Complement
1,Introduction
2,The Complement Components
3,Complement Activation
4,Regulation of the Complement System
5,Biol...
1,Introduction
Belgian bacteriologist and
immunologist who received the
Nobel Prize for Physiology or
Medicine in 1919 for...
Sheep antiserum + vibrio cholerae
Lysis of bacteria

Heated sheep antiserum + vibrio cholerae
destroyed
Lysis of bacteria
...
Paul Ehrlich in Berlin independently
carried out similar experiments and
coined the term complement,
defining it as “the a...
Complement
A group of sequentially reacting proteins, which upon
activation, mediate a number of biological reactions that...
2, The Complement Components
Sequential reaction
I
Ia

Ib
IIb

III
IIIa

II
IIa

IIIb
biological effects
(1)The complement components in serum
name

molecule weight kDa

Classical pathway
C1q
C1r
C1s
C4
C2

C3

Alternative path...
(2)Nomenclature
①“C” - designation for 11 of the complement proteins (C1, C2,
etc.)
②Factor - designation for many alterna...
 (3)physical and chemical properties of complement 
① The concentration of complement in serum is stable( 10% of
serum pro...
3,Complement Activation
(1)Classical pathway 
from C1 activated by Ag-Ab complex

(2)Alternative pathway
from C3 by the su...
CLASSICAL          MBL               ALTERNATIVE
  pathway               pathway                   pathway

C3a
C5a

C3
C5...
(1)Classical Pathway
The binding of antibody to its antigen often triggers the
complement system through the so-called cla...
Antigen
Binding Site
( Fab )
NH3+
VH
VL

CH1
CL

Hinge region

CH2
CH3

Complement Binding
Site ( Fc )

COO–
The changes of structure of IgG molecule
by binding antigen
Before binding antigen

After binding antigen

b
Fa
CH1

CH2

...
① Phase of recognition (initiation )
The structure and function of C1

C1
C1q

C1r C1s

C1qr2s2

Ab
Ag

<40nm

Ag

C1: C1q...
②Phase of activation
C1s Cleavage of C4
C4a

C4
C1qr2s2

C1s
antibody

antigen

<40nm

antigen

C4b
C1s Cleavage of C2
C2b

C4b

C2

C1s
C4b

C3 Convertase Formation

C2a
C3 Cleavage
C3

C3a

C3 Convertase
C4b

C2a

C3b
C5 Convertase formation
(Classical Pathway)

C5a

C5
C2a

C4b

C3b

C5b
③Phase of attack( effector)
(Common terminal pathway)
1) Formation of the Membrane Attack Complex (MAC)
2) Effect of MAC
M...
C5b+C6+C7+C8+C9 = MACs

The structure of MACs

C6C7
C5b

C9
C8

poly
mer

10-17

MACs-induced lesion on the
membrane
Figure 2-35
(1)Classical Pathway
(2)MBL(The lectin) pathway
The pathway is activated by the binding of mannose-binding
lectin, MBL( also called mannose-bin...
C1q

MBL

The function and structure of MBL are similar to that of C1q in
the complement pathway.
C4

mannose

mannose
MBL

C4a + C4b

+
MASP

C2

MBL

C4b2b

( C3 convertase )

MASP

C2a + C2b

MASP : MBL-associated ser...
(3)The Alternative Pathway
There is a spontaneous conversion of C3 to C3b. However,
ordinarily C3b is quickly inactivated:...
C3 is the most abundant protein of the complement system
(~1.3 mg/ml).
Because of its abundance and its ability to activat...
C3 Convertase Formation

Factor D

C3b

Factor
B

Ba
C3b Bb

LPS
C3 Cleavage

C3 convertase

C3
C3a

C3b Bb
C3b

LPS
C5 Convertase Formation
(Alternative pathway)

C3
C3 convertase

C3b Bb

C5

C5a

C3b

C5b

LPS
Contains a labile thioester bond

C3b can bind to cell surfaces
Inactivated on host cells by
surface sialic acids

Schemat...
Comparison of three pathways
classical
Activator

Ag-Ab complex

Components

MBL
MBL-mannose

Alternative
Bacterium, LPS

...
CLASSCAL PATHWAY
Antigen-antibody
C1qr2s2

C1qr2s2
C2b

C2
C4

LECTIN PATHWAY
MBL

MASP

C4b
C4a

C4b2a
(C3 convertase)

A...
4,Regulation of the Complement System
The explosive potential of the complement system requires
to be kept under tight con...
5,Biological Consequences of
Complement Activation
(1)The Membrane-Attack Complex Can Lyse a Broad
Spectrum of Cells
The c...
form
(2)Cleavage Products of Complement
Components Mediate Inflammation
Anaphylatoxins : C3a,C4a, C5a
Kinin-like action: C2a, C...
(3)C3b and C4b Binding Facilitates Opsonization
The process that phagocytosis of phagocytes are
enhanced by antibody or co...
(4)The Complement System Also
Neutralizes Viral Infectivity
virus
C3b

