Complement functions

1
Complement functions

• ???????????? ? ?????????
• ????? ???? ??? ???????
• ???????
• ??????? ????????? ????? ? ??????? ????
• ????? ???? ???? ??????? B ? ???? ???? ??? ?????
  ???????

2

• ????? ??????? ???? ?????????? ???????? ? ????? ??
  ???? ?? ?? ?????? ? ?? ???? ????????? ????? ?????
  ????? ?? ????
• ??? ????? ?????? ???????? ? ?? ???? ???????? ??
  ?? ???????? ????? ???? ?????????? ??????? ?? ???
• ???? ??? ??? ????? ?????? ?????????? ?????? ?? ??
  ??? ??????? ????? ?????? ???? ????? ?????? ???

3
Proteins of the complementsystem (nomenclature)

• C1(qrs), C2, C3, C4, C5, C6, C7, C8, C9
• factors B, D, H and I, properdin (P)
• mannose binding lectin (MBL), MBL associated
  serine proteases (MASP-1 MASP-2)
• C1 inhibitor (C1-INH, serpin), C4-binding protein
  (C4-BP), decay accelerating factor (DAF),
  Complement receptor 1 (CR1), protein-S
  (vitronectin)

4
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)
5
Pathways of complement activation
LECTIN PATHWAY
CLASSICAL PATHWAY
ALTERNATIVE PATHWAY
6
Components of the Classical Pathway

C4
C2
C3
C1 complex
7
Classical Pathway Generation of C3-convertase
C4

8
Classical Pathway Generation of C3-convertase
C2
C4a

_____ C4b2a is C3 convertase
Mg
C4b
9
Classical Pathway Generation of C5-convertase
C2b
C4a

________ C4b2a3b is C5 convertase it leads into
the Membrane Attack Pathway
Mg
C3
C4b
10
Lytic pathway
Generation of C5 convertase leads to the
activation of the Lytic pathway
11
Components of the lytic pathway
C6
C5
C 9
12
Lytic pathwayC5-activation
C5
13
Lytic pathwayassembly of the lytic complex
C6
14
Lytic pathwayinsertion of lytic complex into
cell membrane
C 9
C 9
C 9
C 9
C 9
C 9
C 9
C 9
C 9
15
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
16
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
17
C1-inhibitor deficiencyhereditary angioedema
18
Components of mannose-binding lectin pathway
C4
MASP2
C2
MASP1
19
Mannose-binding lectin pathway
_____ C4b2a is C3 convertase it will lead to
the generation of C5 convertase
C4
C2
MASP2
MASP1
20

• ???????? ???????? ??? MBL ???????? ?? ?? ???
  ?????????? ????? ???????? ???? ?? ???? ? ?????
  ??????? ????? ?????? ???? ?? ???
• MBL ?? ????? ? ??????? ?? ?????????? ?? ????
  ??-????? ????????? ????????? ?? ????
• ??? ??????? ?? ???? ?????????? ???
  MASP1,MASP2,MASP3 ???? ?? ????
• ??? ????????? MASP ???? ?? C1r ? C1s ?????

21
Components of thealternative pathway
D
C3
B
P
22
Spontaneous C3 activation
Generation of C3 convertase
D
H2O
B
C3
C3
C3iBb complex has a very short half life
23
C3-activationthe amplification loop
If spontaneously-generated C3b is not degraded
D
B
C3
24
C3-activationthe amplification loop
D
B
C3
C3a
25
C3-activationthe amplification loop
D
B
C3
C3a
C3a
26
C3-activationthe amplification loop
C3a
C3a
C3a
27
C3-activationthe amplification loop
C3a
C3a
C3a
28
(No Transcript)
29
Regulation of complement activation

• ???? ??????? ?? ?????? ??????? ??? ??????? ?????
  ?????? ? ???? ????? ???? ??? ?????? ??????? ???
  ??? ??????? ??????? ? ????????? Ag-Ab ???
  ?????????? ?????? ? ?????? ???? ???

30
Regulatory mechanisms

• ????? ? ????? ?????? ????? ??????? ?? ?????
  ?????? (?? ????? ?? ?????? ??????) ????? ???????
  ?????? ???? ?? ????.
• 1-???? ????? C3?????????
• 2- ????? ?? ??? ???? ???? ?????????
• 3-???? ????? ?????? ???? ?? ????

31
????? ????????? ??????

