The Complement System

The Complement System

• is a major effector of the humoral branch of the immune system representing some 30 proteins of circulating blood plasma which remain inactive until cleaved by a protease in turn making themselves  proteases
• it is so called because it "complements" the action of the antibody → while antibodies provide specificity, the complement system gives actual protection
• comprises mainly of proteolytic enzymes called convertases
• this is heat labile component of blood plasma

Functions

• lysis of cells, bacteria, viruses
• opsonization of particular antigen
• binding to complement receptors → triggering specific cell functions → inflammation, secretion of immunoregulatory molecules
• immune clearance → deposition of Ag═Ab complexes in spleen and liver

Components

• soluble proteins, glycoproteins produced by the liver hepatocytes
• constitute 5% (weight) of serum globulin fraction
• cleavage of a component into larger and smaller subcomponents:
• larger → binds the targer near site of activation
• smaller → diffuses from the site and initiates localized inflammatory responses by binding to specific receptors

Complement Activation Pathways

1. Classical Pathway

• begins with for the formation of soluble Ag═Ab complexes which induces conformational changes in the Fc portion of IgM that exposes a binding site for C1 component of the complement system
• C1 = C1q + 2 C1r + 2 C1s → gives C1qr₂s₂ (stabilized by Ca²⁺)
  
  

  

  The Classical Pathway of the Complement System. (J. Kuby et al.)

Scheme

1. C1q binding to the Ag═Ab complex activates C1r autocatalytically which activates the second C1r which in turn leads to the activation of C1s
2. C1s cleaves C4 and C2 → C4 cleavage exposes binding site for C2 → C4 binds the surface near C1 and C2 binds C4b forming C4b2a also known as C3 convertase
3. C4b2a hydrolyzes many C3 molecules which combines with the C4b2a to give C4b2a3b also known as C5 convertase
4. The C3b subcomponent of C4b2a3b binds C5 leading to cleavage of C5 into C5a and C5b
5. C5b goes on to bind C6 → formation of Membrane Attack Complex (MAC)

• a single C3 convertase can generate 200 molecules of C3b
• some of the C3b:
• combines with C4b2a
• binds directly to cell membranes
• diffuses and coats immune complexes and particulate antigen (opsonin)

2. Alternative Pathway

• is a component of the innate immune system
• does not require Ag═Ab complex, i.e. is antibody-independent
• activates 4 serum proteins
• C3
• factor B
• factor D
• properdin

Alternative Pathway of the Complement System ( Journal of Biochemistry)

Scheme

1. C3 hydrolyzes spontaneously into C3a and C3b → C3b attaches to foreign surface
2. Factor B binds to C3b which exposes site acted on by factor D → cleavage results in formation of C3 convertase, which is stabilized by Mg2+
3. Binding of properdin stbilizes C3 convertase (which otherwise has a decrease half life of about 5 min.)
4. C3 convertase = C3b → binds to C3 convertase → activation of C5 convertase → C5b binds to antigenic surface → final phase of the lytic cycle now commenced

3. Lectin Pathway

• lectins are proteins which activate the complement system by binding specific carbohydrate (mannose)  residues
• also antibody-independent

Scheme

1. Mannose-binding lectin (MBL) binds to the foreign surface
2. MBL-associated proteases MASP-1 and MASP-2 then bind to MBL
3. This complex cleaves and activated C4 and C2 → → → MAC

Bacially, this pathway utilizes the components of the classical pathway except for the C1 proteins!

**The three pathways converge at the MAC formation step.

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