Atlas One · Molecular · Plasma Glycoprotein / Immune Effector
Liver-synthesised; the most abundant complement protein; proteolytically activated by C3 convertases
Structure
| Feature | Detail |
|---|---|
| α-chain | 110 kDa; N-terminal C3a anaphylatoxin domain; internal thioester bond (Cys988-Gln991); cleaved by convertase releasing C3a |
| β-chain | 75 kDa; disulfide-linked to α-chain; contains binding sites for Factor B/D and regulatory proteins |
| Thioester bond | Metastable –C(=O)–S– between Cys988 and Gln991; masked in native C3; exposed in C3b → reacts with OH or NH₂ on pathogen surface → covalent opsonisation |
| Conformational change | Convertase cleavage → Arg726-Ser727 bond cut → C3a released → large C3b undergoes dramatic conformational rearrangement exposing reactive thioester |
Three Activation Pathways
All converge at C3 convertase → C3a + C3b → amplification loop → MAC
┌─────────────────────┬──────────────────────┬──────────────────────┐
│ CLASSICAL (CP) │ LECTIN (LP) │ ALTERNATIVE (AP) │
│ │ │ │
│ IgM/IgG + Ag bind │ MBL/Ficolin bind │ Spontaneous C3 │
│ C1q → C1r/s activ. │ mannose/GlcNAc on │ hydrolysis (tick- │
│ │ pathogen surface │ over ~1%/hr) │
│ C1s cleaves C4 → C4b│ → MASP-1/2 activate │ C3(H₂O) + Bb │
│ C4b + C2 → C2a │ C4 and C2 │ → fluid phase C3Bbb │
│ │ │ → cleaves C3 → C3b │
└────────────────────────────┬───────────────────────────────────────┘
│ All 3 pathways generate C3 convertases:
│ CP/LP: C4b2a
│ AP: C3bBb (+ Properdin stabilises)
▼
C3 + Convertase
│
┌──────────────┴──────────────┐
▼ ▼
C3a C3b
(Anaphylatoxin) (Opsonin — covalently
C3aR on mast cells attached to surface)
→ Mast cell degranulation │
→ Histamine release ├─ + Factor B + Factor D
→ Smooth muscle contraction │ → C3bBb (AP C3 conv)
→ Chemotaxis (weak) │ → Amplification loop
│
├─ C3b + C4b2a → C5 conv
│ → C5a + C5b
│
▼
C5b + C6 + C7 + C8 + C9(×18)
│
MAC (Membrane Attack Complex)
poly-C9 pore in lipid bilayer
→ lysis of Gram-negative bacteria,
RBCs (PNH), complement targets
C3b Opsonisation and Receptor Interactions
| Fragment | Receptor | Cell type | Outcome |
|---|---|---|---|
| C3b | CR1 (CD35) | Macrophages, neutrophils, B cells, erythrocytes | Phagocytosis; immune complex clearance; erythrocyte complement catabolism |
| iC3b (Factor I + CR1 → iC3b) | CR3 (CD11b/CD18, Mac-1) | Macrophages, NK cells, neutrophils | Phagocytosis without inflammation; adhesion |
| C3d/C3dg (further cleavage) | CR2 (CD21) | B cells, follicular DCs | B-cell co-stimulation (10³-fold ↑ B-cell activation threshold lowering) |
Regulation
Multiple levels of control prevent autologous complement activation
| Regulator | Mechanism | Location |
|---|---|---|
| Factor H (CFH) | Competes with Factor B for C3b binding; cofactor for Factor I → degrades C3b to iC3b; preferentially binds self surfaces (polyanions) over pathogens | Plasma; binds C3b on self cells |
| DAF / CD55 | Decay-accelerating factor; accelerates dissociation of C3 convertases (C4b2a and C3bBb) | GPI-anchored on all blood cells |
| MCP / CD46 | Membrane cofactor protein; cofactor for Factor I → C3b cleavage to iC3b on self cells | All nucleated cells |
| CD59 (protectin) | Inhibits MAC formation by blocking C9 insertion into lipid bilayer | GPI-anchored on all blood cells |