• C1INH
• Membrane cofacto protein(MCP)
• Complement receptor-1(CR-1)
• Decay accelerating factor(DAF)
• factor H
• C4-binding protein(C4bp)
• CD59
• Factor I
• S-protein

32
C1-Inhibitor

• C1INH ?? ??????? ???????? ??? ?? ?? ?????? ??????
  ????? ??? ?? ???.??? ??????? ??? ???????? C1r ?
  C1s ??????? ???? ??? ?? ????? C1q ?? ???? ????
  ????? ?????? ????? ??????? C1INH ??? ??? ?????
  ??? C1r ?C1r ????? ?? ??? ????? ???????? ?? ???
  ??????? ?? ???? ?? ???? ???? ??????? ???
  ????????? ?? C1q ?? ?????????? ??? ???? ??????
  ?????? ????? ????? ?????? ?? ???

33
?????? ?? ????? ??????? ??

• ?????? C3b ??? ???? ??????? ?????? ?????????? ???
  ?????? ????? ??????? ????? ??? MCP,CR-1,DAF ???
  ??????? ???????? ???? ?????? H ???? ???
• C4b ?? ??? ??????? ?????? ???? ????? ?????? DAF ?
  CR-1 ??? ??????? ???????? ???? C4bp ???? ??
  ????
• ?? ????? ??? ??????? ?? ?? C3b ? C4b ? ????
  ?????? ???? ?? ????? ???? ????? C3 ??????? ??? Bb
  ?????? ???? ? C2a ?????? ?????? ?? ????????????
  ???? ?? ?????? ????? ??????? ?? ????.
• ???? ?????? ???? ?? ??? ??????? ?????????? ????
  ????? ?????? H ?? ?????? B ???

34

• DAF ?? ??????? ????? ??? ?? ?? ?????
  ?????????????? ????????? ?? ???? ???? ???
  ????????? ? ??????????? ???? ???.
• ??? ?????? ???????? ?? ???? ???? ?????
  ?????-??????? ???? ??? ???? ?? ??? ?? ???? ??????
  ????????????? ??? DAF ?CD59 ?????????????? ????
  ?????? paroxysmal nocturnal hemoglobinuria(PNH)
  ??? ?? ??????? ?? ?????? ???? ????? ??? ?? ??
  ????? ???? ?? ??? ????? ?????? ??????? ???
  ???????? ???? ????.

35
Factor I

• ?? ???? ??????? ???? factor I ?? ????? C3b ?????
  ?? ??? ?????? ?? ?? ???? ????????? ????? ????? ??
  ??? MCP,factor H,C4bp,CR-1 (?????? ????????)??
  ???? ? ????? iC3b,C3d,C3dg ????? ?? ???? ?? ???
  ????????? ??? ?????? ???????? ????? ??????? ????
  ???????? ???? ????? C3 ?C5 ??????? ??? ???? ????
  ? ???? ?? ????

36
???? ????? MAC

• CD59 ??????? ????? ??? ?? ??? ?????? ???????
  ?????? ???? ?? ?????? ??????? ????? ????? ??????
  MAC ???? ?? ??????? ?? ?????? C5b678 ?? ???? ????
  ??????? ???? ??? ? ???? ?? ????? ??? ????????? C9
  ?? ????.
• ??????? S ?? ?????? ?? ????? ?? ?????? C5b67
  ????? ????? ?? ??????? ??? ?????? ?? ???? ????
  ???? ?? ?? ????

37
C1qrs breakdown
C1Inh

38
Control of spontaneousC3 activation via DAF
DAF prevents the binding of factor B to C3b
B
39
Control of spontaneousC3 activation via DAF
DAF dislodges C3b-bound factor Bb
40
Control of spontaneousC3 activation via CR1
H
I
I
DAF
Autologous cell membrane
41
Degradation of spontaneously produced C3b
42
C3b stabilization andC5 activation
This is stable C5 convertase of the alternative
pathway
D
P
B
C3
43
C3b regulation on self and activator surfaces
C3b
44
C5-convertase of the two pathways
C5-convertase of the Classical and lectin Pathways
C5-convertase of the Alternative Pathway
Bb
C3b
C3b
45
Complement Receptors

• CR-I(CD35) promote phagocytosis
• ??? ?????? ?? ??? ?????????? ? ????????? ?? ?
  ???????? ? ??????????? ???????????? ? .. ???? ??
  ???.?????? ?? C3b ?C4b ?? ????
• CR-II(CD21) coreceptor for B cell activation
• ?????? ??? ?????? C3d ? C3dg
• CR-III (Mac-1) phagocytosis
• ??? ?????? ?? ??? ??????? ??????? ? ???? ???? ?
  ??????? NK ???? ?? ??? ??????? ??iC3b ?? ????.???
  ?????? ?????? ?????????? ?? ?????
• CR-IV phagocytosis
• ???? ?? ?????? ??? ?? ???? .

