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Biomaterials Research - Manfred Maitz The Complement System and Kinin System Manfred Maitz www.manfred.maitz-online.de Biomaterials Research - Manfred Maitz 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 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 • • • • • • 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 • • • • • • 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 – – – 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) Biomaterials Research - Manfred Maitz 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 Biomaterials Research - Manfred Maitz 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 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 • • • • • • 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 • • • • • • 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 • • • • • • 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 • • • • • • 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 • • • • • • 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 – – – – 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 • • • • 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
