Transcript The Complement System and the Kinin System

Biomaterials Research - Manfred Maitz
The Complement System
and Kinin System
Manfred Maitz
www.manfred.maitz-online.de
Biomaterials Research - Manfred Maitz
Outline
Complement System
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Background
Reactions of the complement cascade
Regulation and activation of the complement cascade
Effects of Complement activation
Evaluation methods
Consequences for biomaterials
Kinin System
• Reactions and interactions with other systems
Summary and Conclusions
Biomaterials Research - Manfred Maitz
Background
• Evolutionary old system
• Non specific defence system
– Constitutive
• Very fast
– Selectivity and self-tolerance
– Activation by antibodies possible
• Interaction with the specific immune system
• Functions
– Lysis of cells/ bacteria and viruses
– Opsonization for phagocytes
– Immune Clearance
• Similarities and crosstalks with the clotting cascade
– Cascade of serine proteases, which activate each other
– Two (three) pathways of activation
– Factor XIIa (Hageman-Factor) activates both the clotting cascade
and the complement cascade
Biomaterials Research - Manfred Maitz
Outline
Complement System
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Background
Reactions of the complement cascade
Regulation and activation of the complement cascade
Effects of Complement activation
Evaluation methods
Consequences for biomaterials
Kinin System
• Reactions and interactions with other systems
Summary and Conclusions
Biomaterials Research - Manfred Maitz
The Membrane Attack Complex
C5a
C5
70-100 Å
C8
C9C9
C9
C9
C9
C9
C9
C9 C9
C9C9
C6 C5b C7
Biomaterials Research - Manfred Maitz
The Complement Cascade
The Alternative Pathway
C3bB
P
C3a
Properidin
Ba
B
C3b
C3
C3bBb
C3bBbP
C3bBb3b
C5a
D
C3a
B
C3iBb
C3iB
Ba
C3i
C3
C5
The Tick-over Activation
C3
The Classical Pathway
C5b
Antibody +
C1qrs
C4
C4b
C4a
C4b2a
C2
C2b
C4b2a3b
C3
C3a
Biomaterials Research - Manfred Maitz
Outline
Complement System
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•
•
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Background
Reactions of the complement cascade
Regulation and activation of the complement cascade
Effects of Complement activation
Evaluation methods
Consequences for biomaterials
Kinin System
• Reactions and interactions with other systems
Summary and Conclusions
Biomaterials Research - Manfred Maitz
Regulation of the Complement Cascade
• Short half-time of
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C3b
C3bBb
C5b
• C1 inhibitor
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Inhibits the C1s activity
• Protein S in Serum
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
Binds to C5b67
Inhibits Formation of the Membrane Attack Complex
• HRF or CD59
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Bind to C8
Inhibits C9 binding
• Factor H
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Binds to C3b
Facilitates binding of Factor I
 cleaves C3b to inactive iC3b
 cleaves C4b to inactive fragments
• Decay Accelerating Factor
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Increased dissociation of C3 convertase (both pathways)
Biomaterials Research - Manfred Maitz
Complement Activation
General
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Hydrophobic surfaces
Oxides
Strong binding of C3(b) to nucleophilic groups (-NH2, -OH)
Higher absorption of C3 to crystalline TiO2 than to amorphous
Kallikrein directly activates C5
Plasmin directly activates C5
Classical Pathway
– Antibodies IgM, IgG1, IgG2, IgG3
– Lectin via the mannan binding protein (MBP) “Lectin Pathway”
– Hageman Factor (F XIIa)
• Rough surfaces
– C-reactive protein (CRP)
– (Zirkonium, transiently)
Alternative Pathway
– PE debries
– Acetylated chitosan
Biomaterials Research - Manfred Maitz
Outline
Complement System
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Background
Reactions of the complement cascade
Regulation and activation of the complement cascade
Effects of Complement activation
Evaluation methods
Consequences for biomaterials
Kinin System
• Reactions and interactions with other systems
Summary and Conclusions
Biomaterials Research - Manfred Maitz
Complement Receptors
Receptor
Ligand
Cellular distribution
CR1 (CD35)
C3b>iC3b
C4b
B-Cells
Phagocytes
RBC
follicular dendritic cells
CR2 (CD21)
iC3b
C3dg
B cells
epithelial cells
CR3 (CD18/11b)
iC3b
Zymosan
ICAM-1
Phagocytes
NK Cells
follicular dendritic cells
CR4 (CD18/11c)
iC3b
Phagocytes
Biomaterials Research - Manfred Maitz
Anaphylatoxins
Fragments C5a, C3a, C4a
• Degranulation of Phagocytes
– Reactive oxygen species
– Prostaglandins
– Monocytes
 IL-1, IL-6
– Mast cells
 Histamine
• Chemotaxis
– Only C5a
Biomaterials Research - Manfred Maitz
Consequences in vitro
• Lysis of “innocent” neighbour cells
– Red blood cells
• Activation of phagocytic cells
– Release of reactive oxygen species
– Release of mediators
Biomaterials Research - Manfred Maitz
Consequences in vivo
• Factors of complement activation at revised hip implants
• One single study
(Tang L. et al. J Biomed Mater Res 41: 333-340 (1998))
Au-Mercaptoglycerol induces strong inflammatory
response in control animals.
