1. Overview
The complement system is part of the innate immune system (vs adaptive)
It is named “complement system” because it was first identified as a heat-labile component of serum that “complemented” antibodies in the killing of bacteria
It is now known that it consists of over 30 proteins.

2. Biological function of complement system
Ch. 7

3. “Classical” Pathway
Begins with antibody binding to a cell surface and ends with the lysis of the cell
The proteins in this pathway are named C1-C9
When complement is activated it is split into two parts
a – smaller part
B – larger part and usually the active part (except with factor 2)

4. “Classical Pathway” ACTIVATION
C1q portion of C1 attaches to the Fc portion of an antibody
Only IgG and IgM can activate complement
Once activated C1s is eventually cleaved which activates C4 and C2
C4b & C2a come together to form the C4b2a which is the C3 convertase
C3 convertase activates C3 to C3a and C3b

5. “Classical Pathway” ACTIVATION
C3a binds to receptors on basophils and mast cells triggering them to release there vasoactive compounds (enhances vasodilation and vasopermeability)
C3a is called an anaphylatoxin
C3b serves as an opsonin which facilitates immune complex clearance
C3b binds to C4bC2a to form the C5 convertase C4bC2aC3b
C5 convertase cleaves C5 leading to the formation of the Membrane attack Complex (C5-C6-C7-C8-C9)
The MAC “punches holes” in cell walls resulting in lysis

6. C3a binds to receptors on basophils and mast cells triggering them to release there vasoactive compounds (enhances vasodilation and vasopermeability) - ANAPHYLATOXIN
C5a is a:
Potent anaphylatoxin
Chemoattractant for neutrophils C3
C1q C2 C4
C3a C5
C3b 2a 4a 4b 2b
C5b
C5a
C5-Convertase
C3-convertase C7 C8 C9 C6
Classical Pathway

7. “Alternative Pathway”
Requires no specific recognition of antigen in order to cause activation
ACTIVATION
Spontaneous conversion from C3 to C3b occurs in body
Normally, C3b is very short lived and quickly inactivated by proteins on the surface of the body’s own cell walls (DAF)
However, bacteria or other foreign material may lack these surface proteins allowing C3b to bind and stay active

8. “Alternative Pathway”
Factor B binds to C3b
Factor B is then cleaved by factor D into Ba and Bb
C3bBb remains which acts as a C3 convertase (C3  C3a and C3b)
C3bBbC3b is formed which acts as a C5 convertase
C5 is cleaved to C5a and C5b
C5b then starts the assembly of the Membrane Attack Complex

9. Alternative Pathway D Bb B Ba C3a C3 C3b C3 Anaphylatoxin C5
C3-Convertase
C5-Convertase
C3a
C3b
C5b
C5a D C7 B Bb Ba C8 C6 C9

10. MEMBRANE ATTACK COMPLEX
C5-C9 MAC C9 C8 C7 C6
Bacterium
Lysis
C5a
C5b C5
MBL
MASP C4 C2
C4b2b
C3 CONVERTASE
C4b2b3b
C5 CONVERTASE
C4a
C4b
C2b
C2a C3
“lectin Pathway”
C3a
C3b

11. Complement Regulation
C1 inhibitor (C1INH) bind to and inactivate the serine protease activity of C1r, and C1s
Factor I cleave C3b and C4b thereby reducing amount of C5 convertase available
Factor H enhance activity of factor I on C3b
As spontaneously produced C3b binds to autologous host membranes it interacts with DAF (decay accelerating factor), a membrane bound protein which can act to accelerate dissociation of C3 convertase of both pathways.

12. Summary - Activation
Complement can be activated by the binding of antibody (Classical) or by the adherance of C3b to foreign material (Alternative)
The two pathways converge at the formation of the C5 convertase (C4b2a3b or C3bBbC3b)
The final common pathway is the formation of the membrane attack complex

13. Summary - Function Opsonization – C3b
Chemotaxis – C5a (attracts neutrophils)
Increases vasodilation & permeability of capillary beds via mast cell and basophil activation – C3a & C5a (Anaphylatoxins)
Cellular Lysis via the MAC

14. Complement deficiencies and disease.
Pathway/Component
Disease
Mechanism
Classical Pathway
C1INH
Hereditary angioedema
Overproduction of C2b (prokinin)
C1, C2, C4
Predisposition to SLE
Opsonization of immune complexes help keep them soluble, deficiency results in increased precipitation in tissues and inflammation
Lectin Pathway
MBL
Susceptibility to bacterial infections in infants or immunosuppressed
Inability to initiate the lectin pathway
Alternative Pathway
Factors B or D
Susceptibility to pyogenic (pus-forming) bacterial infections
Lack of sufficient opsonization of bacteria C3
Susceptibility to bacterial infections
Lack of opsonization and inability to utilize the membrane attack pathway
C5, C6, C7 C8, and C9
Susceptibility to Gram-negative infections
Inability to attack the outer membrane of Gram-negative bacteria
Properdin (X-linked)
Susceptibility meningococcal meningitis
Lack of opsonization of bacteria
Factors H or I
C3 deficiency and susceptibility to bacterial infections
Uncontrolled activation of C3 via alternative pathway resulting in depletion of C3