Chapter 6 Complement
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Transcript of Chapter 6 Complement
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Chapter 6Chapter 6
ComplementComplement
Chapter 6Chapter 6
ComplementComplement
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The end of 19 century
Jules Bordet (1870-1961)
Chapter 6 Complement
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• Fresh serum containing an antibacterial antibody was added to the bacteria at physiologic temperature (37℃), bacteria were lysed.
• If the serum was heated to 56℃ or more , it lost its lytic capacity.
• This loss of lytic capacity was not due to decay of antibody activity because antibodies are heat-stable and even heated serum was capable of agglutinating the bacteria.
• Bordet concluded that the serum must contain another , heat-labile component that assists the lytic function of antibodies, and this component was later given the name “complement”
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Definition of complement systemDefinition of complement system ::
A system of serum and cell surface proteins ( including more than 30 proteins ) that interact with one another and with other molecules of the immune system to generate important effectors of innate and adaptive immune response.
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Contents• PartⅠ The components and properties of
complement system• PartⅡ Activation of complement system• PartⅢ Regulation of complement system• Part Ⅳ Complement receptors• PartⅤ Biological functions of complement• PartⅥ Complement and disease
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PartⅠ The components and properties of complement system
(I) The components and nomenclature(I) The components and nomenclature of complement systemof complement system
(II) Physical and chemical features of complement(II) Physical and chemical features of complement
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(I). The components and nomenclature of (I). The components and nomenclature of complement systemcomplement system
1.1. Components participating complement activationComponents participating complement activation
• Classical pathway: C1 (C1q,C1r,C1s)Classical pathway: C1 (C1q,C1r,C1s) ,, C2C2 , , C3C3 , , C4C4
• MBLMBL (( mannan-binding lectin) pathway: MBL, MASP( MBL-associated mannan-binding lectin) pathway: MBL, MASP( MBL-associated serine protease) serine protease)
• Alternative pathway: factor B, factor DAlternative pathway: factor B, factor D
• Common terminal pathwayCommon terminal pathway :: C5C5 ,, C6C6 ,, C7C7 ,, C8C8 ,, C9C9
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2. Regulatory components of complement system
factor I, factor H, S protein, properdin(factor P), C1 inhibitor(C1 INH) , C4-binding protein(C4BP), SP40/40, membrane cofactor protein(MCP), decay accelerating factor(DAF), homologous restriction factor(HRF), membrane inhibitor of reactive lysis(MIRL)
3. Complement receptors
CR1~CR5, C3aR, C2aR, C4aR, etc
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Nomenclature of the complement system
• Intrinsic components in classical pathway:C1~C9
• Intrinsic components in alternative pathway: factor D
• Regulatory proteins:C1INH,C4BP• Cleaved fragments:C3a, C3b; C2a, C2b• Activated components:C1• Inactivated components:iC3b• Complement receptor:CR
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(Ⅱ) . The physical and chemical features of complement
1. Synthesized sites: liver, macrophage, small intestine epithelium 2. The concentration of complement in serum is stable( 10% of
serum proteins) , C3 is the highest in all of complement components:1~2 g/L
3. Heat–labile feature: 56℃ 30min—inactivation 0~10℃ for 3~5 days 4. The concentration of complement is the highest in the serum of guinea pig.
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humoural complements name Molecule weight (kDa) concentration(g/ml)
460
80
83 50 83 50 200 600 102 20
Classical pathway C1q C1r C1s C4 C2 C3 185 1300
24
Alternative pathway D factor B factor 90
1
210
MBL pathway MBP
30 x 3
1
Terminal pathway C5
204
70
C6 120 65
C7 120 55 C8 160 55
C9 70 60
Regulatory protein C1 INH
105
200
C4BP 550 250
Factor H 150 480
Factor I 88 35
Factor P 4 x 56 20
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PartⅡ Activation of the complement system
• The soluble proteins of the complement system are synthesized in the liver and are secreted as non-active forms called zymogens.
Zymogen: The cleavage is required for activation
• The cleavage of a zymogen usually produces a large active fragment with enzymatic activity and a small fragment with inflammatory effects.
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Three different pathwayspathways of complement activation:
1.Classical pathway: from C1 by Ag-Ab
2.Alternative pathway: from C3 by the surface of microbe
3.MBL pathway: from C4 and C2 by binding of MBL mannan on the surface of microbes
Terminal pathway : formation of MAC (membrane
attack complex), same in the three pathways
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(C4b,2a)
(C4b,2a,3b)
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Ⅰ. The Classical pathway of complement activation
1.Initiating substances: antigen-antibody complex or immune complex
2.Components: C1q ,C1r,C1s,C4,C2,C3,5,6,7,8,9
3.Process:
C1q,C1r,C1s C4,C2,C3,5,6,7,8,9
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The process of complement activation
in classical pathway:
1. Initiation step: recognizing unit (C1qrs),
activated C1
2. Activation step: activating unit( C4,C2,C3),
C3 convertase and C5 convertase
3. Effector step: membrane-attack complex (MAC) ,
C5~9
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1. Initiation step
recognizing unit (C1qrs) --- activated C1
• IgG1~3 and IgM can activate complement by classical pathway
• The complement component C1 binds to the Fc part of the antibodies(CH2 of IgG or CH3 of IgM), and then is turned into activated C1 (C1)
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monomer
pentamer
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C1q=6
2 C1r+2C1s+6C1q = C1
6
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The first protein in the classical pathway is C1
2 C1s2 C1r
C1q
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• IgG
The C1 must bind to at least two IgG molecules that are close enough together so that it can bind to both of them at the same time.
