Complement

1
Complement
2
Complement History

• Discovered in 1894 by Bordet
• It represents lytic activity of fresh serum
• Its lytic activity destroyed when heated at 56C
  for 30 min

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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

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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)

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Definitions

• C-activation alteration of C proteins such that
  they interact with the next component
• C-fixation utilization of C by Ag-Ab complexes
• Hemolytic units (CH50) dilution of serum which
  lyses 50 of a standardized suspension of
  Ab-coated r.b.c
• C-inactivation denaturation (usually by heat)
  of an early C-component resulting in loss of
  hemolytic activity
• Convertase/esterase altered C-protein which
  acts as a proteolytic enzyme for another
  C-component

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

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

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Classical Pathway Generation of C3-convertase
C2
C4a

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

________ C4b2a3b is C5 convertase it leads into
the Membrane Attack Pathway
Mg
C3
C4b
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Biological Activities of Classical Pathway
Components
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Control of Classical Pathway Components
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C1-inhibitor deficiencyhereditary angioedema
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Components of mannose-binding lectin pathway
C4
MASP2
C2
MASP1
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Mannose-binding lectin pathway
_____ C4b2a is C3 convertase it will lead to
the generation of C5 convertase
C4
C2
MASP2
MASP1
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Components of thealternative pathway
D
C3
B
P
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Spontaneous C3 activation
Generation of C3 convertase
D
H2O
B
C3
C3
C3iBb complex has a very short half life
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C3-activationthe amplification loop
If spontaneously-generated C3b is not degraded
D
B
C3
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C3-activationthe amplification loop
D
B
C3
C3a
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C3-activationthe amplification loop
D
B
C3
C3a
C3a
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C3-activationthe amplification loop
C3a
C3a
C3a
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C3-activationthe amplification loop
C3a
C3a
C3a
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Control of spontaneousC3 activation via DAF
DAF prevents the binding of factor B to C3b
B
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Control of spontaneousC3 activation via DAF
DAF dislodges C3b-bound factor Bb
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Control of spontaneousC3 activation via CR1
H
I
I
DAF
Autologous cell membrane
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Degradation of spontaneously produced C3b
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C3b stabilization andC5 activation
This is stable C5 convertase of the alternative
pathway
D
P
B
C3
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C3b regulation on self and activator surfaces
C3b
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C5-convertase of the two pathways
C5-convertase of the Classical and lectin Pathways
C5-convertase of the Alternative Pathway
Bb
C3b
C3b
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Lytic pathway
Generation of C5 convertase leads to the
activation of the Lytic pathway
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Components of the lytic pathway
C6
C5
C 9
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Lytic pathwayC5-activation
C5
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Lytic pathwayassembly of the lytic complex
C6
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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
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Biological effects of C5a
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Biological properties of C-activation products
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Biological properties of C-activation products
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Biological properties of C-activation products
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Complement Deficiencies and DiseaseClassical
Pathway
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Complement Deficiencies and DiseaseLectin Pathway
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Complement Deficiencies and DiseaseAlternative
Pathway
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Complement Deficiencies and DiseaseAlternative
Pathway cont.
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Opsonization and phagocytosis
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C1qrs breakdown
C1Inh