Complement System (Week 4) Flashcards
complement system
- proteins that mark
pathogens for degradation - Important to both innate and adaptive immunity for eliminating pathogens and dying cells
- Complement protein coating of
pathogens = increased phagocytosis by neutrophils and macrophages
Complement activation
- cascade of enzymatic reactions to cleave and activate proteases
- Complement component 3 (C3) protein cleaved into C3a and C3b fragments
- C3b attached to pathogen surface
3 Major Pathways of Complement
- Alternative pathway: first to act
- Lectin pathway: second to act
- Classical pathway: third to act
Alternative pathway
pathogen surface creates local environment conducive to complement activation
1. Hydrolysis of C3 protein = iC3
2. iC3 binds Factor B
3. Factor D cleaves this creating Bb (protease) attached to iC3 = iC3Bb and Ba
4. iC3Bb (C3 Convertase) cleaves C3
Lectin pathway
mannose-binding lectin binds to pathogen surface
1. MBL binds pathogen surface, activating MASP-2
2. C4 binds MBL and is cleaved into C4a (released) and C4b (fixed) by MASP-2
3. C2 binds MBL and gets cleaved into C2a and C2b (released) by MASP-2
4. C2a binds to surface C4b forming classical C3 convertase, C4b2a
5. C4b2a binds C3 and cleaves it to C3a and C3b
Classical pathway
C-reactive protein or antibody binds to specific antigen on pathogen surface
- Very similar to lectin pathway
- C1 binds to C-reactive protein
- C1 cleaves both C4 and C2 in the pathway
- can also be activated by antibody binding to pathogen (slower)
What is different in the alternative pathway when it occurs at the pathogen surface?
- C3b not iC3 is involved
- C3 convertase = C3bBb
1. C3b binds Factor B
2. Factor D cleaves this creating Bb (protease) attached to C3b = C3bBb and Ba
3. C3bBb cleaves C3
C3a and C5a
- (soluble) proteins induce local
inflammation = Anaphylatoxins - mediate immune cell
migration, cytokine production
and function
How do anaphylatoxins work?
- act on blood vessels to increase vascular permeability
- increased permeability allows increased fluid leakage from blood vessels and extravasation (leakage) of complement and other plasma proteins at site of infection
- migration of monocytes and neutrophils from blood into tissue is increased
- microbicidal (destruction of bacteria) activity of macrophages and neutrophils is increased
complement control proteins
- either stabilize or degrade C3b
includes: - properdin (factor P)
- factor H
- Decay accelerating factor (DAF)
- membrane cofactor protein
Properdin (Factor P)
- Complement control protein
- increased complement activation by binding C3bBb
- stabilizes it on pathogen surface
Factor H
- Complement Control Protein
- protein that binds C3b and
promotes its cleavage by Factor I
Membrane cofactor protein (MCP)
- Complement Control Protein
- can dissociate C3bBB like DAF and
promotes C3b cleavage by Factor I = inactive iC3b
Decay Accelerating Factor (DAF)
- Complement Control Protein
- binds C3bBb
- promotes dissociation of C3b and Bb = inactive
Mannose binding lectin (MBL)
- C-type Lectin
- Binds mannose in carbohydrates of
pathogens and acts as an opsonin (tag foreign substances for phagocytosis) - Circulates as a complex with two zymogens, MBL-associated serine proteases: MASP1 and MASP2
C-reactive Protein (CRP)
- member of the pentraxin family
- Acts like an opsonin to initiate Classical Complement Pathway
- C1 binds to C-reactive protein, gets activated and binds to C4
- C4 is cleaved into C4a (released)
and C4b (fixed)
Antibodies in Classical complement pathway
- Antibodies act as opsonins that recruit the C1 protein like C-reactive proteins
1. C1 protein binds to antibodies on pathogen surface
2. C1 cleaves C4 and C2
3. C1 cleaves C2, creating C3 convertase, C4b2a
4. C3 convertase hydrolyzes C3
Membrane Attack Complex (MAC)
- large pore assembled in pathogen membrane to kill them
- comprises C5, C6, C7, C8 and C9 and is activated by all three pathways of complement
How membrane attack complex (MAC) is activated?
- C5 convertase = C3b2Bb (Alternative pathway)
- C5 binds to C3b2Bb and is cleaved into C5a (released) and C5b (initiator of MAC)
- Once C5b is made, C6 and C7 bind C5b
- C5bC6C7 inserts into membrane
- C8 binds and inserts into membrane
- C9 polymerizes and forms MAC
S protein, Clusterin and Factor J
- complement control proteins
- prevent C5b, C6 and C7 to insert into membrane
- does not allow MAC to form
Homologous Restriction Factor (HRF) and CD59 (Protectin)
- complement control proteins
- CD59 binds to C5b678 complex and prevents recruitment of C9 to form the pore
- prevent C9 recruitment and
polymerization - does not allow MAC to form
