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The%20Complement%20System%20and%20Kinin%20System

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Title: The%20Complement%20System%20and%20Kinin%20System


1
The Complement Systemand Kinin System
  • Manfred Maitz
  • www.manfred.maitz-online.de

2
Outline
  • Complement System
  • 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

3
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

4
Outline
  • Complement System
  • 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

5
The Membrane Attack Complex
C5
C9
C9
C9
C9
C9
C9
C9
C9
C9
C9
C9
C7
C8
C6
6
The Complement Cascade
C5a
C5
7
Outline
  • Complement System
  • 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

8
Regulation of the Complement Cascade
  • Short half-time of
  • C3b
  • C3bBb
  • C5b
  • C1 inhibitor
  • Inhibits the C1s activity
  • Protein S in Serum
  • Binds to C5b67
  • Inhibits Formation of the Membrane Attack Complex
  • HRF or CD59
  • Bind to C8
  • Inhibits C9 binding
  • Factor H
  • Binds to C3b
  • Facilitates binding of Factor I
  • cleaves C3b to inactive iC3b
  • cleaves C4b to inactive fragments
  • Decay Accelerating Factor
  • Increased dissociation of C3 convertase (both
    pathways)

9
Complement Activation
  • General
  • 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

10
Outline
  • Complement System
  • 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

11
Complement Receptors
Receptor Ligand Cellular distribution
CR1 (CD35) C3bgtiC3bC4b B-CellsPhagocytesRBCfollicular dendritic cells
CR2 (CD21) iC3bC3dg B cellsepithelial cells
CR3 (CD18/11b) iC3bZymosanICAM-1 PhagocytesNK Cellsfollicular dendritic cells
CR4 (CD18/11c) iC3b Phagocytes
12
Anaphylatoxins
  • Fragments C5a, C3a, C4a
  • Degranulation of Phagocytes
  • Reactive oxygen species
  • Prostaglandins
  • Monocytes ? IL-1, IL-6
  • Mast cells? Histamine
  • Chemotaxis
  • Only C5a

13
Consequences in vitro
  • Lysis of innocent neighbour cells
  • Red blood cells
  • Activation of phagocytic cells
  • Release of reactive oxygen species
  • Release of mediators

14
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.

15
Outline
  • Complement System
  • 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

16
The Complement Cascade
C5a
C5
17
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

18
Outline
  • Complement System
  • 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

19
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

20
Outline
  • Complement System
  • 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

21
The Clotting Cascade
Intrinsic Pathway
Extrinsic Pathway
Surface Contact Collagen FXII activator
Tissue/Cell Defect
F XIIa
F XII
F VII
F VIIa
Ca2
F XIa
F XI
Ca2
F IXa
F IX
F III (Tissue Thromboplastin)
Ca2
F VIIIa
F VIII
Platelet Factor 3
Factor F Xa
Factor F X
Factor F X
Ca2
Ca2
Prothrombin I
Thrombin
Ca2
F XIIIa
F XIII
Fibrinmonomers
Fibrinpolymers
Fibrinogen
CrosslinkedFibrin Meshwork
22
The Kinin System
  • Effects
  • vascular smooth muscle relaxation
  • Increased permeability of blood vessels ? Oedema
  • Pain
  • Interaction with clotting cascade
  • Interaction with fibrinolytic cascade
  • Interaction with complement cascade

23
Outline
  • Complement System
  • 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

24
Conclusions
  • The blood plasma has four cascade systems
  • 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

25
(No Transcript)
26
General Conclusions
  • Biomaterials research is an interdisciplinary
    field
  • Physics/Materials science
  • Modification and check of physical surface
    properties
  • Roughness
  • Surface free energy
  • Hardness, tribological properties
  • Surface charges, electrical and electronic
    properties
  • Bulk properties
  • Chemistry
  • Corrosion
  • Polymers
  • Chemical surface modification
  • Chemical reactions of the biomolecules with the
    biomaterial
  • Life science
  • Knowledge about the normal biochemical situation
  • Knowledge about changes at certain diseases
  • Check of influences due to the biomaterial
  • Support of the physiological situation
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