73 COMPLEMENT SYSTEM
# 74 COMPLEMENT SYSTEM
Detailed notes
The complement system is a cascade of around 30 plasma proteins (numbered C1–C9, plus factors B, D, H, I, P and several regulators) that forms the humoral arm of innate immunity. The proteins circulate as inactive zymogens, produced almost entirely by hepatocytes, and become activated by sequential proteolysis — each enzyme cleaves and activates the next, amplifying the signal at every step.
Complement does three things:
- Opsonisation — coats microbes with C3b so phagocytes can grip them.
- Inflammation and chemotaxis — releases anaphylatoxins (C3a, C5a) that recruit neutrophils and degranulate mast cells.
- Direct lysis — assembles the membrane attack complex (MAC, C5b-9) that punches pores through pathogen membranes.
👩⚕️ Five facts will earn you almost every complement mark in MRCS Part A:
➡ All three pathways converge on C3
➡ C3b = opsonin
➡ C3a and C5a = anaphylatoxins (C5a is also the strongest chemoattractant)
➡ MAC = C5b-9
➡ Complement is made by the liver
The three activation pathways
All pathways generate a C3 convertase, which cleaves C3 into C3a + C3b. C3b then forms a C5 convertase, which cleaves C5 and initiates assembly of the MAC. The difference between the pathways is only in how the C3 convertase is formed.
| Pathway | Trigger | Recognition molecule | C3 convertase |
|---|---|---|---|
| Classical | Antigen–antibody complex | C1q binds Fc of IgM or IgG | C4b2a |
| Lectin | Microbial sugars (mannose) | Mannose-binding lectin (MBL) | C4b2a |
| Alternative | Spontaneous C3 hydrolysis ("tickover") stabilised on microbial surface | C3b itself + factor B | C3bBb |
Key points worth knowing cold:
- Classical pathway needs antibody — so it bridges innate and adaptive immunity. C1q is the recognition arm and binds the Fc portion of IgM (most efficient — one pentameric IgM is enough) or IgG (needs two adjacent molecules).
- Lectin pathway is antibody-independent. MBL recognises mannose residues on bacterial and fungal walls; it then activates MASPs which mimic C1.
- Alternative pathway is constantly ticking over at low level. On host cells it is shut down immediately by regulators; on a microbial surface it amplifies, providing a fast first response before antibody is available.
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Functions of the key components
| Component | Role | Memory hook |
|---|---|---|
| C1q | Binds Fc of IgM/IgG — initiates classical pathway | "1 q for antibody" |
| C3b | Opsonin — tags microbe for phagocytosis (CR1 on neutrophils/macrophages) | "b = binds bug" |
| C3a | Anaphylatoxin (mast cell degranulation) | "a = anaphylatoxin" |
| C5a | Strongest chemoattractant; also anaphylatoxin | C5a recruits neutrophils |
| C5b-9 (MAC) | Forms pore in cell membrane → osmotic lysis | "MAC attack" |
👩⚕️ Examiners love the a vs b trick: the small cleavage fragment (a) floats off as an anaphylatoxin; the big fragment (b) binds the membrane and continues the cascade.
Regulation — keeping complement off host cells
Because the alternative pathway is always firing, host cells must actively defend themselves. The major regulators are:
- Decay-accelerating factor (DAF / CD55) — GPI-anchored; dissociates the C3 convertase.
- CD59 (MAC inhibitory protein) — GPI-anchored; blocks C9 insertion, preventing MAC formation.
- Factor H — fluid-phase regulator that helps factor I cleave C3b on host surfaces.
- Factor I — protease that cleaves C3b and C4b.
- C1 esterase inhibitor (C1-INH) — inactivates C1r/C1s and also dampens the kinin pathway (key to hereditary angioedema below).
