@Sid already asked something similar earlier on but I didn’t see a response). How would the analysis change if BMI was added as mediator?

 

But wouldnt we know if liver disease was common in ME? Because then a lot of people with ME would be dying of liver disease or needing liver transplants.

 

I don’t know whether this applies to urine tests, but my GP told me that non-repeated elevated liver markers in blood tests can simply be due to having taken a tablet recently such as a paracetamol or an antihistamine.

 

Also on the insulin resistance, insulin resistance is common in PCOS (polycystic ovary syndrome), and PCOS is a common comorbodity with ME I think?

 

Perhaps something weird is happening in the liver in ME which is not consistent with Liver Disease or currently known liver pathologies.

 

Sounds like a major confounder. Good catch.

 

No, we are not talking about liver disease but about changes in liver cell behaviour. In rheumatoid arthritis there is Kuppfer cell activation. There might well be in ME/CFS since this is a type of macrophage responding to an immune stimulus. The result in RA is that the alkaline phosphatase level tends to be a bit higher than average across a population although even the AP is mostly not outside the normal range. It never gets beyond that because the liver can cope with Kuppfer cells being activated.

In ME/CFS this is probably not the answer though because Kuppfer cell activation also raises the CRP as much as anything does. Beentjes found CRP up a tiny bit but not anything like in RA.

 

Checking some old results my alkaline phosphatase level seemed to go up (but very much well within range) after I got ill. Only a few before and after data points and it may be noise.

I was always interested in the within normal range changes I saw in blood test results though, not from any knowledge, just because to me changes seem important when things change.