C3b
C3b
C3b

C3b

C3b
C3b

C3b
C3b
C3b
C3b
C3b

+
(5)The Complement System Clears
Immune Complexes from Circulation
The coating of soluble immune complexes with C3b is
thou...
Learning Objectives
1,Master the concept of complement
2,Understand basic components of complement system and their
nomenc...
5 complement
5 complement
5 complement
5 complement
5 complement
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5 complement

  1. 1. Complement 1,Introduction 2,The Complement Components 3,Complement Activation 4,Regulation of the Complement System 5,Biological Consequences of Complement Activation
  2. 2. 1,Introduction Belgian bacteriologist and immunologist who received the Nobel Prize for Physiology or Medicine in 1919 for his discovery of immunity factors in blood serum; this was a development vital to the diagnosis and treatment of many dangerous contagious diseases.  Jules Bordet (1870-1961), discoverer of complement
  3. 3. Sheep antiserum + vibrio cholerae Lysis of bacteria Heated sheep antiserum + vibrio cholerae destroyed Lysis of bacteria Fresh serum without antibody + unable restored Lysis of bacteria
  4. 4. Paul Ehrlich in Berlin independently carried out similar experiments and coined the term complement, defining it as “the activity of blood serum that completes the action of antibody.”   Paul Ehrlich ( 1854~1915 )
  5. 5. Complement A group of sequentially reacting proteins, which upon activation, mediate a number of biological reactions that are important to host defense. Lysis of cells, bacteria and viruses Opsonization Immune clearance B cell activation Chemotaxis Inflammation
  6. 6. 2, The Complement Components Sequential reaction I Ia Ib IIb III IIIa II IIa IIIb biological effects
  7. 7. (1)The complement components in serum name molecule weight kDa Classical pathway C1q C1r C1s C4 C2 C3 Alternative pathway D factor B factor MBL pathway MBL Terminal pathway C5 C6 C7 C8 C9 Regulatory factors C1-INH C4-bp H I P con. in serum mg/ml 460 83 83 200 102 185 80 50 50 600 20 1300 24 90 1 210 30 x 3 1 204 120 120 160 70 70 65 55 55 60 105 550 150 88 4 x 56 200 250 480 35 20
  8. 8. (2)Nomenclature ①“C” - designation for 11 of the complement proteins (C1, C2, etc.) ②Factor - designation for many alternative pathway components (factor B) ③Overbar - indicates an enzymatically active protein or complex (C3bBb) ④Lower case letters - indicates a proteolytic cleavage fragment (C3a or C5a) ⑤“R” - designation for receptors in the complement system (CR1 or C5aR)
  9. 9.  (3)physical and chemical properties of complement  ① The concentration of complement in serum is stable( 10% of serum proteins) , C3 is highest one in all of complement components:1.20-1.60g/L  ②  Heat –labile feature 56 °C 30 min—inactivation  ③  Synthesized sites: liver cells, macrophages ④ The concentration of complement is highest in the serum of guinea pig
  10. 10. 3,Complement Activation (1)Classical pathway  from C1 activated by Ag-Ab complex (2)Alternative pathway from C3 by the surface of microbe (3)MBL pathway: from C4 and C2 by the binding of MBL to mannose surface of microbes
  11. 11. CLASSICAL          MBL               ALTERNATIVE   pathway               pathway                   pathway C3a C5a C3 C5 C3b C5b + C6-C9 TERMINAL pathway
  12. 12. (1)Classical Pathway The binding of antibody to its antigen often triggers the complement system through the so-called classical pathway. It can occur in solution or when the antibodies have bound to antigens on a cell surface. ①Phase of recognition (initiation ):  recognizing unit (C1qrs) :activated C1 ②Phase of activation: activating unit( C4,C2,C3):C3 convertase and C5 convertase ③Phase of attack( effector): membrane-attack complex (MAC) ,C5-9
  13. 13. Antigen Binding Site ( Fab ) NH3+ VH VL CH1 CL Hinge region CH2 CH3 Complement Binding Site ( Fc ) COO–
  14. 14. The changes of structure of IgG molecule by binding antigen Before binding antigen After binding antigen b Fa CH1 CH2 Fc C1q binding site covered IgM CH3 region , IgG CH2 region C1q binding site exposed
  15. 15. ① Phase of recognition (initiation ) The structure and function of C1 C1 C1q C1r C1s C1qr2s2 Ab Ag <40nm Ag C1: C1q C1r×2 C1s×2 Each C1q molecule must bind to at least two Fc sites for a stable C1-antibody interaction to occur. Then C1r and C1s are activated and complement activation is initiated.
  16. 16. ②Phase of activation C1s Cleavage of C4 C4a C4 C1qr2s2 C1s antibody antigen <40nm antigen C4b
  17. 17. C1s Cleavage of C2 C2b C4b C2 C1s C4b C3 Convertase Formation C2a
  18. 18. C3 Cleavage C3 C3a C3 Convertase C4b C2a C3b
  19. 19. C5 Convertase formation (Classical Pathway) C5a C5 C2a C4b C3b C5b
