Learning Objective

Explain the activation pathways, functions, regulatory mechanisms, and clinical relevance of the complement system, including the roles of major complement components (C3a, C3b, C5a, MAC).

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The complement system consists of hepatically synthesized plasma proteins that function in innate immunity, inflammation, opsonization, and microbial killing. A key effector is the membrane attack complex (MAC), which is especially important for defense against Gram-negative bacteria.

The CH50 test assesses the activity of the classical complement pathway.

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Complement Activation Pathways

Classical Pathway

• Triggered by IgG or IgM bound to an antigen.
• G (IgG) and M (IgM) activate the classic pathway.

Alternative Pathway

• Triggered by bacterial products (e.g., LPS).

Lectin Pathway

• Triggered by mannose or other sugars on microbial surfaces.
• Mediated by MBL–MASP complex.

All pathways converge to form:

• C3 convertase → generates C3a and C3b
• C5 convertase → generates C5a and C5b

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Activity

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Major Complement Functions

C3b – Opsonization

• Coats microbes → enhances phagocytosis.
• Binds LPS on bacteria.
• Helps clear immune complexes.
• One of the two main opsonins (C3b and IgG).

C3a, C4a, C5a – Anaphylatoxins

• Trigger mast-cell degranulation → histamine release.
• Increase vascular permeability and inflammation.

C5a – Chemotaxis

• Strong chemoattractant for neutrophils.

C5b–C9 – Membrane Attack Complex (MAC)

• Creates holes in bacterial membranes, leading to cytolysis.
• Essential for killing Neisseria species.

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Visual Overview of Complement Actions

• Opsonization: C3b → phagocytes ingest microbes
• Inflammation: C3a, C4a, C5a → mast cells, permeability
• Chemotaxis: C5a → recruits neutrophils
• Cytolysis: MAC (C5b–C9) → punches holes in membrane

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Regulation of Complement: Complement Inhibitors

• DAF (Decay-Accelerating Factor) / CD55
  → Prevents complement deposition on host cells.
• C1 inhibitor (C1-INH)
  → Blocks classical pathway activation.

Deficiency leads to excessive complement activation, resulting in host cell damage.

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Clinical Pearls

• C1-INH deficiency → hereditary angioedema
• DAF/CD55 deficiency → paroxysmal nocturnal hemoglobinuria (PNH)
• MAC deficiency (C5–C9) → recurrent Neisseria infections
• Low C3 → recurrent pyogenic infections
• CH50 low → classical pathway defect

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Activity