C3b

**Origin:** C3 is the most abundant complement protein. It is cleaved by C3 convertases into C3a (small fragment, anaphylatoxin) and C3b (large fragment, opsonin). Convertases: Classical/lectin pathway = C4b2a; Alternative pathway = C3bBb (stabilized by properdin). Spontaneous "tick-over" hydrolysis of C3 to C3(H2O) continuously seeds the alternative pathway at a low level. Exposed thioester bond in C3b allows covalent binding to microbial surfaces.

**Functions (high-yield):** 1. **Opsonization:** C3b on microbial surfaces binds CR1 (CD35) on macrophages/neutrophils → phagocytosis. Especially important for encapsulated organisms (S. pneumoniae, H. influenzae, N. meningitidis). Remember: IgG and C3b are the main opsonins. 2. **Amplification loop:** C3b + factor B → (factor D cleaves B) → C3bBb (alternative pathway C3 convertase) → more C3b (positive feedback). 3. **C5 convertase formation:** Adding another C3b to a C3 convertase yields C4b2a3b (classical/lectin) or C3bBb3b (alternative), which cleaves C5 into C5a (chemotaxis, anaphylatoxin) and C5b (starts MAC: C5b-C9 → lysis, especially Neisseria). 4. **Immune complex clearance:** C3b binds immune complexes; CR1 on RBCs transports them to the spleen/liver for removal. Deficiency of early classical components (C1, C2, C4) → SLE-like disease.

**Regulation:** - **Factor H and Factor I:** Factor I (with cofactors factor H, CR1, MCP/CD46) cleaves C3b to inactive iC3b. Factor H displaces Bb from C3b (decay acceleration). - **DAF (CD55)** and **CD59** on host cells: DAF (GPI-anchored) accelerates decay of C3 convertases; CD59 blocks MAC formation. - Deficiency of DAF/CD59 (PIGA mutation, GPI anchor defect) → **paroxysmal nocturnal hemoglobinuria** (complement-mediated intravascular hemolysis; Ham test/flow cytometry; treat with eculizumab, a C5 inhibitor). - **C1 esterase inhibitor** deficiency → hereditary angioedema (↑ bradykinin; low C4). - Factor H/I deficiency or autoantibodies → uncontrolled C3b activity → ↓ C3, atypical HUS, C3 glomerulopathy/membranoproliferative GN. C3 nephritic factor (autoantibody stabilizing C3bBb) → type II MPGN (dense deposit disease) with low C3.

**Clinical associations:** - **C3 deficiency:** Severe recurrent pyogenic sinopulmonary infections (encapsulated bacteria), ↑ risk of type III hypersensitivity/GN. Most severe complement deficiency for infections. - **Low C3 (hypocomplementemia):** Post-streptococcal GN, SLE (low C3 and C4 in active disease), MPGN, subacute bacterial endocarditis, cryoglobulinemia. - **Type II and III hypersensitivity:** C3b deposition contributes to tissue damage. Coombs-positive warm/cold AIHA: C3b-coated RBCs cleared by splenic macrophages (extravascular hemolysis); anti-C3 detected on direct Coombs test. - **Spleen:** Splenectomy increases susceptibility to encapsulated organisms due to impaired clearance of opsonized (C3b/IgG-coated) bacteria; vaccinate. - **Pathogen evasion:** Some bacteria inhibit C3b deposition (e.g., S. aureus protein A binds IgG Fc; S. pyogenes M protein binds factor H).

**Mnemonic:** "C3b binds bacteria" (opsonin); C3a, C4a, C5a = anaphylatoxins (C5a is also the main neutrophil chemotaxin, along with IL-8, LTB4); "C5b-9 = MAC."

**Memory pearl:** Classical pathway = IgG/IgM-antigen complexes (C1q); lectin = mannose-binding lectin; alternative = spontaneous C3 hydrolysis on microbial surfaces. All converge at C3 → C3b.