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).