The Classical Pathway of Complement Activation is one of the most important mechanisms of the immune system. It acts as a bridge between adaptive immunity (antibodies) and innate immunity (complement proteins).
This pathway is called classical because it was the first complement activation pathway to be discovered and studied.
Unlike other complement pathways, the classical pathway is antibody-dependent, making it especially important in specific immune responses.
What Triggers the Classical Pathway?
The classical pathway is initiated by the formation of antigen–antibody complexes, also known as immune complexes.
Key Activators
- IgM (most efficient activator)
- IgG (IgG1, IgG2, IgG3)
📌 Note: Free antibodies cannot activate complement. Antibodies must be bound to antigen.
Role of the C1 Complex
The C1 complex is the first component of the classical pathway.
Composition of C1 Complex
- C1q – recognition unit
- C1r (2 molecules) – serine protease
- C1s (2 molecules) – serine protease
- Held together by calcium ions (Ca²⁺)
When C1q binds to the Fc region of IgM or IgG, it activates C1r, which then activates C1s—starting the complement cascade.
Step-by-Step Mechanism of the Classical Pathway
Step 1: Activation of C1
- C1q binds to antigen-bound antibodies.
- This causes conformational change in C1q.
- C1r becomes activated → activates C1s.
Step 2: Formation of Classical C3 Convertase
- Activated C1s cleaves C4 into:
- C4a (weak anaphylatoxin)
- C4b (binds covalently to pathogen surface)
- C1s then cleaves C2 into:
- C2b
- C2a (larger fragment)
- C4b + C2a → C4b2a
✅ C4b2a is the Classical C3 Convertase
Step 3: Cleavage of C3 (Amplification Step)
- C3 convertase cleaves C3 into C3a and C3b
- C3b deposits abundantly on pathogen surface
- This step amplifies the immune response significantly
Step 4: Formation of Classical C5 Convertase
- Some C3b molecules bind to C4b2a
- This forms C4b2a3b
✅ C4b2a3b is the Classical C5 Convertase
Step 5: Terminal Pathway and Cell Lysis
- C5 convertase cleaves C5 into C5a and C5b
- C5b sequentially binds:
- C6 → C7 → C8 → multiple C9
- This forms the Membrane Attack Complex (MAC)
🔴 MAC creates pores in the target cell membrane, causing osmotic lysis and cell death
Biological Functions of the Classical Pathway
1. Direct Killing (Cytolysis)
- MAC lyses bacteria, viruses, and infected cells
2. Opsonization
- C3b and C4b coat pathogens
- Enhances phagocytosis by macrophages and neutrophils
3. Inflammation
- C3a, C4a, and C5a act as anaphylatoxins
- Increase vascular permeability and recruit immune cells
4. Immune Complex Clearance
- Prevents deposition of immune complexes in tissues
- Protects against autoimmune damage
Regulation of the Classical Pathway
Uncontrolled complement activation can damage host tissues. Therefore, tight regulation is essential.
Key Regulatory Protein
- C1 Inhibitor (C1-INH)
Function:
- Prevents spontaneous activation of C1r and C1s
- Stops excessive complement activation
📌 Clinical Correlation:
Deficiency of C1-INH causes Hereditary Angioedema, characterized by severe swelling due to excess bradykinin.
Exam-Oriented Key Points (High Yield)
- Classical pathway is antibody-dependent
- Most efficient antibody: IgM
- Classical C3 convertase: C4b2a
- Classical C5 convertase: C4b2a3b
- Central molecule: C3
- MAC components: C5b–C9
Frequently Asked Questions (SEO Booster)
Is the classical pathway part of innate or adaptive immunity?
It is part of both—it requires antibodies (adaptive immunity) but uses innate complement proteins.
Which antibody cannot activate the classical pathway?
IgG4 cannot activate complement.
What is the end result of the classical pathway?
Formation of the Membrane Attack Complex (MAC) leading to cell lysis.