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Immunology Long Question: Complement Activation Pathways

I. Three Pathways of Complement Activation

The complement system is activated via three distinct pathways, all of which converge at C3 and ultimately produce the Membrane Attack Complex (MAC):

#	Pathway	Trigger	Key Early Proteins
1	Classical	Antigen-antibody (IgM/IgG) complexes	C1 (C1q, C1r, C1s), C4, C2
2	Alternative	Direct microbial surfaces (no antibody needed)	C3, Factor B, Factor D, Properdin
3	Lectin (MBL)	Mannose residues on microbial surfaces	MBL, MASP-1, MASP-2, C4, C2

All three pathways share a common terminal (late) pathway: C3b --> C5 convertase --> C5b --> C5b-C6-C7-C8-(C9)n = MAC --> cell lysis.

II. Classical Pathway - Brief Description with Flowchart

Trigger

Binding of IgM or IgG (subclasses 1, 2, 3) to antigen forms an immune complex. IgM is more efficient because as a pentamer, it can bind two C1q molecules simultaneously.

Step-by-Step:

1. Recognition unit - C1 activation

C1 is a calcium-dependent complex: C1q + C1r2 + C1s2
C1q binds the Fc region of antibody (μ or γ heavy chains)
Each C1q must bind at least two Ig Fc regions for activation
Conformational change in C1q activates C1r, which cleaves and activates C1s

2. Activation unit - C3 convertase formation

C1s cleaves C4 --> C4a (anaphylatoxin) + C4b (binds cell surface)
C2 complexes with C4b, then C1s cleaves C2 --> C4b2a = classical C3 convertase

3. C3 cleavage

C4b2a cleaves C3 --> C3a (anaphylatoxin/chemotaxin) + C3b (opsonin)
C3b binds to C4b2a --> forms C4b2a3b = classical C5 convertase

4. Terminal pathway (common to all)

C5 convertase cleaves C5 --> C5a (potent anaphylatoxin + chemotaxin) + C5b
C5b binds C6, C7, C8, then 12-16 molecules of C9 polymerize
Forms the MAC (C5b-C9) --> pore in membrane --> osmotic lysis

Classical Pathway Flowchart

Complement Reaction Sequence Flowchart - Classical, MBL, and Alternative Pathways

Classical pathway simplified:

Ag-Ab complex (IgG/IgM)
        |
        v
    C1 (C1q binds Fc)
        |
   C1r + C1s activated
        |
   C4 --> C4a + C4b
   C2 --> C2a + C2b
        |
   C4b2a  <--- C3 convertase
        |
   C3 --> C3a (anaphylatoxin) + C3b (opsonin)
        |
   C4b2a3b  <--- C5 convertase
        |
   C5 --> C5a (anaphylatoxin/chemotaxin) + C5b
        |
   C5b + C6 + C7 + C8 + (C9)n
        |
   MAC (C5b-C9) --> Cell Lysis

Biological Effects of Classical Pathway Activation

Opsonization - C3b coats pathogens, enhancing phagocytosis
Anaphylatoxins - C3a, C4a, C5a cause mast cell degranulation, histamine release, vasodilation, increased vascular permeability
Chemotaxis - C5a attracts neutrophils and monocytes to infection site
Cytolysis - MAC directly lyses target cells/bacteria

III. Regulators of the Complement Pathway

To prevent excessive/uncontrolled complement activation that could damage host tissues, the following regulatory proteins exist:

Regulator	Point of Action	Mechanism
C1 inhibitor (C1-INH)	Classical pathway - C1	Covalently binds and inactivates C1r and C1s serine proteases; dissociates them from C1q; reduces half-life of activated C1 to ~13 sec. Deficiency causes Hereditary Angioedema
C4-Binding Protein (C4BP)	Classical pathway - C3 convertase	Enhances spontaneous decay of C4b2a; acts as cofactor for Factor I to degrade C4b
Factor I	Classical + Alternative - C3/C4b	Serine protease that cleaves and inactivates C3b and C4b, reducing available C5 convertase
Factor H	Alternative pathway - C3b	Enhances Factor I's action on C3b; accelerates decay of C3bBb convertase; acts as a cofactor to degrade C3b into iC3b (inactive)
Properdin (Factor P)	Alternative pathway - C3 convertase	A positive regulator - stabilizes C3bBb by delaying Bb release; prolongs the half-life of the alternative pathway C3 convertase
Decay Accelerating Factor (DAF / CD55)	All three pathways	Cell surface protein (GPI-anchored on blood cells/endothelium); accelerates dissociation of C3 convertases of all pathways; prevents C3 convertase assembly. Deficiency (with CD59 deficiency) causes PNH
CD59 (Protectin / MIRL)	Terminal pathway - MAC	Inhibits MAC formation by preventing C9 polymerization. GPI-anchored membrane protein. Deficiency causes PNH
Membrane Cofactor Protein (MCP / CD46)	C3b/C4b on cell surface	Acts as cofactor for Factor I to degrade C3b and C4b on host cells
Clusterin (SP-40,40) & Vitronectin (S-protein)	Terminal pathway	Inhibit insertion of C5b-7 complex into membranes; soluble phase regulators
Carboxypeptidase N	Anaphylatoxins	Inactivates C3a, C4a, and C5a by cleaving C-terminal arginine

Key Clinical Points on Regulators:

C1 inhibitor deficiency → Hereditary angioedema (uncontrolled bradykinin + C2a release)
DAF (CD55) + CD59 deficiency → Paroxysmal Nocturnal Hemoglobinuria (PNH) - RBCs lysed by complement
Factor H deficiency → Uncontrolled alternative pathway activation; susceptibility to Neisseria infections
Factor I deficiency → Secondary C3 depletion; recurrent pyogenic bacterial infections

Sources: Jawetz, Melnick & Adelberg's Medical Microbiology 28e; Mulholland and Greenfield's Surgery 7e; Medical Microbiology 9e

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