Step 1 · Immunology

Complement System

Name: Complement System
Creator: Veli Bakalov, MD

One cascade, three triggers, and a deficiency for every classic disease

Immunology·Innate·4 min read·8 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Three pathways converge on C3: classical (antigen-bound IgG or IgM; C1 → C4 → C2 → C3), alternative (microbial surface/LPS, spontaneous C3 activation), and lectin (mannose-binding lectin); only the classical pathway needs antibody.
C3 convertase cleaves C3 into C3a + C3b; C3b builds the C5 convertase, and C5b recruits C6–C9 to form the C5b-9 membrane attack complex that lyses cells.
C3b is the main complement opsonin (with IgG, the two principal opsonins); C3a, C4a, and C5a are anaphylatoxins, and C5a is also a potent neutrophil chemoattractant.
C1 esterase inhibitor deficiency → hereditary angioedema (autosomal dominant, bradykinin-mediated, low C4, no urticaria); ACE inhibitors are contraindicated; treat attacks with C1-INH concentrate, icatibant, or ecallantide.
Terminal complement (C5–C9) deficiency → recurrent Neisseria meningitidis and gonorrhoeae infections.
C3 deficiency → severe recurrent pyogenic infections with encapsulated organisms plus immune-complex (type III) disease; early classical (C1q, C2, C4) deficiencies → SLE.
PNH: acquired PIGA mutation removes GPI-anchored DAF (CD55) and CD59 → complement-mediated intravascular hemolysis, morning hemoglobinuria, and thrombosis (e.g., Budd-Chiari, the leading cause of death).
Eculizumab and ravulizumab (anti-C5) treat PNH and atypical HUS but raise meningococcal risk, so vaccinate against N. meningitidis first.

Three pathways, one cascade

Overview. Complement is a cascade of plasma proteins, mostly made by the liver, that forms the humoral arm of innate immunity. It opsonizes microbes, recruits leukocytes, and lyses cells. Three activation pathways — classical, alternative, and lectin — all converge on C3.

Classical pathway. Triggered by IgG or IgM bound to antigen: C1q binds the antibody Fc, and activation proceeds C1 → C4 → C2 → C3. The classical C3 convertase is C4b2a.

"GM makes classic cars": IgG and IgM activate the classical pathway.

Alternative pathway. Triggered by microbial surfaces and endotoxin (LPS) with spontaneous, low-level C3 activation — no antibody needed. C3b deposited on a microbe binds factor B, which factor D cleaves to form the alternative C3 convertase, C3bBb; host cells are protected by regulators that microbes lack.

Lectin pathway. Mannose-binding lectin binds mannose residues on microbial surfaces and activates associated serine proteases that cleave C4 and C2, forming the same C3 convertase as the classical pathway — again without antibody.

Complement activation pathways

Feature	Classical	Alternative	Lectin
Trigger	IgG or IgM bound to antigen (immune complex)	Microbial surface, LPS; spontaneous C3 activation	Mannose-binding lectin on microbial mannose
Antibody needed	Yes	No	No
C3 convertase	C4b2a	C3bBb	C4b2a

Convergence on C3 and the membrane attack complex

Classical / alternative / lectinThree triggers
C3 convertaseCleaves C3
C3b + C3aOpsonin + anaphylatoxin
C5 convertaseBuilt with C3b; cleaves C5 into C5a + C5b
C5b-9 MACMembrane attack complex; osmotic lysis

Complement cascade

The MAC. Every pathway forms a C3 convertase that cleaves C3 into C3a and C3b. C3b joins the convertase to build the C5 convertase, which splits C5 into C5a and C5b. C5b then assembles C6, C7, C8, and multiple C9 molecules into the C5b-9 membrane attack complex, which punches pores in membranes and causes osmotic lysis. MAC-mediated lysis is crucial against Neisseria.

What the fragments do

Opsonization. C3b is the main complement opsonin: it coats microbes so phagocytes, which carry C3b receptors, can engulf them, and it helps clear immune complexes. The two principal opsonins overall are C3b and IgG.

"C3b binds bacteria."

Anaphylatoxins and chemotaxis. C3a, C4a, and C5a are anaphylatoxins that trigger mast cell and basophil degranulation (histamine release), increasing vascular permeability. C5a does double duty as a potent neutrophil chemoattractant.

Complement fragments and their jobs

Fragment	Main function
C3b	Opsonin; immune complex clearance; forms C5 convertase
C3a, C4a	Anaphylatoxins (mast cell and basophil degranulation)
C5a	Anaphylatoxin AND neutrophil chemotaxis
C5b-9	Membrane attack complex: pore formation and lysis

Regulators and deficiencies

Regulators protect self. C1 esterase inhibitor blocks activated C1 (and also kallikrein of the kinin system). DAF (CD55) and CD59 are GPI-anchored proteins on host cells: DAF accelerates the decay of C3 and C5 convertases, and CD59 blocks MAC assembly. Losing these REGULATORS — not the cascade proteins — causes hereditary angioedema and PNH.

C1 esterase inhibitor deficiency. Causes hereditary angioedema (autosomal dominant): episodic non-pitting angioedema of the face, airway, and GI tract, without urticaria, driven by excess bradykinin. C4 is low because unchecked C1 consumes it. ACE inhibitors are contraindicated because they block bradykinin breakdown. Acute attacks are treated with C1-INH concentrate, icatibant (a bradykinin B2 receptor antagonist), or ecallantide.

Terminal (C5–C9) deficiency. Without the MAC, patients have recurrent Neisseria infections (N. meningitidis, N. gonorrhoeae), because MAC-mediated lysis is the key defense against these thin-walled organisms. A young adult with a second episode of meningococcal disease should be tested.

C3 deficiency. Causes severe, recurrent pyogenic infections with encapsulated organisms, beginning early and often sinopulmonary, plus increased type III hypersensitivity (immune complex disease) from impaired clearance.

Early classical deficiencies. C1q, C2, and C4 deficiencies impair immune complex clearance and markedly raise the risk of SLE.

Paroxysmal nocturnal hemoglobinuria (PNH). An acquired PIGA mutation in a hematopoietic stem cell blocks GPI-anchor synthesis, so the cell's descendants lose DAF and CD59. The result is complement-mediated intravascular hemolysis, thrombosis, and morning hemoglobinuria (dark first-void urine). Flow cytometry shows absent CD55 and CD59 on blood cells.

Thrombosis, often in unusual sites such as the hepatic veins (Budd-Chiari), is the leading cause of death in PNH.

Deficiency to disease

Missing protein	Disease	Clue
C1 esterase inhibitor	Hereditary angioedema	Bradykinin; low C4; worse with ACE inhibitors
C1q, C2, C4	SLE-like disease	Poor immune complex clearance
C3	Severe pyogenic infections	Encapsulated organisms + immune complex disease
C5–C9 (MAC)	Recurrent Neisseria	Repeated meningococcal disease
DAF (CD55) / CD59	PNH	PIGA mutation; intravascular hemolysis, thrombosis

Blocking complement therapeutically

Anti-C5 antibodies. Eculizumab and ravulizumab are monoclonal antibodies against C5 that prevent MAC formation. They are used in PNH and atypical HUS, a thrombotic microangiopathy driven by uncontrolled alternative pathway activity.

Blocking C5 recreates terminal complement deficiency, so these drugs sharply raise the risk of Neisseria meningitidis infection: meningococcal vaccination is required before starting.