> Pearl: DAF and CD59 are tethered to the cell membrane by a GPI anchor. Lose the anchor — as in paroxysmal nocturnal haemoglobinuria (PNH) — and red cells are stripped of their complement defence, leading to chronic intravascular haemolysis, dark morning urine, and a markedly raised risk of thrombosis. Treatment: eculizumab, a monoclonal antibody against C5.
Clinical syndromes — pattern recognition
This is the section that wins exam marks. Match the deficient component to the syndrome:
| Deficiency | Clinical picture | Why |
|---|---|---|
| C1 esterase inhibitor | Hereditary angioedema — recurrent non-pitting, non-itchy swelling of face, lips, larynx, bowel | Uncontrolled C1 activation and bradykinin release |
| C2 / C4 | SLE-like illness, increased pyogenic infection | Failure to clear immune complexes |
| C3 | Recurrent infection with encapsulated bacteria (S. pneumoniae, H. influenzae, N. meningitidis) | Loss of opsonisation |
| C5–C9 (MAC) | Recurrent Neisseria meningitidis infection | Neisseria is killed mainly by MAC-mediated lysis |
| Factor H or I | Atypical haemolytic uraemic syndrome (aHUS), membranoproliferative glomerulonephritis | Uncontrolled alternative pathway damages endothelium |
| DAF / CD59 (GPI anchor) | Paroxysmal nocturnal haemoglobinuria (PNH) | Host red cells unprotected from MAC |
👩⚕️ Hereditary angioedema is a surgical emergency the exam loves. Swelling is mediated by bradykinin, not histamine — so adrenaline, antihistamines and steroids do not work. Treatment is C1 esterase inhibitor concentrate or icatibant (bradykinin B2-receptor antagonist). Fresh frozen plasma is a second-line alternative. Always check the family history.
Why this matters in surgery
- Asplenia and post-splenectomy sepsis (covered in Lesson 51): the spleen filters opsonised encapsulated bacteria. Without it, complement opsonisation alone is insufficient — hence lifelong penicillin prophylaxis and vaccination against pneumococcus, meningococcus and H. influenzae type b.
- Meningococcal vaccination is essential before starting eculizumab (used for PNH and aHUS) because blocking C5 mimics terminal complement deficiency and dramatically increases Neisseria risk.
- Ischaemia-reperfusion injury, transplant rejection and burns all involve complement activation; this is increasingly the target of new therapies.
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Test yourself
Which of the following statements about the complement system is true?
- ((C3 causes mast cell degranulation::C3a and C5a are the anaphylatoxins, not parent C3.))
- ((C4b is the primary opsonin::C4b helps form the classical C3 convertase; C3b is the opsonin.))
- ((C5a6789 can lyse cell membranes::Wrong sequence — the MAC begins with C5b, not C5a.))
- ((C5b6789 can lyse cell membranes::☑️ MAC = C5b-9 forms transmembrane pores causing osmotic lysis.))
- ((C3b is the strongest chemoattractant::C3b opsonises; C5a is the dominant chemoattractant.))
👩⚕️ Remember the a vs b rule: small fragment (a) = anaphylatoxin; big fragment (b) = binds membrane.
Complement proteins are primarily produced by which cells?
- ((Hepatocytes::☑️ Liver is the main source of plasma complement proteins.))
- ((Macrophages::Make small local amounts but not the bulk of circulating complement.))
- ((T lymphocytes::Produce cytokines, not complement.))
- ((Mast cells::Release histamine and tryptase, not complement.))
- ((Neutrophils::Effectors that respond to C5a; they do not synthesise complement.))
A 28-year-old presents with his third episode of meningococcal meningitis. Which deficiency is most likely?
- ((C3::Causes encapsulated infections broadly, but recurrent Neisseria specifically points to terminal complement.))
- ((C5–C9 (terminal complement / MAC)::☑️ Neisseria are killed mainly by MAC; recurrent meningococcal disease is the classic clue.))
- ((C1q::Causes SLE-like illness and immune complex disease.))
