Which of the following complement fragments is the most potent chemotactic agent and primary driver of neutrophil recruitment in acute inflammation?

Explanation

## Complement-Mediated Chemotaxis in Acute Inflammation **Key Point:** **C5a is the most potent chemotactic agent** generated during complement activation. It is 100–1000 times more potent than C3a in recruiting neutrophils and is the primary complement-derived chemoattractant in acute inflammation. ### Mechanism of C5a-Mediated Neutrophil Recruitment 1. **Generation:** C5a is produced when C5 is cleaved during complement activation (classical, alternative, or lectin pathway) 2. **Receptor Binding:** C5a binds to **C5aR (CD88)** on neutrophil surfaces 3. **Signal Transduction:** G-protein coupled receptor activation → increased intracellular Ca²⁺ 4. **Cellular Response:** - Chemotaxis (directed migration toward the source) - Increased adhesion molecule expression (CD11b/CD18) - Respiratory burst activation (ROS production) - Degranulation ### Comparative Potency of Complement Anaphylatoxins | Fragment | Chemotactic Potency | Primary Target | Biological Effects | |----------|-------------------|-----------------|--------------------| | **C5a** | **Highest (100–1000× C3a)** | Neutrophils, macrophages, mast cells | Chemotaxis, vasodilation, mast cell degranulation | | C3a | Moderate | Mast cells, smooth muscle | Vasodilation, mast cell degranulation | | C4a | Minimal | — | Weak vasodilation | | C3b | Opsonin (not chemotactic) | Pathogens, apoptotic cells | Complement amplification, phagocytosis | **High-Yield:** C5a is called an **anaphylatoxin** because it triggers mast cell and basophil degranulation, causing vasodilation and increased permeability — mimicking anaphylaxis. ### Clinical Correlations **Clinical Pearl:** - **C5a deficiency** → impaired neutrophil recruitment, recurrent infections - **C5a receptor antagonists** (e.g., iptacopan) → being studied for inflammatory diseases (ARDS, sepsis) - **Complement inhibitors** (e.g., eculizumab, C5 inhibitor) → used in paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) **Mnemonic:** **C5a = "5 is fine, 3 is less"** — C5a is the most potent chemotactic anaphylatoxin; C3a is weaker. **Warning:** Do not confuse C3b (an opsonin that enhances phagocytosis) with C5a (a chemotactic mediator). C3b is critical for complement amplification and pathogen clearance, but it is NOT chemotactic. [cite:Robbins 10e Ch 2]