The complement system
Complement is the immune system’s always-on alarm and clean-up cascade — useful aimed at the right target, dangerous when its off-switch fails and it turns on your own tissue. It is the shared engine behind several conditions in this book.
Go deeper
2 layers below. Open any one.Three routes switch it on — classical, lectin, and the alternative pathway, which idles constantly and must be actively braked. C3 is the hub they converge on. Strong evidence The pattern low C3 with a normal C4 is the fingerprint of the alternative pathway rather than another route — which is why that pair, measured together, tells a doctor where to look.
When regulation fails, the debris damages tissue — in the kidney (C3G, aHUS), the blood (PNH), and parts of lupus. Good evidence A wave of complement-blocking drugs (anti-C5 like eculizumab; factor B/D inhibitors like iptacopan) has turned several of these from untreatable into targetable — which is why finding the complement cause is worth the effort.
Questions to bring
Copy these, or read them out. They fit in a short visit.
- Is complement involved — have C3 and C4 been checked together?
- Is a complement-directed drug or trial relevant to my case?
The short version
- Getting ahead of it
- If a complement disease runs in the family, know it; find the cause, because it now often has a drug.
- Your testing regime
- C3 and C4 together, a complement pathway panel, and genetics where indicated.
- What they don’t tell you
- Complement assays are not standardised between labs; low C3 with normal C4 is the alternative-pathway tell.
- What it can spawn
- Kidney disease (C3G, aHUS), blood disorders (PNH), and it drives parts of lupus.
- What it’s confused with
- The individual diseases it underlies, each treated separately without naming the shared engine.
From general immunology; not a diagnosis; nothing here comes from any individual’s medical record.
The longer chapter
From the 11 September 2026 edition (Vermont Synergy Initiative site): “What is the complement system, in plain words?”. Every section below is that edition’s own words; open any one.
One of the things people type into Google most is what is the complement system
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It is your own immune alarm. In this disease it goes off inside the kidney’s filters and does not switch off. This room says that in plain words, and shows the two places the new drugs put a brake on it.
If you came here asking “what is complement”, “what does a low C3 mean”, “why is my own immune system damaging my kidney”, or “what do these new complement drugs actually do” — this page is written for you, and it assumes you know nothing about it.
Beta. This page is real work with its sources shown, and it is not finished. If something here is unclear, that is our failure and we would rather hear it than not. The box at the foot of the page reaches a person.
This part of your immune system never switches off, and it is not supposed to. If anyone has told you your complement is “activated” or “overactive”, that sentence makes much more sense once you know it was already running.
Most of us picture the immune system as something that starts when you get sick. Complement is not like that. It is a set of about thirty proteins that drift through your blood all day, every day, at a low idle — touching every surface they meet and asking one question: are you one of ours?
Your own cells answer yes. They carry markers on their outside that say so, and the moment complement touches one, it shuts itself down. A bacterium has no such markers. It cannot answer. And within seconds, the idle becomes an attack.
Complement has three jobs, and every one of them is something you can picture. If you are ever shown a result with C3, C4, C5 or “MAC” on it, these three jobs are what those letters are doing.
| What it does | How it works | Picture it as |
|---|---|---|
| What it does Tag | How it works Coats the surface of the intruder in a protein called C3b. Scavenger cells carry grabbers shaped to hold C3b, so anything coated gets eaten. | Picture it as Spray-painting a target bright orange so the clean-up crew can find it. |
| What it does Call | How it works Releases small fragments — C3a and C5a — that drift into the surrounding tissue, widen the blood vessels and summon other immune cells. | Picture it as Setting off a flare so help comes running. |
| What it does Destroy | How it works Assembles a ring of proteins that punches a physical hole through the intruder’s outer wall. Its name is the membrane attack complex, or MAC. | Picture it as Holing a boat below the waterline. |
GRADE A Those three functions — coating for removal, summoning inflammation, and punching holes — are the standard description of what complement does, found in every immunology text.
Nothing here is contested. The plain words are ours; the biology is textbook.
There are three separate tripwires, and they all end up pulling the same lever. If your results ever show a low C3 with a normal C4, the difference between these three routes is exactly what that pattern is telling somebody.
The classical route — started by antibodies
When an antibody finds something it recognises and sticks to it, a complement protein called C1 senses the antibody sitting there and sounds the alarm. This is the bridge between the immune system that learns and the one you were born with.
antibody binds → C1 senses it → C4 and C2 are cut → the central lever is pulled
C4 is used up on this route. Remember that; it is why C4 gets measured.
The lectin route — started by sugar patterns
Some proteins in your blood recognise repeating sugar patterns that appear on bacteria and fungi but not on you. When they latch on, they pull the same lever the classical route does — without needing an antibody first.
sugar pattern recognised → C4 and C2 are cut → the central lever is pulled
C4 is used up on this route too.
The alternative route — always running, and this is the one that matters here
This one has no trigger. A small amount of C3 comes apart on its own, constantly, all over your body. The technical name for it is tick-over, and it is a design feature: it means the system is already touching every surface before anything goes wrong.
When that spontaneous C3 lands on one of your own cells, the brakes on that cell shut it down immediately. When it lands on something with no brakes, it recruits a protein called Factor B, and the attack builds on itself.