• IgMThe C1 must bind at least 2 CH3 domains of one IgM molecule to be activated.
IgM is the best complement activator because it is a pentamer.
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Bacteria with antigenic proteins on the surface
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After antibody binds to antigen on the surface of a pathogen , complement-binding sites are exposed
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IgM is the best activator of complement.
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C1 binds to at least two IgG molecules to be activated
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Binding of two or more of the C1q globular domains causes activation of C1r, which then make C1s activated.
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2. Activation step
Formation of C3 convertase ( C4b2a)
and C5 convertase(C4b2a3b)
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( 1 ) Formation of C3 convertase ( C4b2a)
C1
C4 , C2 C4b2a (C3 convertase) C4a,C2b
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The activated C1 cleaves C4 into C4b and C4a.
C4
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C4aC4b
C1 cleaves C4 to produce C4b and C4a.
The C4b fragment binds to the surface of the pathogen.
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C1 then cleaves C2 into C2b and C2a.
C2
C4b
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C2b
C2a
C4b
The activated C1 then cleaves C2 into C2b and C2a.
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C4b and C2b together form the C3 convertase(C4bC2a)
C3 convertase
C2a
C4b
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(2) Formation of C5 convertase
C1 C4 , C2 C4b2a (C3 convertase)
C4a,C2b
C3 C4b2a3b (C5 convertase) C3a
• This is the most important step in the classical pathway
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C3 convertase
C3
C3
C3
C3 convertase cleaves C3 to C3a and C3b
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C3 convertase
C3
C3b
C3
C3 convertase cleaves C3 into C3a and C3b.
C3a
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C3b
The C3b covalently binds to C4b2a to form C4b2a3b complex,C5 convertase
C3b
C3a
C3a
C5 convertase
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4b2a
C2b
C4b2a
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C4b,2a,3b
C4b,2a,3b C4b,2a,3b
C4b2a
C2a
C4b2a
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( C5 convertase )
Classical pathway
IgM/IgG –Ag complexIgM/IgG –Ag complex
C1q : r : s
C4 C4b + C2
C4a C2b
C4b2a
C3 C3b
C3a
Ca++
Mg++
Ca++
( C3 convertase)
C4b2a3b
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3. Effector step: Common terminal pathway
Formation of the Membrane Attack Complex (MAC)
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. The MAC causes lethal ionic and osmotic changes in cells.
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C5 convertase cleaves C5 into C5a and C5b.
C5 convertase
C5b
C5a
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C5b
C5b binds to the surface and C6 binds to C5b,stabilizing it.
C6
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C5b
C6C7
Then C7 binds. C7 inserts into the phospholipid bilayer of the plasma membrane.
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C5b
C6
C7
Then C8 binds to the complex and alsoinserts into the bilayer.
C8
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C5b
C6
C7
Finally, C9 molecules bind to the complex and polymerize. Twelve to fifteen C9 molecules form a pore in the membrane.
C8
C9
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C5b
C6
C7
Twelve to fifteen C9 molecules form a pore in the membrane.
C8
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C5b
C6
C7
The membrane attack complex is a pore in the plasma membrane.
C8
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Effect of MAC• On the surface of cell: lyse the cell
• In the serum:SC5b~7, SC5b~8, SC5b~9
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Ⅱ. Alternative pathway
1.The initiating substances:
some components of microbial cell surface
aggregated IgA or IgG4
---providing a surface for binding of complement
2.Components and process: factor D, factor B, C3,5,6,7,8,9
3.Function: participate in non–specific immunity
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• Normally, C3 in plasma is being continuously cleaved at a low rate to generate C3b in a process.
• A small amount of the C3b in the fluid phase
is unstable and inactive.
• C3b may become covalently attached to the surfaces of cells, including microbes.
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The process of complement activation
in alternative pathway:
1. Initiation step: C3b binds to microbial surface,
binds factor B, and forms C3 convertase.
2. Activation step: form C5 convertase
3. Effector step: membrane-attack complex (MAC) ,
C5-9
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Spontaneous conversion or from classical pathway
C3b
B factor
D factor
C3bBb C3bBbP( C3
convertase)
C3
C3b
C3bnBb ( C5 convertase)enlarge
P factor
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C3bC3bB C3C3
positive feedback loop of C3
D factor
C3b
Bb
B factor
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Important characteristics
In alternative pathway, complement can recognize self from nonself----complement regulatory protein
Alternative pathway is the important enlarge mechanism of complement
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Ⅲ. MBL or Lectin Pathway 1.Initiating substances: MBL combine with
mannose on the surface of microbe.
