25B17: Exam Report

Describe the complement system using the following headings:

  1. Components (30% of marks)
  2. Activation pathways (10% of marks)
  3. Role and functions (50% of marks)
  4. Control and regulation (10% of marks)

54% of candidates passed this question.

  1. The key components of the complement system are the C3 convertase, C5 convertase and membrane attack complex. These components are present as inactive precursors.
  2. Broadly speaking the activation pathways include the classical (activated by immune complexes) and alternate (activated by microbial polysaccharides or pattern recognition receptors).
  3. The main role of the complement system is to defend against bacterial infection. It is an important component of the innate immune system. The key functions are 9 opsonization and phagocytosis (via C3b), cell lysis, agglutination of microbes, chemotaxis (via C5a), modulation of B cell function, clearance of immune complexes and mast / basophil activation (via C3a, C4a and C5a).
  4. Control is achieved via the short half-life of the activated factors and specific complement inactivators.

S1ii / 25B17: Describe the complement system

1) Components

Complement pathway – Key humoral component of innate immune system, with roles in regulation of adaptive immune system

  • Series of ~25 glycoproteins produced by the hepatocytes
  • Activate in cascade sequence
  • Proenzymes -> cleaved to active enzymes
  • Key role in bacterial innate defence

Key components

  • C3 Convertase – Stimulated by upstream activation of classical/alternate/MBL pathways. Cleaves C3 to C3a and C3b (more active). 1) Initiates activation loop for more C3b creation, 2) Binds to complement receptors on phagocytes (opsonisation), 3) initiates the “terminal complement” pathway, and formation of the membrane attack complex (MAC)
    • C3a involved in histamine release and vascular permeability, and chemotaxis
  • C5 Convertase – Produced by classical pathway, cleaves C5 to C5a and C5b. C5b binds to C6, then C7. C5b67 complex then binds to C8 & C9 forming the MAC
    • C5a involved in chemotaxis and phagocyte recruitment
  • Membrane Attack Complex (MAC) – Pore-forming structure composed of multiple complement proteins joined together. Main role is to initiate cell lysis through pore formation on cells.
    • Also has role in cell signalling and chemotaxis

2) Activation

  • Classical – immune complex (IgG/IgM) activated. Immunoglobulin binds to cell, C1q binds to Fc portion of immunoglobulin
  • Alternate – contact with foreign (cell) surfaces (lipopolysaccharide, endotoxin, IgA), C3 activation
    • C3 spontaneously cleaves, C3b binds to AAs or hydroxyl groups on non-self cell surfaces
    • Complement B binds to C3b
  • Mannose-binding lectin (similar structure to C1q, circulating protein produced in the liver) – MBL binds to CHO (mannose) on target pathogen (bacteria, fungi, viruses) → C4 activation
    • Similar to classical, without need for C1q
    • MBL also binds mannose binding protein associated serene protease (MSAP) → this acts like a convertase & cleaves C3 to C3b → cascade activates thereafter

3) Role & functions

  • Opsonisation (C1/2/3) – coating of bacterial cell walls to attract and bind phagocytes -> phagocytosis of cell
  • Chemotaxis & granulocyte (neutrophils and mononuclear phagocytes) activation – via C3a, C5a, & MAC– as described previously
  • Regulation of mast cell degranulation & basophil activation – C3a, C4a and C5a
  • Regulation of viral particle release
  • Cell lysis – formation of membrane attack complex (C5b -> C6/7/8/9). Attaches to cell wall creating a pore, leading to cell lysis & death
  • Lymphocyte (B-Cell) activation – immunomodulates B-cell responses by binding to complement receptors on B-Cells -> enhanced antibody/immunological response and memory
  • Clearance – of immune complexes and apoptic cells (C1q, C3, C4)
  • Vasodilation and increased vascular permeability (C3a fragments)
  • Agglutination – Alteration to cell surfaces of pathogens causing them to adhere to one-another

4) Regulation

  • Given its non-specific targeting/response, it is possible for complement systems to damage “host” cells, so are tightly regulated.
  • In general, the cascade is regulated by delaying activation of complement cascade, acceleration of cascade at key points (i.e. C3 & C5), breakdown of complement components, and inhibition of MAC formation

 

General:

  • Short-half-life of activated factors means rapid deactivation. Ongoing stimulus required to maintain complement pathway activation.
  • Also, a number of regulatory proteins on cell surfaces distinguish host tissues, and prevent complement targeting them. Also, some plasma proteins have similar effects.
  • Complement proteins are inactivated by circulating plasmin

 

Specific Regulation:

C1

  • C1 inhibitor – preventing excessive complement activation in classical and lectin pathways.

 

Convertase / C3b targeting

  • Decay-accelerating protein – disassembles convertases, stops cleaving of C3 & C5 to active fragments
  • Factor I – Protease that inactivates C3 and C4b
  • Membrane cofactor protein – co-factor for factor I
  • C4 binding protein – Cofactor for factor I
  • Factor H – Regulates alternate pathway, preventing activation by host-cells. Inactivates C3b and accelerates decay of C3 convertase.

 

MAC Formation

  • C8-beta – binds to C5b67 complex and prevents insertion into host cells
  • S-proteins – Bind C5b67 & prevents insertion into host cells, stabilising the complex in plasma
  • Protectin (CD59)– blocks formation of MAC on host cells
  • MAC Endocytosis & shedding – Host cells can either internalise or externalise MAC before they become functional pores
Complement system pathways diagram in immunology.

References: Kam & Power, 4th Edition, p335

Author: Nathan Abraham