  20. 20. ③Phase of attack( effector) (Common terminal pathway) 1) Formation of the Membrane Attack Complex (MAC) 2) Effect of MAC MAC: a lytic complex of the terminal components of the complement cascade, including C5,6,7,8 and multiple copies of C9, that forms in the membrane of target cells . Since ions and small molecules can diffuse freely through the central channel of the MAC, the cell cannot maintain its osmotic stability and is killed by an influx of water and loss of electrolytes.
  21. 21. C5b+C6+C7+C8+C9 = MACs The structure of MACs C6C7 C5b C9 C8 poly mer 10-17 MACs-induced lesion on the membrane
  22. 22. Figure 2-35
  23. 23. (1)Classical Pathway
  24. 24. (2)MBL(The lectin) pathway The pathway is activated by the binding of mannose-binding lectin, MBL( also called mannose-binding protein, MBP ) to mannose residues on glycoproteins or carbonhydrates on the surface of the microorganisms. *Independent on the antibody *The mechanism is more like that of the classical pathway
  25. 25. C1q MBL The function and structure of MBL are similar to that of C1q in the complement pathway.
  26. 26. C4 mannose mannose MBL C4a + C4b + MASP C2 MBL C4b2b ( C3 convertase ) MASP C2a + C2b MASP : MBL-associated serine protease (similar to C1r and C1s).
  27. 27. (3)The Alternative Pathway There is a spontaneous conversion of C3 to C3b. However, ordinarily C3b is quickly inactivated: if C3b binds to inhibitory proteins and sialic acid present on the surface of body's own cells, the process is aborted. After C3b binds to the surface of bacteria, the alternative pathway will be initiated. Antibody-independent
  28. 28. C3 is the most abundant protein of the complement system (~1.3 mg/ml). Because of its abundance and its ability to activate itself, it greatly magnifies the response.
  29. 29. C3 Convertase Formation Factor D C3b Factor B Ba C3b Bb LPS
  30. 30. C3 Cleavage C3 convertase C3 C3a C3b Bb C3b LPS
  31. 31. C5 Convertase Formation (Alternative pathway) C3 C3 convertase C3b Bb C5 C5a C3b C5b LPS
  32. 32. Contains a labile thioester bond C3b can bind to cell surfaces Inactivated on host cells by surface sialic acids Schematic diagram of intermediates in the formation of bound C5b by the alternative pathway of complement activation. The C3bBb complex is stabilized by binding of properdin. Conversion of bound C5b to the membrane-attack complex occurs by the same sequence of reactions as in the classical pathway.
  33. 33. Comparison of three pathways classical Activator Ag-Ab complex Components MBL MBL-mannose Alternative Bacterium, LPS C1~C9 C2~C9 C3,C5~C9, Factor D,B, P Activated enzyme C1s MASP Factor D C3 convertase C4b2a C4b2b C3bBb C5 convertase C4b2a3b C4b2b3b C3bBb3b Specific immune response Non-specific immune response in the early infection Function Non-specific immune response in the early infection
  34. 34. CLASSCAL PATHWAY Antigen-antibody C1qr2s2 C1qr2s2 C2b C2 C4 LECTIN PATHWAY MBL MASP C4b C4a C4b2a (C3 convertase) Activated C1-like complex Microbial cell wall C3b C3a C3 B C3b Microbial surfaces MAC C3a C3 C3a C4b2a3b (C5 convertase) C5 C5b C6C7C8C9 C5a Ba C3bBb (C3 convertase) Factor D ALTERNATIVE PATHWAY C3bBb3b (C5 convertase)
  35. 35. 4,Regulation of the Complement System The explosive potential of the complement system requires to be kept under tight control. At least 12 proteins are known to contribute to regulation of the complement system.
  36. 36. 5,Biological Consequences of Complement Activation (1)The Membrane-Attack Complex Can Lyse a Broad Spectrum of Cells The complement system lyses target microbe cells through alternative pathway and MBL pathway of complement-activating in absence of antibody and through classical pathway in presence of antibodies.
  37. 37. form
  38. 38. (2)Cleavage Products of Complement Components Mediate Inflammation Anaphylatoxins : C3a,C4a, C5a Kinin-like action: C2a, C4a Chemokine-like action: C3a, C5a
  39. 39. (3)C3b and C4b Binding Facilitates Opsonization The process that phagocytosis of phagocytes are enhanced by antibody or complement binding to microbial surface is call opsonization. The bound C3b ,C4b to CR1 on macrophage and neutrophils enhances their actions.
  40. 40. (4)The Complement System Also Neutralizes Viral Infectivity virus C3b C3b C3b C3b C3b C3b C3b C3b C3b C3b C3b C3b +
  41. 41. (5)The Complement System Clears Immune Complexes from Circulation The coating of soluble immune complexes with C3b is thought to facilitate their binding to CR1 on erythrocytes. Erythrocytes may carry these complexes to the liver and spleen where immune complexes are removed and phagocytosed.
  42. 42. Learning Objectives 1,Master the concept of complement 2,Understand basic components of complement system and their nomenclature 3,Master three pathways of complement activation and their comparison 4,Master biological Consequences of Complement activation
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