C3 comes apart by itself → lands on a surface → your cell: brakes stop it · a bacterium: Factor B joins and it accelerates
C4 is not used on this route. That single fact is why the pattern in the next section works.
C3 is used by all three routes. C4 is used by only two of them. If you are ever told your complement was checked, this is the question that tells you whether it was checked usefully.
That difference turns two ordinary blood tests into a signpost:
| Pattern | What it suggests |
|---|---|
| Pattern C3 low, C4 normal | What it suggests Something is consuming C3 without touching C4 — which points at the alternative route, the always-on one. |
| Pattern C3 low, C4 also low | What it suggests C4 is being consumed too, so a route that uses C4 is involved. That points somewhere else entirely. |
| Pattern Both normal | What it suggests Does not rule complement out. It means the blood is not showing it today. |
“Have my complement levels been checked — both C3 and C4 together?” The word together is doing the work. One without the other does not show the pattern.
GRADE A The alternative route consumes C3 without consuming C4, which is why a low C3 with a normal C4 is read as a signature of alternative pathway activity.
Standard complement immunology, and the basis on which C3 glomerulopathy is defined. It is a pattern in a blood test, not a diagnosis. What it does is tell a doctor where to look, which is worth a great deal when nobody has been looking anywhere.
Your cells are not invisible to complement — they are protected from it, by named proteins doing a named job. If a condition is ever explained to you as “your immune system attacking you”, this is the more accurate and more useful version of that sentence.
Factor H — the one that comes up most often
Factor H recognises surfaces that belong to you and helps take apart the complement machinery that has landed on them. It is the principal brake on the always-on route.
This is the brake most often at fault in C3 glomerulopathy — sometimes because of an inherited change in the gene, sometimes because an antibody sits on it and blocks it.
CD55 — makes the machinery fall apart
Sits on the outside of your cells and causes the assembled complement machinery to come apart before it can do damage. Its longer name is decay-accelerating factor, which for once says exactly what it does.
CD59 — stops the hole being punched
Blocks the last step. Even if everything upstream has gone wrong, CD59 prevents the membrane attack complex from finishing. It is the brake closest to the damage.
The same failure produces different conditions depending on where it happens. If you have been given one of these names, the mechanism above is the thing they all share.
| Where | What happens |
|---|---|
| Where The kidney’s filters — C3 glomerulopathy | What happens The runaway loop leaves complement debris in the finest sieves in the body. They clog, they inflame, and protein leaks into the urine. There is a page on this. |
| Where Red blood cells — paroxysmal nocturnal haemoglobinuria | What happens The cells are missing their surface brakes, so complement bursts them. |
| Where The retina — geographic atrophy | What happens Local overactivity contributes to the loss of retinal cells. |
The newer complement drugs differ in where on the chain they act, and that difference is the whole point of them. If a treatment is ever proposed to you, this is the question to bring: where on the chain does this one act, and what does it leave working?
GRADE B C3 blockers bind C3 itself. Because all three routes must pass through C3, this shuts the whole system down at its single bottleneck — including the coating step that would otherwise mark your own cells for removal.
GRADE B Factor B blockers act only on the always-on route’s amplifier. The classical and lectin routes keep working, so ordinary antibody-driven defence is left largely intact. They can be taken as a tablet rather than an infusion, because Factor B sits in the blood at far lower concentrations than C3 does.
Graded B deliberately. The mechanisms are well described and the drugs are real, but this account is assembled from secondary explanations rather than read from the primary literature or the labels. It is good enough to tell you what to ask and not good enough to decide anything by. Nothing here is a recommendation, and no drug is endorsed.
GRADE U The claim that most of the final complement effect comes from the always-on amplifier even when the trigger was somewhere else. It is widely repeated, with figures around eighty per cent, and we have not traced it to a primary measurement.
U is not a failing grade. It means the evidence does not settle it either way, which is different from evidence of no effect. If it is right, it explains why blocking one route helps in conditions that did not appear to start there — worth knowing, and worth not overstating.
These are written to be said out loud, or pasted into a portal message.
- “Have my complement levels been checked — both C3 and C4 together?”
- “Was the pattern a low C3 with a normal C4? What does that suggest to you?”
- “Has anyone looked for a reason the brakes are not working — a gene, an antibody, or an abnormal protein?”
- “If a complement drug is being considered, where on the chain does it act, and what does it leave working?”
- “Does blocking this part of my immune system change what vaccinations or precautions I need?”
✓ What complement is, the three things it does, the three ways it starts, why C3 and C4 are measured together, the named brakes, and where the newer drugs act.
→ The diagram is missing. This is a system far easier to see than to read, and one good illustration would do more than another paragraph. It is the next thing to go on this page.
→ The treatment section needs its grades done properly against the primary literature rather than quickly.
Nothing here is a diagnosis, and none of it replaces someone who can examine you. Every claim above carries the grade of the evidence behind it, and the grade travels with the claim.
This is written for you, and we do not know you. Help us by honestly offering your thoughts and your criticisms. We know they are normally just exercises in politeness. Please test us, and let us reply.