Complement

1. COMPLEMENT
SYSTEM
DR. MALEEHA ASLAM

2. Complement system (nomenclature)
• Protective cascading system- composed of 25
proteins
• Can be activated via Classical and Alternate
pathways
• Culminates in three useful results–
phagocytosis, lysis and inflammation
• Classical pathway C1- C9= C1(qrs), C2, C3,
C4, C5, C6, C7, C8, C9
• Alternate pathway = factors B, D, and IF,
properdin (P)
• C3b inactivator, anaphylotoxin inhibitors

3. Activation product of complement
proteins (nomenclature)
When enzymatically cleaved, the larger moiety,
binds to the activation complex or membrane
and the smaller peptide is released in the
microenvironment
Letter “b” is usually added to the larger,
membrane-binding, peptide and “a” to the
smaller peptide (e.g., C3b/C3a, C4b/C4a,
C5b/C5a), EXCEPT C2 (the larger, membrane-
binding moiety is C2a; the smaller one is C2b)
Activated component are usually over-lined: e.g.
C1qrs

4. GENERAL PROPERTIES OF
COMPLEMENT SYSTEM
• PRESENT IN NORMAL SERA
• DOES NOT INCREASE ON IMMUNIZATION
• DESTROYED AT 56oC IN 30 MINUTES
• NOT A SINGLE SUBSTANCE- COMPLEX
• IN CLASSICAL PATHWAY- 9 PROTEINS COMPLEX
• IN ALTERNATE PATHWAY- 13 PROTEINS COMPLEX
• IgM, IgG-1,2,3 REACT WITH COMPLEMENT
• ACTIVATION BY ANTIGEN ANTIBODY COMPLEX
• ACTIVATION BY POLYSAC/ ENZYMES –
ALTERNATE PATHWAY
• INACTIVATORS AND INHIBITORS PRESENT IN
SERUM

5. COMPLEMENT FUNCTIONS
• Host benefit:
– opsonization to enhance
phagocytosis
– phagocyte attraction and activation
– lysis of bacteria and infected cells
– regulation of antibody responses
– clearance of immune complexes
– clearance of apoptotic cells
• Host detriment:
– Inflammation, anaphylaxis

6. Pathways of
complement activation
CLASSICAL
PATHWAY
ALTERNATIVE
PATHWAY
activation
of C5
LYTIC ATTACK
PATHWAY
antibody
dependent
LECTIN
PATHWAY
antibody
independent
Activation of C3 and
generation of C5 convertase

7. CLASSICAL PATHWAY
3 GROUPS
• RECOGNITION UNIT
CI( C1q, C1r, C1s)
•ACTIVATION COMPLEX
C4,C2,C3
•MEMBRANE ATTACK COM
C5,C6,C7,C8,C9
ALTERNATE PATHWAY
IMPORTANT PROTEINS
•FACTOR B- C3 PROACTIVATOR
•FACTOR D- C3 PROACTIVATOR
CONVERTASE – SPLIT FACTOR B

8. Activation of Complement

9. THE CLASSICAL AND ALTERNATE PATHWAYS

11. Components of the
Classical Pathway
C4C2 C3
C1 complex
Ca++
C1r C1s
C1q

12. Ca++
C1r C1s
C1q
C4
C4a
b
Classical Pathway
Generation of C3-convertase

13. Generation of C3-convertase
C4b
Mg++
C4a
Ca++
C1r C1s
C1q
C2
C2b
a
C2a
_____
C4b2a is C3 convertase

14. Classical Pathway
Generation of C5-convertase
C4b
Mg++
C4a
Ca++
C1r C1s
C1q
C2b
C2a
C3
C3a
b
________
C4b2a3b is C5 convertase;
it leads into the Membrane
Attack Pathway

15. ALTERNATE PATHWAY

16. Components of the
alternative pathway
C3 B
D
P

17. Spontaneous C3 activation
C3
H2O
i
B
D
Generation of C3 convertase
C3iBb complex has a very short half life
b
C3
C3a
b