2.Components: Mannose-binding lectin (MBL) , MBL-associated serine protease (MASP) , C4,C2,C3,5,6,7,8,9
3.Process:
MBL-mannose-MASP----C4,C2,C3,5,6,7,8,9
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• The MBL and c-reactive protein were produced by liver after microbe infection
• MBL binds to mannose residues on polysaccharide of microbe
• The MBL, structurally similar to C1q.
The MBL activate MASP( mannan-associated serine protease) and then MASP activate C4,C2(MASP is similar to C1r and C1s)
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Mannose-binding lectin
MBL is Structurally similar to C1q
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MBL binds to mannose on glycoproteinson the surface of microorganisms. Then MASPsbind to it.
MASP-1MASP-1
MASP-2MASP-2
MASP = mannose associated serine protease
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mannose
MBL
mannose
MASP
C4 C4a + C4b
C2 C2a + C2b
C4b2a(C3
convertase)
+ MASP
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(C4b,2a)
(C4b,2a,3b)
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PartⅢ Regulation of complement system
• The explosive potential of the complement system requires that it is kept under tight control.
• At least there are 12 proteins known that do this.
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Mechanism of complement regulation
Ⅰ. Regulation of self-inactive :decay
Ⅱ. Action of regulatory factors
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Ⅰ. Regulation of self-inactive : decay
Spontaneous decay of complement Cleaved components C3b,C4b,C5b C3 convertase (C4b2a,C3bBb) C5 convertase (C4b2a3b,C3bnBb)
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Ⅱ. Action of regulatory factors
1. Regulation of C1 activation: C1 inhibitor (C1INH) binds to sites on
activated C1r and C1s shutting down their proteolytic activity.
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Inhibition of C1 activation
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2. Regulation of C3 convertase formation
Factor H removes Bb from the alternative pathway C3 convertase,breaking the positive feedback loop.
Factor I inactivates C3b and C4b DAF -----binds to C4b and C2a, preventing formation of C3 convertase
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H and I factors depredate C3b
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Inhibition of the C3 convertase formation
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Inhibition of the C3 convertase formation
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3. Regulation of MAC
Homologous restriction factor(HRF): HRF(C8bp )------interferes with binding of
C9 and C8, prevents formation of MAC
Membrane inhibitor of reactive lysis(MIRL): MIRL(CD59)------interferes with binding of C5b6 complex and C7,C8, and prevents formation of MAC
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Regulation of terminal pathway
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Part Ⅳ Complement receptors
1.CR1(CD35,C3b/C4bR): Mainly express on blood cells Combine with C3b and C4b with
high affinity Participate in opsonization,
immune adhesion et al
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2. CR2(CD21) :Mainly express on B cellCombine with C3dg,C3d and iC3bPromote B cell to be activated Act as the receptor of EBV(epstein-
barr virus)
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3. CR3 :• Combine with iC3b• Neutrophil,phagocyte,B cell,NK
4. CR4(CD11c/CD18), CR5 :• Combine with iC3b and C3dg• Neutrophil,phagocyte
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PartⅤ Biological functions of
complement
Ⅰ. Lyse bacteria and cells Ⅱ. Opsonization Ⅲ. Elimination of immune complex Ⅳ. Induce inflammation reactionⅤ. Regulation of immunity
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I. Lyse bacteria and cells
Complement activation by
classical pathway, MBL pathway or alternative pathway leads to the formation of MAC.MAC mediates lysis of target cell.
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C3b,C4b ---- CR1
Ⅱ. Opsonization:
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C3b and C4b in the surface of microorganisms attach to C-receptor (CR1) on phagocytic cells and promote phagocytosis.
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Ⅲ. Elimination of immune complex
Ag-Ab-C3b complex can adhere to the C3bR which exists on the surface of RBC or platelet.This facilitates phagocytosis of immune complex by phagocytes.
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Clearance of immune complex -----Immune adherence C3b,C4b----CR1
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C3b coats immune complexes facilitating binding to CR1 on erythrocytes, which carry the immune complexes to the liver or spleen where they can be removed and phagocytized
C4b,2a,3b
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Ⅳ. Induce inflammatory reaction
Kinin-like action: C2aAnaphylatoxins:C3a,C4a,C5aChemokine-like action: C5a
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Ⅴ. Regulation of immunity
Help APC to present Ag
Promote the proliferation and differentiation of B cell
Enhance ADCC by CR1
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Chemotaxis effect
Lyse target cell degranulation
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PartⅥ Complement and disease
1. Congenital defects of the complement system
• C1INH defect C2a,C3a,C5a hereditary angioneurotic edema(HAE)
2. Hypercomplementemia• Acute inflammation, cancer
3. Hypocomplementemia• Chronic inflammation, some autoimmune
disease