46
Biological effects of C5a
47
Biological properties of C-activation products
48
Biological properties of C-activation products
49
Biological properties of C-activation products
50
Opsonization and phagocytosis
51
Complement level

• ??? ??????? ???? ??? ?? ????? ??? ???? ????
• ???) ????
• ?) ???????
• 1) ???? ????( ????? ??? ????? ????? ?????????
  ????????? ??????? ??? SLE ? ???????? ? ?????????
  ????? ????? ? ???? ??? ? ?????? ???? ? ...)
• 2) ???? ????? ( ??? ????? ? ????????? ???? )
• ?? ?????? ??? ?? ???? ????? ?? ??????? ??? ???
  ??? ??? ??????? ??? ??????? ??? ?????? ?? ????.
• ????? ??????? ??? ???? ?? ???? ???? ?????????
  ????? ???? ?? ???.??? ?????? ????? ?? ???? ??????
  ???? ??? ??????? ? ??? ?????? ?? ?????? ???? ???
  ????? ???? ?? ????.
• ????? ??????? ??? ??? ????? ?? ????? ?? ????
  ????? ?? ? ???? ??? ???? ???.

52

• The genetic deficiency of early components of the
  classical pathway (C1q, C1r/s, C2, C4) tend to be
  linked with autoimmune diseases
• whereas C5 to C9 may have enhanced susceptibilty
  to meningococcal disease.
• Deficiencies in complement predispose patients to
  infection via 2 mechanisms
• (1) ineffective opsonization
• (2) defects in lytic activity (defects in MAC).

53

• Th e effects of these deficiencies highlight the
  importance of the early complement reactions in
  generating C3b and C3bs role in the
  solubilization and clearance of immune complexes.
  In addition, as described above, C1q has been
  shown to bind apoptotic blebs. In the absence of
  C1q binding, cells bearing these apoptotic blebs,
  or the blebs themselves, can act as autoantigens
  and lead to the development of autoimmune
  diseases
• Individuals with deficiencies in the early
  complement components may also suffer from
  recurrent infections by pyogenic (pus-forming)
  bacteria such as streptococci and staphylococci

54

• A deficiency in MBL, the first component of the
  lectin pathway, has been shown to be relatively
  common, and results in serious pyrogenic
  (fever-inducing) infections in babies and
  children. Children with MBL deficiency suffer
  from respiratory tract infections. MBL deficiency
  is also found with a frequency two to three times
  higher in SLE patients than in normal subjects,
  and certain mutant forms of MBP are found to be
  prevalent in chronic carriers of hepatitis B.
  Defi ciencies in factor D and properdinearly
  components of the alternative pathwayappear to
  be associated with Neisseria infections but not
  with immune-complex disease. People with C3
  deficiencies display the most severe clinical
  manifestations of any of the complement
  deficiency patients, reflecting the central role
  of C3 in opsonization and in the formation of the
  MAC.

55

• Defi ciencies of complement regulatory proteins
  have also been reported. As described above,
  C1INH, the C1 inhibitor, regulates activation of
  the classical pathway by preventing excessive C4
  and C2 activation by C1. However, as a serine
  protease inhibitor, it also controls two serine
  proteases in the blood clotting system. Th
  erefore, patients with C1INH deficiency suff er
  from a complex disorder that includes excessive
  production of vasoactive mediators (molecules
  that control
• blood vessel diameter and integrity), which in
  turn leads to tissue swelling and extracellular
  fl uid accumulation. Th e resultant clinical
  condition is referred to as hereditary
  angioedema.
• It presents clinically as localized tissue edema
  that oft en follows trauma, but sometimes occurs
  with no known Th e edema can be in subcutaneous
  tissues within the bowel, where it causes
  abdominal pain or in the upper respiratory
  tract, where it can result in fatal obstruction
  of the airway. C1INH defi ciency is an autosomal
  dominant condition with a frequency of 1 in 1000
  in the human population
•  

56
????? ???????
57
???????????? ????????????

• ?????? ???? ?? ????? ???? ??????? ????? ?????? ?
  ?? ????????? ???? ?? ??? ?????? ??????? ???? ???
  C3b ? iC3b ? ?? C4b ??????? ?? ???? ? ??? ???
  ??????? ?? ?? ???? ?????? ??? ???? CR1 ??
  ???????? ?? ? ?????????? ???? ??? ??? ????? ???
  ?????? ?????? ??? ???????? ??? ??????? ?? ????.