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The Complement System and Kinin System. Manfred Maitz www.manfred.maitz-online.de. Outline. Complement System Background Reactions of the complement cascade Regulation and activation of the complement cascade Effects of Complement activation Evaluation methods

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the complement system and kinin system

The Complement Systemand Kinin System

Manfred Maitz

www.manfred.maitz-online.de

outline
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

background
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
outline4
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

the membrane attack complex

C5a

70-100 Å

C5b

The Membrane Attack Complex

C5

C9

C9

C9

C9

C9

C9

C9

C9

C9

C9

C9

C7

C8

C6

the complement cascade

The Alternative Pathway

C3

P

C3a

Properidin

Ba

B

C3b

C3bB

C3bBb

C3bBbP

C3bBb3b

D

B

C3a

C3iBb

C3iB

C3i

C3

Ba

The Tick-over Activation

C3

The Classical Pathway

C5b

Antibody + C1qrs

C4

C4b

C4b2a

C4b2a3b

C2

C3

C2b

C3a

C4a

The Complement Cascade

C5a

C5

outline7
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

regulation of the complement cascade
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)
complement activation
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
outline10
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

anaphylatoxins
Anaphylatoxins

Fragments C5a, C3a, C4a

  • Degranulation of Phagocytes
    • Reactive oxygen species
    • Prostaglandins
    • Monocytes  IL-1, IL-6
    • Mast cells Histamine
  • Chemotaxis
    • Only C5a
consequences in vitro
Consequences in vitro
  • Lysis of “innocent” neighbour cells
    • Red blood cells
  • Activation of phagocytic cells
    • Release of reactive oxygen species
    • Release of mediators
consequences in vivo
Consequences in vivo
  • Factors of complement activation at revised hip implants
  • One single study(Tang L. et al.J Biomed Mater Res41: 333-340 (1998))

Au-Mercaptoglycerol induces strong inflammatory response in control animals.

No reaction in Complement-depleted animals.

outline15
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

the complement cascade16

The Alternative Pathway

C3

P

C3a

Properidin

Ba

B

C3b

C3bB

C3bBb

C3bBbP

C3bBb3b

D

B

C3a

C3iBb

C3iB

C3i

C3

Ba

The Tick-over Activation

C3

The Classical Pathway

C5b

Antibody + C1qrs

C4

C4b

C4b2a

C4b2a3b

C2

C3

C2b

C3a

C4a

The Complement Cascade

C5a

C5

methods for investigation
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
outline18
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

biomaterials consequences
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
outline20
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

the clotting cascade

F Va

F V

The Clotting Cascade

Intrinsic Pathway

Extrinsic Pathway

Surface Contact

Collagen

FXII activator

Tissue/Cell Defect

F XII

F XIIa

F VIIa

F VII

Ca2+

F XI

F XIa

Ca2+

F IX

F IXa

F III (Tissue Thromboplastin)

Ca2+

F VIII

F VIIIa

Platelet Factor 3

Factor F X

Factor F Xa

Factor F X

Ca2+

Ca2+

Prothrombin I

Thrombin

Ca2+

F XIIIa

F XIII

Fibrinpolymers

Fibrinmonomers

Fibrinogen

CrosslinkedFibrin Meshwork

the kinin system

Surface

Fibrinolytic Pathway

Clotting Cascade (intrinsic pathway)

F XII

F XIIa

Plasmin

Complement Activation

Kallikrein

Pre-Kallikrein

Plasminogen

KininogenHMWK, LMWK

Kinine.g. Bradykinin

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
outline23
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

conclusions
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
general conclusions
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