Biology · MU Pleven

44.Complement. Pathways of complement activation.

Explains the complement system as an effector arm of innate immunity and then walks through its three activation pathways: classical, alternative and lectin. For each it sets out the triggers, the convertase steps, and the regulators. Also covers the membrane attack complex, a table of fragment effects, complement fixation and a test method, and host benefits and harms such as opsonisation and anaphylaxis.

Inside: 10 sections · 3 labelled pictures · 1 table · 15 flashcards · 5 min

Topic 44 of 63 in the MU Pleven syllabus for Biology (Medicine, Year 1). The free AceMed note covers it in 10 sections, about 709 words (5 min of reading), with 15 flashcards.

In this note

  1. Complement. Pathways of complement activation.
  2. COMPLEMENT SYSTEM
  3. Biochemical Pathways of Complement Activation
  4. Complement Protein Groups
  5. Biological Functions of Complement
  6. Host Benefits
  7. Complement Fixation (MAC Formation)
  8. Clinical Effects of Complement Activation
  9. Mast Cell & Basophil Activation
  10. Inflammatory Amplification

COMPLEMENT SYSTEM

The complement system is a major effector arm of innate immunity. As the name suggests, it “complements” the actions of antibodies and phagocytes in clearing pathogens. Even though it is innate (non-adaptive and constant throughout life), it can be activated by antibodies, allowing crosstalk with the adaptive immune system.

Complement proteins are small, mostly liver-derived plasma proteins that circulate as inactive precursors (pro-proteins). Once activated, these proteins participate in tightly regulated enzymatic cascades leading to inflammation, opsonization, and microbial killing.

Biochemical Pathways of Complement Activation

There are three major pathways:

1. Classical Pathway

Triggered by C1 complex binding to:

  • Antigen-bound IgM (very efficient — 1 molecule is enough)
  • Antigen-bound IgG (several molecules needed)
  • Pathogen surfaces directly

The C1 complex = C1q + 2 C1r + 2 C1s (C1qr₂s₂)

• C1q binds Ig → activates C1r (a serine protease) → activates C1s

• Activated C1s cleaves C4 → C4a + C4b and C2 → C2a + C2b

C4b + C2b = Classical Pathway C3 Convertase

→ Cleaves C3 → C3a + C3b

C3b joins the C3 convertase to form the C5 convertase (C4b2b3b).

Regulation

  • C1-INH inhibits C1r and C1s
  • DAF (CD55) dissociates C3-convertases
  • Defect in GPI-anchored DAF → Paroxysmal nocturnal hemoglobinuria

2. Alternative Pathway

This pathway is continuously and spontaneously activated at low levels due to slow hydrolysis of C3’s internal thioester bond.

Key concepts:

  • Fluid-phase C3b is quickly inactivated by Factor H & Factor I
  • But when C3b binds covalently to pathogen surfaces, it is protected from inactivation

Steps:

  1. 1. Surface-bound C3b binds Factor B → C3bB
  2. 2. Factor D cleaves this to Ba + Bb, leaving C3bBb (alternative C3 convertase)
  3. 3. Properdin (Factor P) stabilizes C3bBb → C3bBbP

This stabilized convertase massively amplifies C3 cleavage, coating pathogens with C3b and iC3b.

Self vs Non-Self Recognition

  • Host cells express complement regulators (CD35, CD46, CD55, CD59)
  • Most pathogens do not, so they accumulate C3b/iC3b
  • This makes the alternative pathway a crucial part of innate immunity

Formation of C5 Convertase

  • C3bBb binds an extra C3b → C3bBbC3bP

→ Cleaves C5 → C5a (potent anaphylatoxin) + C5b (initiates MAC)

Then:

C5b + C6 + C7 + C8 + multiple C9 = Membrane Attack Complex (MAC)

→ Creates pores → causes osmotic lysis

3. Lectin Pathway

This pathway mimics the classical pathway but uses mannose-binding lectin (MBL) or ficolins instead of C1q.

  • MBL binds carbohydrate residues (mannose) on microbial surfaces

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