No reaction in Complement-depleted animals.
Biomaterials Research - Manfred Maitz
Outline
Complement System
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Background
Reactions of the complement cascade
Regulation and activation of the complement cascade
Effects of Complement activation
Evaluation methods
Consequences for biomaterials
Kinin System
• Reactions and interactions with other systems
Summary and Conclusions
Biomaterials Research - Manfred Maitz
The Complement Cascade
The Alternative Pathway
C3bB
P
C3a
Properidin
Ba
B
C3b
C3
C3bBb
C3bBbP
C3bBb3b
C5a
D
C3a
B
C3iBb
C3iB
Ba
C3i
C3
C5
The Tick-over Activation
C3
The Classical Pathway
C5b
Antibody +
C1qrs
C4
C4b
C4a
C4b2a
C2
C2b
C4b2a3b
C3
C3a
Biomaterials Research - Manfred Maitz
Methods for Investigation
General/Common pathway
– Lysis of sheep red blood cells
– Solid phase methods (ELISA, RIA)
• Products: C3a, C5a, sC5b-9
• Consumption of C3
– Ellipsometry
Classical Pathway
– Measurement of C1qrs
– Measurement of C2b or C4b2a
Alternative Pathway
– Measurement of Ba or C3bBb
– Measurement of Properidin
Biomaterials Research - Manfred Maitz
Outline
Complement System
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•
•
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Background
Reactions of the complement cascade
Regulation and activation of the complement cascade
Effects of Complement activation
Evaluation methods
Consequences for biomaterials
Kinin System
• Reactions and interactions with other systems
Summary and Conclusions
Biomaterials Research - Manfred Maitz
Biomaterials Consequences
• Testing for complement activation included
in standard test programs
• Covalent binding of Factor H to the surface
of a blood contacting implant
– Reduced C3a, sC5b-9
• Inhibition of FXII activation by Heparin-ATIII
Biomaterials Research - Manfred Maitz
Outline
Complement System
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Background
Reactions of the complement cascade
Regulation and activation of the complement cascade
Effects of Complement activation
Evaluation methods
Consequences for biomaterials
Kinin System
• Reactions and interactions with other systems
Summary and Conclusions
Biomaterials Research - Manfred Maitz
The Clotting Cascade
Intrinsic Pathway
Extrinsic Pathway
Surface Contact
Collagen
FXII activator
F XII
Tissue/Cell Defect
F XIIa
F XI
F IXa
Ca2+
F VII
F III (Tissue
Thromboplastin)
F VIIIa
Platelet Factor 3
Factor F X
Ca2+
Factor F Xa
F Va
Prothrombin I
F XIIIa
Crosslinked
Fibrin Meshwork
Ca2+
F XIa
Ca2+
F IX
F VIII
F VIIa
Ca2+
Ca2+
Factor F X
FV
Thrombin
F XIII
Fibrin
polymers
Fibrin
monomers
Fibrinogen
Biomaterials Research - Manfred Maitz
The Kinin System
Surface
F XII
F XIIa
Pre-Kallikrein
Kininogen
HMWK, LMWK
Clotting Cascade
(intrinsic pathway)
Fibrinolytic
Pathway
Complement
Activation
Kallikrein
Kinin
e.g. Bradykinin
Effects
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Plasmin
vascular smooth muscle relaxation
Increased permeability of blood vessels  Oedema
Pain
Interaction with clotting cascade
Interaction with fibrinolytic cascade
Interaction with complement cascade
Plasminogen
Biomaterials Research - Manfred Maitz
Outline
Complement System
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•
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Background
Reactions of the complement cascade
Regulation and activation of the complement cascade
Effects of Complement activation
Evaluation methods
Consequences for biomaterials
Kinin System
• Reactions and interactions with other systems
Summary and Conclusions
Biomaterials Research - Manfred Maitz
Conclusions
• The blood plasma has four cascade systems
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Clotting cascade
Fibrinolytic cascade
Complement system
Kinin system
• All four systems are proteolytic cascades
• Besides the main streams there are many cross connections with
minor importance
– Common activators and cross activation
– Common inhibitors/ regulators
• C1 Esterase Inhibitor
• Hageman Factor (F XII)
– Effective in all systems
– Directly activated by surfaces (esp. negatively charged)
– 1-3% people have deficiencies without clinical syndromes
• Plasmin
– Directly effective in three systems
– Indirectly also effective on the clotting cascade
Biomaterials Research - Manfred Maitz
Biomaterials Research - Manfred Maitz
General Conclusions
Biomaterials research is an interdisciplinary field
• Physics/Materials science
– Modification and check of physical surface properties
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Roughness
Surface free energy
Hardness, tribological properties
Surface charges, electrical and electronic properties
– Bulk properties
• Chemistry
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Corrosion
Polymers
Chemical surface modification
Chemical reactions of the biomolecules with the biomaterial
• Life science
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Knowledge about the normal biochemical situation
Knowledge about changes at certain diseases
Check of influences due to the biomaterial
Support of the physiological situation