Complement levels - C3 and C4

Resurrecting this thread as it seems the best place to put this. I know @Daisybell went on to be diagnosed with another condition.

@Jonathan Edwards, you have made some interesting comments about complement here over the years, and I wanted to ask if you think there might be anything to learn from it in ME/CFS (or people presenting with something that looks like ME/CFS, as the case may be)?

It seems to be measured to rule out other things, like lupus, but do complement levels in ME/CFS tell us anything about mechanism?

In the Opala case study discussed here they mentioned complement:
The immunological laboratory diagnostics revealed only slightly elevated antinuclear antibodies (ANAs) and a reduced value of the classical pathway of complement activity...A slightly reduced activity of the classical complement pathway is considered to have no pathological relevance in the absence of susceptibility to infections, especially those caused by encapsulated bacteria, and in the absence of evidence of complement consumption (C3c and C4), as well as given the potential for preanalytical variability.
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The combination of the patient’s abnormal laboratory findings, including elevated IL-2, IL-6, interferon gamma, vascular endothelial growth factor, total histamine, CCL5 (RANTES), ANAs, and leukotrienes C4, D4, and E4, as well as reduced levels of complement components C3a and C4, does not correspond to any established rheumatologic or immunologic disease entity.
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I have had C3 and C4 have been measured twice, and C4 has been borderline low both times, with C3 normal once and borderline low once:
  1. Four years into illness, mild ME/CFS heading for moderate:
    • C3 1.12 (no range given, but looks normal based on range below)
    • C4 0.14 (no range given, but looks just outside the normal range based on range below)
  2. Ten years into illness, severe ME/CFS
    • C3 0.83 (range 0.83-1.93)
    • C4 0.14 (range 0.15-0.57) flagged as low, but clearly only just outside the normal range

Maya et al. 2026 reported high C3 in a questionable cohort of ME/CFS (see thread).

Would be curious to know if complement can tell us anything.
 
There have been suggestions of shifts in complement activity but on a statitical basis and not wildly out of range (e.g. Beentjes). I doubt complement values are of any use in interpreting individual's problems. If they were we would have had some clue of that by now.

Part of the problem may be that lupus-like illness comes in all sorts of variations, often with mild complement disturbance. Lupus is probably the most common mimic of ME/CFS at least in young women. Moreover, its margins are fuzzy.

Another problem is that there are at least 15 complement proteins, any of which might be slightly off, so mild complement shifts may turn up by chance in studies relatively often.
 
Jonathan Edwards said:
There have been suggestions of shifts in complement activity but on a statitical basis and not wildly out of range (e.g. Beentjes). I doubt complement values are of any use in interpreting individual's problems. If they were we would have had some clue of that by now.

Part of the problem may be that lupus-like illness comes in all sorts of variations, often with mild complement disturbance. Lupus is probably the most common mimic of ME/CFS at least in young women. Moreover, its margins are fuzzy.

Another problem is that there are at least 15 complement proteins, any of which might be slightly off, so mild complement shifts may turn up by chance in studies relatively often.
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Thank you for explaining. The Beentjes paper is over my head, to be honest.

I'm no longer young, but I could be on a fuzzy margin.

Mild shifts turning up by chance makes sense.
 
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