Complement System. Jil Schrader 16 th of May 2018 Immunology Lecture

Transcription

1 Source: letzter Zugriff: Complement System Jil Schrader 16 th of May 2018 Immunology Lecture

2 Contents What is the complement system in general? C1-complex Source: Murphy et al.: Janeway s Immunology, 7th German edition, 2009 How is the complement system activated? Membrane Attacking complex Source: created by Sara Allyn Liva wikimediacommons How does it act and protect the body against pathogens? Crystal structure of C3bBb inhibited by SCIN. Source: Rooijakkers et al., Nat Immunol, Why does it only act against pathogens and doesn t also act against human cells? 2

3 The Greater Picture: Immune System Innate Immunity Adaptive Immunity Cellular Humoral Cellular Humoral Granulozytes Monozytes Makrophages Dendritic cells Mast cells Zytokines Complement System T- Lymphocytes B-Lymphocytes Antibodies à All work together somehow and are connected! 3

4 What is the Complement System (CS)? History Heat sensitive part of the plasma Heat-sensitive Non-specific Toxic effect àcomplement Heat-stable Specific Sensitizing effect Increases the opsonization and killing of bacteria Antibody opsonization is the process by which the pathogen is marked for ingestion and eliminated by the phagocytes. Wikipedia à activity of CS believed to complement the activity of the antibodies Known today : can also be activated without antibodies part of the innate immune system Jules Bordet, winner of the Nobel prize of Physiology and Medicine in 1919 Source: obel_prizes/medicine/laureat es/1919/bordet-bio.html; letzter Zugriff:

5 What is the Complement System (CS)? Consists of many different plasma proteins in their inactive form Zymogenes= inactive proteases, that are activated by fragmentation via other proteases Activation via triggered enzyme cascade à Amplification Inactive protease Cuts next zymogene Active protease 2 Cuts next zymogene activation Activated protease 1 Infection mediator Active protease 3 Infection mediator 5

6 Complement activation and way of acting Classical Pathway MB-Lectin Pathway Alternative Pathway Antigen:Antibody complexes Lectin binding to pathogen surface Pathogen surface, spontaneous activation Complement activation C3-convertase Recruitment of inflammatory cells Opsonization of pathogens Killing of pathogens 6

7 Classical Pathway of Activation Activation of the C1-complex activates the classical pathway C1 is always present in serum, but only operate on activating surface C1q binds to either of the three: Fc region of antibodies in antigen-antibody complexes Indirectly through C-reactive protein, which binds to N-Acetylglucosamine Directly to Pathogen à Conformational changeà autocatalytic activity of C1r starts cutting C1s into active Serinprotease X Source: Murphy et al.: Janeway s Immunology, 7 th German edition,

8 Classical Pathway of Activation Activated C1s cleaves C4 to C4a + C4b, which binds to the microbial surface C4b then binds C2, which is cleaved by C1s to C2a + C2b, forming the C4b2b complex C4b2b is an active C3 convertase cleaving C3 into C3a + C3b, which binds to the microbial surface or to the convertase itself One molecule of C4b2b can cleave up to 1000 C3 molecules to C3b, many bind to the surface Source: Murphy et al.: Janeway s Immunology, 7th German edition,

9 MB-Lectin Pathway of Activation Mannose-binding lectin Activation is similar to C1-Complex activation: Mannose-binding lektin (MBL) binds to mannose on pathogen surface Ficolines bind to specifically N-Acetylglucosamine of oligosaccharides Binding of MBL/Ficoline activates MASP-2 to cut C4 and C2 Ficoline C2bC4b build a complex that is a C3 convertase Source: Murphy et al.: Janeway s Immunology, 7 th German edition,

10 Alternative Pathway of Activation Does not depend on a protein binding a pathogen 1. Spontaneous separation of C3 into C3(H 2 O) à tickover 2. Factor B can bind 3. Plasmaprotease Factor D can cut Factor B into Ba +Bb 4. C3(H 2 O)Bb-complex is a C3 convertase in liquid solution 5. Cuts C3 into C3a +C3b, C3b sticks to Factor B, Factor D cuts into Ba and Bb, building the complex C3bBbà C3 convertase on cells Source: letzter Zugriff:

11 Complement activation and way of acting Classical Pathway MB-Lectin Pathway Alternative Pathway Antigen:Antibody complexes Lectin binding to pathogen surface Pathogen surface, spontaneous activation Complement activation C3-convertase Recruitment of inflammatory cells Opsonization of pathogens Killing of pathogens 11

12 C3-Convertase The Key Player Serinprotease cutting C3 into C3a + C3b Two forms: C2bC4b (classical and Lectin pathway) or C3bBb (alternative pathway) Regulation point à Development of C3-convertase crucial for the activation of the later complement system Crystal structure of C3bBb inhibited by SCIN. Source: Rooijakkers et al., Nat Immunol,

13 How is C3b effecting the infection? 1. Opsonization of pathogens C3b binds covalently onto pathogen, marking it for phagocytes, that have receptors for C3b 2. Recruitment of inflammatory cells Chemoattractors allure phagocytes 3. Killing of pathogens C3b binds to C3-convertaseà C5-Convertaseà C5b starts later Complement system: Series of polymerization reaction, where the terminal CS-fragments build a membrane-attacking complex à Pore in cell membrane of specific pathogens Membrane Attacking complex Source: created by Sara Allyn Liva wikimediacommons 13

14 Why does it only act against pathogens and doesn t also act against human cells? Activation of the CS mostly on surface of the pathogen that initiated the activation: C4b has reactive thioester group binding to surface of pathogens Active components of CS get inactivated fast if unbound if remaining unbound the thioester get hydrolysed rapidly à no diffusion to human cells Regulatory proteins interfere at certain points Source: Murphy et al.: Janeway s Immunology, 7 th edition,

15 Complement activation and way of acting Classical Pathway MB-Lectin Pathway Alternative Pathway Antigen:Antibody complexes Lectin binding to pathogen surface Pathogen surface, spontaneous activation Complement activation C3-convertase Recruitment of inflammatory cells Opsonization of pathogens Killing of pathogens 15

16 Take home message for you What is the CS in general? Mix of many plasma proteins and zymogenes in the innate immune system that interact with each other in order to opsonize and activate a series of inflammatory reactions How is the CS activated? Three pathways: Classical (Antibody-antigene complex), Lectin (pathogen surface) and Alternative (spontaneous on pathogen surface) pathwayà all activating C3-convertase Triggered enzyme cascades of proteases How does it act and protect the body? Recruitment of inflammatory proteins Opsonization of pathogens Killing the pathogens via a membrane attacking complex pore formation 16

17 Literature Murphy K, Travers P, Walport M, Janeway s immunology, Garland Sciences, 7 th German edition, Rooijakkers S H M, et al., Structural and functional implications of the complement convertase stabilized by a staphylococcal inhibitor, Nat Immunol., 10(7): , Pezzutto A, Ulrichs T, Burmester G-R, Aicher A, Taschenatlas der Immunologie, Georg Thieme Verlag, 1 st edition, Schütt C, Bröker B, Grundwissen Immunologie, Spektrum Akadeischer Verlag, 2 nd edition,

18 Do you have any questions? J 18