18. B
D
bC3b
If spontaneously-generated
C3b is not degraded
C3-activation
the amplification loop
C3C3a b

19. C3a
C3a BbC3b
C3bC3 BbB
D
bb
C3a
C3-activation
the amplification loop
C3b

20. C3a
C3a BbC3b
BbBbC3b
C3a
C3-activation
the amplification loop
C3bC3b

21. Control of spontaneous
C3 activation via DAF
C3b
DAF prevents
the binding of
factor B to
C3b
B
Autologous cell membrane
DAF
CR1

22. Control of spontaneous
C3 activation via DAF
DAF dislodges
C3b-bound
factor Bb
Bbb C3b
Autologous cell membrane
DAF
CR1
B b

23. C3b stabilization and
C5 activation
C3b
C3b finds an activator
(protector) membrane
C3
C3a
b
B
D
b
P
This is stable C5 convertase
of the alternative pathway

24. C5-convertase of the two
pathways
C3b Bb C3b
C5-convertase of the
Alternative Pathway
C4b C2a C3b
C5-convertase of the
Classical and lectin
Pathways

25. Generation of C5 convertase
leads to the activation of the
Lytic pathway
Lytic pathway

26. Components of the lytic pathway
C6
C
9
C8
C7
C5

27. Lytic pathway
C5-activation
C3b
C2 aC4b
C5 b
C5a

28. Lytic pathway
assembly of the lytic complex
C5 b
C6
C7

29. Lytic pathway:
insertion of lytic complex into cell
membrane
C5 b
C6
C7
C8
C
9
C
9
C
9
C
9C
9
C
9 C
9
C
9
C
9

30. Products and their Control Factors
Fragment Activity Effect Control Factor (s)
C2a
Prokinin, accumulation of
fluids
Edema C1-INHIBITOR
C3a
Basophil and mast cells
degranulation;
enhanced vascular
permeability, smooth
muscle contraction
Anaphylaxis C3a-INACTIVATOR
C3b
Opsonin, phagocyte
activation
Phagocytosis Factors H and I
C4a
Basophil and mast cells
degranulation;
enhanced vascular
permeability, smooth
muscle contraction
Anaphylaxis
(least potent)
C3a-INACTIVATOR
C4b Opsonin Phagocytosis C4-BP and Factor I
C5a
Basophil and mast cells
degranulation;
enhanced vascular
permeability, smooth
muscle contraction
Anaphylaxis
(most potent)
C3a-INACTIVATORChemotaxis, stimulation of

31. Biological Activities of Classical
Pathway Components
Component Biological Activity
C2b Prokinin; cleaved by plasmin to yield kinin,
which results in edema
C3a Anaphylotoxin; can activate basophils and mast
cells to degranulate resulting in increased
vascular permeability and contraction of smooth
muscle cells, which may lead to anaphylaxis
C3b Opsonin
Activation of phagocytic cells
C4a Anaphylaotoxin
C4b Opsonin

32. Product Biological Effects Regulation
Biological properties of
C-activation products
anaphylactic as C3, but
much more potent;
attracts & activates PMN
causes neutrophil
aggregation, stimulation
of oxidative metabolism
and leukotriene release
C5a
(chemotactic
factor)
carboxy-
peptidase-B
(C3-INA)
C5b67 protein-Schemotaxis, attaches
to other membranes

33. Biological effects of C5a

34. Control of Classical Pathway
Components
Component Regulation
All C1-inhibitor (C1-INH); dissociates C1r and C1s
from C1q
C3a C3a-inactivator (C3a-INA; Carboxypeptidase B)
C3b Factors H and I; Factor H facilitates the
degradation of C3b by Factor I
C4a C3a-INH
C4b C4 binding protein (C4-BP) and Factor I; C4-BP
facilitates degradation of C4b by Factor I; C4-BP
also prevents the association of C2a with C4b
thus blocking formation of C3 convertase

35. 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
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

36. C1-inhibitor deficiency:
hereditary angioedema