U01.02.019 Complement

The complement system is a crucial component of innate immunity and inflammation, consisting of hepatically synthesized plasma proteins. A central function is the formation of the Membrane Attack Complex (MAC), which defends against gram-negative bacteria. Clinical assessment of the complement system includes the CH50 test, which screens for classical pathway activation.

Activation Pathways

The complement system is activated through three primary pathways:

Pathway	Trigger	Mnemonic
Classical	IgG or IgM bound to antigens (antigen-antibody complexes)	GM makes classic cars (IgG and IgM activate Classical pathway)
Alternative	Microbial surface molecules (spontaneous activation)	–
Lectin	Mannose or other sugars on microbial surfaces	–

Functions of Complement Components

Component	Function
C3b	Opsonization: Tags pathogens for phagocytosis; also helps clear immune complexes.
C3a, C4a, C5a	Anaphylaxis: Induce inflammation and recruit immune cells.
C5a	Neutrophil chemotaxis: Attracts neutrophils to the site of infection.
C5b-9 (MAC)	Cytolysis: Forms pores in bacterial membranes, leading to lysis.

Opsonins

C3b and IgG are the primary opsonins that enhance phagocytosis.
Opsonin (Greek: “to prepare for eating”) refers to molecules that mark pathogens for immune attack.

Regulation of Complement Activation

To prevent damage to self-cells (e.g., RBCs), the complement system is tightly regulated by inhibitors:

Inhibitor	Function
Decay-accelerating factor (DAF, CD55)	Prevents complement activation on self-cells.
C1 esterase inhibitor	Inhibits the classical pathway by blocking C1 activation.

Simplified Pathway Diagram

Overview of Key Steps

Activation of C3:
- Classical and Lectin pathways: Convert C2 and C4 into C3 convertase (C4b2b).
- Alternative pathway: Spontaneous generation of C3bBb as C3 convertase.
C5 Convertase Formation:
- Classical/lectin: C4b2b3b.
- Alternative: C3bBb3b.
MAC Formation:
- Sequential binding of C5b to C6-C9, forming the Membrane Attack Complex (C5b-9).

Key Pathway Components	Action
C3 Convertase	Converts C3 to C3a and C3b (initiates amplification).
C5 Convertase	Converts C5 to C5a and C5b (initiates MAC formation).
MAC	Final structure (C5b-9) causing lysis of pathogens.

Points to Remember

Complement system enhances both innate and adaptive immunity.
C3b plays dual roles: opsonization and clearance of immune complexes.
C5a is a potent chemoattractant for neutrophils.
CH50 test assesses the functional integrity of the classical pathway.
Regulatory proteins like DAF and C1 esterase inhibitors are critical to prevent self-damage.

Bibliography Reference Links

Abbas, A. K., & Lichtman, A. H. Basic Immunology. Elsevier.
Parham, P. The Immune System. Garland Science.
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