## Anaphylatoxins in the Complement System **Key Point:** C5a is the most potent anaphylatoxin generated during complement activation, produced by all three pathways (classical, alternative, and lectin). ### Potency Hierarchy of Anaphylatoxins | Anaphylatoxin | Potency | Source Pathways | Biological Effects | |---|---|---|---| | C5a | Most potent (1×) | All three | Chemotaxis, vasodilation, mast cell degranulation, neutrophil activation | | C3a | Moderate (1/40 of C5a) | All three | Mast cell degranulation, vasodilation | | C4a | Least potent (1/200 of C5a) | Classical & lectin | Weak vasodilation | | C2a | Minimal activity | Classical & lectin | Negligible anaphylatoxin activity | ### Why C5a is Most Potent 1. **Receptor affinity:** C5a binds to C5aR (CD88) on mast cells, basophils, and neutrophils with high affinity 2. **Concentration threshold:** Even small amounts of C5a trigger robust inflammatory responses 3. **Downstream effects:** C5a is the primary driver of the membrane attack complex (MAC) formation via C5 cleavage **High-Yield:** In clinical practice, C5a inhibitors (eculizumab, pegcetacoplan) are used in paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) precisely because blocking C5a prevents the most severe complement-mediated tissue damage. **Clinical Pearl:** C5a is responsible for the systemic inflammatory response in sepsis and is a key mediator in acute respiratory distress syndrome (ARDS).
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