Complement System

The complement system is a plasma protein cascade that enhances innate immunity by promoting:

• Opsonization
• Inflammation
• Cell lysis

It links innate and adaptive immunity.

Complement proteins circulate as inactive zymogens and become activated through proteolytic cleavage cascades.

• Opsonization (C3b)
• Anaphylatoxin production (C3a, C5a)
• Membrane attack complex (MAC) formation (C5b-9)
• Immune complex clearance

All pathways converge at C3 activation.

Triggered by:

• IgG or IgM bound to antigen

Sequence:

C1 → C4 → C2 → C3 convertase (C4b2a)

Requires antibodies → links adaptive to innate immunity.

Triggered by:

• Mannose-binding lectin (MBL) binding to microbial carbohydrates

Sequence:

MBL → MASP proteins → C4 + C2 → C3 convertase (C4b2a)

Antibody-independent.

Triggered by:

• Direct pathogen surface activation
• Spontaneous C3 hydrolysis

Sequence:

C3 → Factor B → Factor D → C3 convertase (C3bBb)

Provides amplification loop.

All pathways generate:

C3 convertase → cleaves C3 into:
  * C3a (anaphylatoxin)
  * C3b (opsonin)

C5 convertase then forms → cleaves C5 into:

• C5a (potent inflammatory mediator)
• C5b → initiates MAC formation

C5b → C6 → C7 → C8 → C9

C5b-9 forms pore in target membrane → cell lysis

Especially important in Neisseria infections.

• C3a
• C5a (most potent)

Effects:

• Mast cell degranulation
• Increased vascular permeability
• Neutrophil chemotaxis

Links to:

• Type I Hypersensitivity
• Leukocyte Recruitment

Host cells express regulatory proteins to prevent self-damage:

• CD55 (DAF) – decay accelerating factor
• CD59 – prevents MAC formation
• Factor H – regulates alternative pathway

Loss of regulation → autoimmune damage.

C3 deficiency:

• Recurrent pyogenic infections

C5–C9 deficiency:

• Increased susceptibility to Neisseria

C1 inhibitor deficiency:

• Hereditary angioedema

Complement overactivation:

• Atypical hemolytic uremic syndrome
• Paroxysmal nocturnal hemoglobinuria

Target complement overactivation.

Class page:

• Complement Inhibitors

Key agents:

• Eculizumab (C5 inhibitor)
• Ravulizumab (C5 inhibitor)
• Pegcetacoplan (C3 inhibitor)
• Avacopan (C5a receptor inhibitor)

Used in:

• Paroxysmal nocturnal hemoglobinuria
• Atypical hemolytic uremic syndrome
• ANCA-associated vasculitis

• Classical pathway requires antibodies.
• Lectin pathway recognizes microbial sugars.
• Alternative pathway amplifies activation.
• All pathways converge at C3.
• C3b = opsonization.
• C5a = strongest anaphylatoxin.
• C5b-9 = membrane attack complex.
• Complement inhibitors block terminal cascade activation.