| Factor I | Serine protease; cleaves C3b (with cofactors) → iC3b → C3d; requires CR1, Factor H, MCP, or C4BP as cofactors | Plasma |
| C1-inhibitor (C1-INH) | SERPIN; irreversibly inhibits C1r, C1s, MASP-1, MASP-2; also inhibits kallikrein, plasmin, thrombin | Plasma |
Pathology
Loss of control or deficiency leads to infections, autoimmunity, and haemolysis
| Disease | Mechanism | Key Features | Treatment |
|---|---|---|---|
| C3 deficiency | Homozygous C3 mutation; loss of all 3 pathway effectors downstream | Recurrent encapsulated bacterial infections (S. pneumoniae, H. influenzae, N. meningitidis); SLE-like illness from ↓ immune complex clearance | Supportive; vaccines; prophylactic antibiotics |
| Dense Deposit Disease (DDD) / C3GN | C3NeF (C3 nephritic factor): IgG autoAb stabilises AP C3 convertase → uncontrolled C3 consumption; C3 deposition in GBM | Low serum C3; haematuria; proteinuria; CKD; partial lipodystrophy (adipocyte complement-mediated) | Eculizumab (C5 inhibitor); avacopan (C5aR antagonist); immunosuppression |
| Paroxysmal nocturnal haemoglobinuria (PNH) | PIGA somatic mutation → loss of GPI anchors (DAF/CD55 + CD59) on haematopoietic stem cell clone → unregulated MAC on RBCs | Intravascular haemolysis; thrombosis (hepatic/portal vein); cytopenias; haemoglobinuria (AM urine) | Eculizumab / ravulizumab (anti-C5); pegcetacoplan (anti-C3); allogeneic SCT |
| Atypical HUS (aHUS) | CFH/CFI/MCP/C3/CFB mutations → uncontrolled AP on glomerular endothelium | Thrombotic microangiopathy; AKI; thrombocytopenia; MAHA; no Stx | Eculizumab (anti-C5) — dramatically effective; plasma exchange as bridge |
| AMD / CFH Y402H | CFH polymorphism → ↓ Factor H binding to C3b in retinal drusen → local complement activation in sub-RPE space | Geographic atrophy; choroidal neovascularisation; >50% of AMD risk attributable to CFH and ARMS2 variants | Anti-VEGF (wet AMD); pegcetacoplan (GA — FILLY/DERBY trials) |
Therapeutic Targeting
| Drug | Target | Indications |
|---|---|---|
| Eculizumab (Soliris) | Anti-C5 monoclonal IgG2/4 hybrid; blocks C5 convertase cleavage → inhibits C5a + MAC | PNH; aHUS; generalised MG (anti-AChR); NMOSD; hMBS |
| Ravulizumab (Ultomiris) | Anti-C5; engineered Fc → longer half-life (~8 weeks vs. 2 weeks eculizumab) | PNH; aHUS; ALS (clinical trial) |
| Pegcetacoplan (Empaveli) | Anti-C3 (PEGylated compstatin analogue) → blocks all 3 pathways downstream | PNH (including C5 inhibitor non-responders); Geographic atrophy — FILLY trial (↓ lesion growth 29%) |
| Avacopan (Tavneos) | C5aR (CD88) antagonist; oral | ANCA vasculitis (replaces high-dose prednisolone — ADVOCATE trial); C3G trials ongoing |
Connections
References
- Walport MJ. "Complement (parts 1 and 2)." N Engl J Med 2001;344:1058–1066 and 1140–1144.
- Ricklin D, et al. "Complement: a key system for immune surveillance and homeostasis." Nat Immunol 2010;11:785–797.
- Legendre CM, et al. "Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome." N Engl J Med 2013;368:2169–2181.
- Jayne DRW, et al. (ADVOCATE). "Avacopan for the treatment of ANCA-associated vasculitis." N Engl J Med 2021;384:599–609.
- Apellis. DERBY/FILLY trials of pegcetacoplan in geographic atrophy. Ophthalmology 2023.