S1iii / 23B15: Describe the components and function of the complement system including the role, activation and control

23B15: Exam Report

Describe the components and function of the complement system including the role, activation and control

15% of candidates passed this question.

Based on the question stem answers should have been structured to address the components of the complement system as well as the role, activation and regulatory mechanisms.

A description of the components should include the number and type of molecule highlighting the important combinations of complement to produce the membrane attack complex.

A description regarding the role in the innate immune response against bacterial infections was then required with a detailed description regarding the many ways this is achieved including opsonisation, phagocytosis, chemotaxis, mast cell / basophil activiation, lysis of cells and clearance of immune complexes.

Information about the 3 pathways of activation where expected; classic, alternate and lectin pathyway, with some detail regarding the downstream effect of each that would take into account for the amplication of the response.

The cessation of complement response is largely due to the limitatations of the half lives of the particular complement glycol-proteins or presence of specific inactivators.

S1i / 23B15: Describe the components and function of the complement system including the role, activation and control

Complement system

A humoral component of the innate immune system that works in concert with the adaptive immune system to destroy pathogens

Role

  • Made of up a system of approx. 25 plasma proteins
  • Produced mainly in the hepatocytes
  • Principle proteins are C1-C9

Functions

  • Opsonisation
    • Coats the walls of bacterial so that they attract and bind to phagocytic cells
  • Chemotaxis
    • Chemical signals mobilise other immune cells to site of injury/pathogen
  • Activation of neutrophils and phagocytes via chemical messengers
  • Lysis of bacteria/foreign cells

Activation

  • The complement system must be activated before it can function
  • There are 3 ways the complement system can be activated:

1. Classical pathway (most commonly)

  • Initiated by an antigen (IgM or IgG) binding to an antibody forming an immune complex
    • Change in conformation of the Fc portion on the antibody
    • Complement binding site becomes uncovered and binds to C1 molecule
    • Initiates the complement cascade
      • C1 activates C 2 + C4
      • C2 and C4 activate C3
      • C3 activates C5
      • C5 activates C6 and C7
      • C6 and C7 activate C8 and C9

2. Alternate pathway

  • Triggered when C3b protein binds to pathogen via lipopolysaccharides on bacterial cell walls
    • C3 convertase cleaves C3 proteins into C3a and C3b
    • This forms a complex that binds a serum protein and activates C5 convertase
    • After this, the cascade follows the same sequence as the classical pathway

3. Lectin pathway

  • Mannose binding lectin binds to carbohydrate residues on bacteria
  • This activates C4 and the classical pathway

Effects

Activation of mast cells and basophils

  • Activated C2, C3, C4, C5 activate mast cells and basophils
    • These cells release histamine, heparin and other substances that increase local blood flow and promote local tissue inflammation

Opsonisation

  • Activated C3 is involved in opsonisation of bacteria

Chemotaxis

  • Activated C5 promotes chemotaxis of white blood cells

Cell lysis

  • Activated C5, 6, 7, 8, 9 forms a membrane attack complex (MAC) that lyses cells

Agglutination

  • The complement proteins change t4h surfaces of pathogens causing th3m to adhere to one another

Neutralisation of viruses

  • Complement proteins attack structures of some viruses

Inflammatory effects

  • Complement releases products that contribute to local inflammation in addition to the effects of mast cells and basophils
    • Increased blood flow
    • Increased capillary leakage of proteins
    • Coagulation of interstitial fluid proteins in the tissues spaces (prevents movement of invading organisms through the tissues)

Regulation

  • The complement system has the potential to be damaging to host tissues
    • Therefore activation must be tightly regulated
  • Regulated via plasma and cell surface complement regulatory proteins
    • Prevent complement attacking host tissues
  • Complement proteins have short half lives, and are therefore subject to inactivation rapidly

Regulation of activation

  • C1 inhibitor
    • Prevents excessive complement activation on target and in plasma for classical and lectin pathway
  • Complement proteins are inactivated by plasmin in plasma

Control of amplification

  • C3 convertases are powerful amplifiers of the complement cascade
    • They are regulated by
      • Membrane proteins e.g. decay accelerating factor, membrane cofactor protein
      • Plasma proteins e.g. C4b binding protein, Factor H

Control of MAC

  • Regulated in plasma (by S protein) and in cells

Complement receptors

  • Complement receptor 1
    • Most peripheral blood cells express this receptor
    • Plays a critical role in clearance of complement activated complement particles
  • Complement receptor 2
    • Expressed on B lymphocytes, follicular dendritic cells, epithelial cells in the pharynx/upper airway, and in low amounts in peripheral T cells
    • Localises complement-bearing immune complexes to B lymphocyte risk areas of spleen and lymph nodes
  • Complement receptor 3 and 4
    • Promotes opsonisation of particles containing C3
  • Other complement receptors located throughout the tissues play a role in binding and neutralising complement

Author: Erin Maylin