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

Question

Accepted Answer

C. C5a. ## 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]

Answer

A. C3b

Answer

B. C4a

Answer

D. C3a

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

Mechanism of C5a-Mediated Neutrophil Recruitment

Comparative Potency of Complement Anaphylatoxins

Clinical Correlations

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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