alternative pathway

**Activation (initiation)** - Spontaneous "tick-over" hydrolysis of C3 forms C3(H2O). Factor B binds it, and factor D cleaves B to form the fluid-phase C3 convertase C3(H2O)Bb. This cleaves more C3 into C3a and C3b. - C3b binds covalently to nearby surfaces (microbes, e.g., bacterial LPS, and also host cells). Factor B binds C3b, and factor D cleaves B to form the surface-bound **C3 convertase, C3bBb**. - **Properdin (factor P)** is the only positive regulator. It stabilizes C3bBb and prolongs its half-life. - Adding another C3b gives **C3bBb3b**, the C5 convertase. This cleaves C5 into C5a and C5b, and C5b starts MAC assembly (C5b-C9). - Amplification loop: the alternative pathway amplifies C3b production for all pathways. Up to about 80–90% of terminal pathway activation may depend on this loop, even when the classical or lectin pathway starts the response.

**Comparison with other pathways** - Classical: IgG or IgM–antigen complexes (C1q), then C4b2a (C3 convertase). Needs antibody. - Lectin: mannose-binding lectin binds microbial mannose, then C4b2a. - Alternative: spontaneous C3 hydrolysis, then C3bBb. Does not need antibody, so it acts early in infection. - All three pathways converge at C3 and share the terminal pathway (C5b–C9, MAC).

**Key effector functions** - C3b: opsonization - C3a, C5a: anaphylatoxins (mast cell degranulation). C5a is also a potent neutrophil chemotaxin. - MAC (C5b-9): lysis, especially of Neisseria

**Regulation (protecting host cells)** - **Decay-accelerating factor (DAF, CD55)** and **factor H** displace Bb from C3b. - **Factor I** cleaves C3b, with cofactors factor H, MCP (CD46), and CR1. - **CD59 (protectin)** blocks MAC formation (C9 polymerization). - Host cells have sialic acid and glycosaminoglycans that recruit factor H. Microbes lack these, so the pathway proceeds on them.

**Clinical correlations (high-yield)** - **Paroxysmal nocturnal hemoglobinuria (PNH):** acquired PIGA mutation in a hematopoietic stem cell causes a GPI-anchor defect and loss of DAF (CD55) and CD59. Complement-mediated intravascular hemolysis follows, with hemoglobinuria (especially at night), thrombosis (e.g., hepatic vein/Budd-Chiari), and cytopenias. Diagnosis is by flow cytometry (CD55/CD59 deficiency). Treatment is **eculizumab** or ravulizumab (anti-C5). - **Atypical hemolytic uremic syndrome (aHUS):** uncontrolled alternative pathway activation from factor H, factor I, or MCP (CD46) mutations, or factor B or C3 gain-of-function. It causes microangiopathic hemolytic anemia, thrombocytopenia, and AKI, without Shiga toxin. Treat with eculizumab. - **C3 deficiency:** severe recurrent pyogenic (encapsulated) bacterial infections and increased type III hypersensitivity (immune-complex) disease. - **Terminal complement (C5–C9) deficiency or properdin deficiency:** recurrent *Neisseria* infections (meningococcemia, gonorrhea). Properdin deficiency is X-linked. Eculizumab use also increases the risk of meningococcal infection, so patients need vaccination (and sometimes prophylaxis). - **Factor D deficiency:** also increases susceptibility to Neisseria. - **C3 glomerulopathy (dense deposit disease/MPGN type II):** C3 nephritic factor (an autoantibody that stabilizes C3bBb) causes persistently low C3 with normal C4 and subepithelial or intramembranous deposits. Low C3 with normal C4 suggests alternative pathway activation, whereas low C4 and C3 suggests classical pathway activation (e.g., lupus). - **Age-related macular degeneration:** associated with factor H polymorphism (Y402H). - **C1 esterase inhibitor deficiency (hereditary angioedema):** affects the classical/lectin pathways and bradykinin, not the alternative pathway. Low C4 is the clue.

**Mnemonics/pearls** - "Alternative = Antibody-independent, Always on (tick-over)." - Alternative pathway components: C3, factors B, D, and P (properdin). - Factor H, factor I, and DAF are the "brakes."