- ((C2::Associated with SLE-like illness, not recurrent Neisseria.))
- ((Factor H::Causes aHUS and MPGN, not recurrent meningococcaemia.))
👩⚕️ Recurrent Neisseria = terminal complement deficiency until proven otherwise. Vaccinate before starting eculizumab for the same reason.
A young woman presents with recurrent facial and laryngeal swelling. Adrenaline and antihistamines have no effect. Which is the most appropriate treatment?
- ((IV hydrocortisone::Ineffective — swelling is bradykinin-mediated, not histamine-mediated.))
- ((IM adrenaline::Useless in hereditary angioedema; the question tells you it has already failed.))
- ((C1 esterase inhibitor concentrate::☑️ Replaces the missing regulator and aborts the attack; icatibant is an alternative.))
- ((Chlorphenamine::Antihistamines do not work in a bradykinin-driven process.))
- ((Eculizumab::Anti-C5 monoclonal used in PNH and aHUS, not hereditary angioedema.))
👩⚕️ Hereditary angioedema = bradykinin, not histamine. Treat with C1-INH or icatibant (B2 receptor antagonist).
Which complement component is the strongest chemoattractant for neutrophils?
- ((C3a::Anaphylatoxin but a weak chemoattractant.))
- ((C3b::Opsonin, not a chemoattractant.))
- ((C5a::☑️ Most potent complement chemoattractant; also an anaphylatoxin.))
- ((C5b::Initiates MAC assembly; not soluble or chemotactic.))
- ((C9::Final pore-forming component of MAC.))
A patient with dark morning urine and recurrent venous thrombosis is found to have a GPI-anchor defect. Which proteins are missing from the red cell surface?
- ((C3 and C5::These are plasma proteins, not membrane-anchored.))
- ((C1q and MBL::Recognition molecules of the classical and lectin pathways.))
- ((Factor H and factor I::Plasma regulators, not GPI-anchored.))
- ((DAF (CD55) and CD59::☑️ GPI-anchored complement regulators lost in PNH, leaving red cells exposed to MAC.))
- ((C4 and C2::Classical pathway components, not membrane regulators.))
👩⚕️ PNH = lost GPI anchor → no DAF or CD59 → MAC-mediated intravascular haemolysis. Treat with eculizumab (anti-C5).
Which pathway is activated by mannose-binding lectin recognising microbial sugars?
- ((Classical::Triggered by antibody-antigen complexes via C1q.))
- ((Lectin::☑️ MBL binds mannose on microbes and activates MASPs, generating C4b2a.))
- ((Alternative::Activated by spontaneous C3 hydrolysis on microbial surfaces.))
- ((Coagulation::Separate cascade; cross-talks but is not a complement pathway.))
- ((Kinin::Bradykinin pathway — relevant to hereditary angioedema, not complement activation.))
Revision summary
- Made by hepatocytes. Three pathways (classical / lectin / alternative) all converge on C3.
- Classical = antibody (C1q binds Fc of IgM > IgG). Lectin = MBL binds mannose. Alternative = spontaneous tickover, amplified on microbes.
- C3a, C5a = anaphylatoxins. C5a = strongest chemoattractant. C3b = opsonin. MAC = C5b-9 = lysis.
- a vs b rule: small fragment (a) floats off as anaphylatoxin; big fragment (b) binds membrane.
- Deficiency syndromes:
- C1-INH → hereditary angioedema (bradykinin; treat with C1-INH or icatibant; adrenaline ineffective)
- C2/C4 → SLE-like illness
- C3 → recurrent encapsulated bacteria
- C5–C9 → recurrent Neisseria meningitidis
- Factor H/I → aHUS
- DAF/CD59 (GPI anchor) → PNH; treat with eculizumab
- Surgical relevance: asplenia needs vaccination against encapsulated organisms; meningococcal vaccination is mandatory before starting eculizumab.