Complement System-Jil Schrader · Immunology, 7thGerman edition, 2009 Membrane Attacking complex Source:createdby„Sara Allyn Liva“ wikimediacommons ComplementSystem –Jil Schrader

Complement SystemJil Schrader – 16th of May 2018 – Immunology Lecture

Source: https://bestprac.dk/2017/05/30/diagnosticering-af-almindelig-variabel-immundefekt-cvid-2/, letzter Zugriff: 14.05.2018

Contents

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What is the complement system in general?

How is the complement system activated?

Why does it only act against pathogens and doesn’t also act against human cells?

How does it act and protect the body against pathogens? Crystal structure of C3bBb inhibited by SCIN.Source: Rooijakkers et al., Nat Immunol, 2009.

C1-complex Source: Murphy et al.: Janeway’sImmunology, 7th German edition, 2009

Membrane Attacking complexSource: created by „Sara Allyn Liva“ wikimediacommons

Complement System –Jil Schrader – 16th of May 2018- Immunology Lecture

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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!


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What is the Complement System (CS)? History

• Heat sensitive part of the plasma

Source: https://www.nobelprize.org/nobel_prizes/medicine/laureates/1919/bordet-bio.html; letzter Zugriff: 10.05.18

Jules Bordet, winner of the Nobel prize ofPhysiology andMedicine in 1919

Heat-sensitiveNon-specificToxic effectàcomplement

Heat-stableSpecificSensitizing 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


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• 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

What is the Complement System (CS)?activation

Inactive protease

Cuts next zymogene

Active protease 2

Infection mediator

Active protease 3 Infection mediator

Cuts next zymogene

Activated protease 1


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Complement activation and way of actingClassical Pathway MB-Lectin Pathway Alternative Pathway

Antigen:Antibodycomplexes

Lectin binding to pathogen surface

Pathogen surface, spontaneous activation

Complement activation

Recruitment of inflammatory cells

Opsonization of pathogens

Killing of pathogens

C3-convertase


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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

Source: Murphy et al.: Janeway’s Immunology, 7th German edition, 2009

X 500 000


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Classical Pathway of ActivationActivated 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



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MB-Lectin Pathway of Activation

• 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

• C2bC4b build a complex that is a C3 convertase

Mannose-binding lectin

Ficoline



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Alternative Pathway of Activation• Does not depend on a protein binding a

pathogen

Source: https://www.researchgate.net/figure/Alternative-complement-pathway-Notes-The-alternative-pathway-is-triggered-by-the_fig2_230659108; letzter Zugriff: 12.05.18

1. Spontaneous separation of C3 into C3(H2O) à “tickover”

2. Factor B can bind3. Plasmaprotease Factor D can cut Factor B into Ba

+Bb4. C3(H2O)Bb-complex is a C3 convertase in liquid

solution5. 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


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C3-convertase


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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, 2009.


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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 complexSource: created by „Sara Allyn Liva“ wikimediacommons


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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, 7th edition, 2009


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C3-convertase


Take home message for you

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• 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

What is the CS in general?

How is the CS activated?

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

• 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


Literature

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• Murphy K, Travers P, Walport M, Janeway’s immunology , Garland Sciences, 7th

German edition, 2009.

• Rooijakkers S H M, et al., Structural and functional implications of the complement

convertase stabilized by a staphylococcal inhibitor, Nat Immunol., 10(7): 721–727, 2009.

• Pezzutto A, Ulrichs T, Burmester G-R, Aicher A, Taschenatlas der Immunologie, Georg

Thieme Verlag, 1st edition, 2007.

• Schütt C, Bröker B, Grundwissen Immunologie, Spektrum Akadeischer Verlag, 2nd edition,

2009.


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Do you have any questions? J


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Complement System-Jil Schrader · Immunology, 7thGerman edition, 2009 Membrane Attacking complex Source:createdby„Sara Allyn Liva“ wikimediacommons ComplementSystem –Jil Schrader