Complement Flashcards
what does the complement systems consist of in steady state conditions (2)
- collection of heat labile serum proteins that circulate the blood
- most are zymogens, inactive precursors of enzymes
complement system: evolution (2)
- system is evolutionary conserved
- present in invertebrates to more complex vertebrates
complement system abbreviation
C’
complement system: characteristic of activation (2)
- acts in a triggered cascade
- each reaction on the cascade results in activation of another C’ component
how can the complement system be activated (2)
- IgG and IgM bind to invading pathogens
- C1 binds to the Fc portion of IgG and IgM antibodies
what does complement activation results in (3)
- opsonization and destruction of the pathogen
- recruitment of cells involved in inflammation
- direct lysis of gram negative bacteria
what occurs to the complement system is the blood is heated
- killing activity of the system disappears due to heat-labile nature of the proteins
what are the proteins involved in the complement system (8)
- initiators
- convertase activators
- enzymatic mediators
- opsonins
- anaphalotoxins
- membrane attack complex
- complement receptors
- regulatory proteins
complement system: pathways (3)
- classical
- lectin
- alternative
what do all complement system pathways generate
- C3 convertase
C’: classical pathway activation (2)
- C1 (C1q, C1r, C1s) usually interacts with Ag-Ab complexes
- activates C4 and C2
C’: lectin pathway initial activation (2)
- mannose binding lectin (MBL) and ficolins bind carbohydrates on pathogen surface
- activates MBL associated proteases (MASPs)
C’: alternative pathway activation
- C3b undergoes spontaneous hydrolysis to C3(H2O)
what is the result of C3 convertase generation (2)
- cleavage of C3
- leaves C3b bound to microbial surface and releases C3a
C3 convertase: classical or lectin
- C4b2a
C3 convertase: alternative
- C3bBb
lectin pathway after activation (5)
- activated MASP-2 cleaves C4 to C4a and C4b
- C4b binds to microbial surface and C2
- C2 is cleaved by MASP-2 into C2a and C2b to form the C4b2a complex
- C4b2a is a C3 convertase, cleaving up to 1000 C3 to C3a and C3b
- C3b bind to microbial surface or to the C4b2a complex
classical pathway after activation (5)
- activated C1/Ab/Ag complex cleaves C4 to C4a and C4b
- C4b binds to microbial surface and C2
- C2 is cleaved by C1/Ab/Ag into C2a and C2b to form the C4b2a complex
- C4b2a is a C3 convertase, cleaving up to 1000 C3 to C3a and C3b
- C3b bind to microbial surface or to the C4b2a complex
what does C3b deposited onto microbial surface do (3)
1 C3b binds factor B
2. bound factor B is cleaved by plasma protease factor D into Ba and Bb
3. C3bBb complex is a C3 convertase, cleaving many C3 molecules to C3a and C3b
alternative pathway after activation (5)
- C3(H2O) binds to factor B
- bound factor B is cleaved by factor D into Ba and Bb
- C3(H2O)Bb complex is a C3 convertase, cleaving many C3 into C3a and C3b
- C3b is rapidly inactivated unless it binds to cell surface
- cycle continues as factor B noncovalently binds to C3b on cell surface and is cleaved to Ba and Bb by factor D
C’: C5 component activation (3)
- C3b binds C4b2a or C3bBb to form active C5 convertase: C4b2a3b and C3b(2)Bb
- C5 binds to Cb3 component of C5 convertase enzyme
- C5 is cleaved by C2a or Bb to form C5a and C5b
C’: C5 component (5)
- C5b binds C6 and C7
- C5b67 binds to pathogen membrane via C7
- C8 binds to complex and inserts into cell membrane
- C9 molecules bind to complex and polymerize
- 10-16 molecules of C9 bind to form a pore in the membrane, creating membrane lesions
functional components of C’ (3)
- C3a and C5a
- C3b
- membrane attack complex
functional components: C3a and C5a (3)
- anaphylatoxins
- increase vascular permeability
- chemotactic (recruit) for inflammatory immune system cells
functional components: C3b
- opsonins; tag pathogens for phagocytosis
what component initiates formation of the membrane attack complex (MAC)
- C5b
what is the MAC composed of (5)
- C5b
- C6
- C7
- C8
- multiple C9
regulation of C’: activation (3)
- C1 esterase inhibitor (C1inh)
- inactivates C1r and C1s from active C1 complex
- inactivates MASPs
regulation of C’: amplification (6)
- decay acceleration factor (DAF)
- C4 binding protein (C4BP)
- complement receptor 1 (CR1 or CD35)
- membrane cofactor protein (MCP1)
- factor I
- factor H
regulation of C’: factor I (2)
- protease that cleaves C4b
- C4BP, CR1 and MCP are cofactors
regulation of C’: factor H (3)
- cofactor for factor I
- factor I cleaves C3b
- CR1 acts as a cofactor
regulation of C’: MAC assembly
- CD59 inhibits insertion of MAC into the membrane
- halts MAC at the C8 to C9 stage
what regulators of C’ affect the C4b2a complex (3)
- DAF
- C4BP
- CR1
regulation of C’: DAF, C4BP, and CR1
- displace C2a from C4b2a complex
- C4b bound by regulator is cleaved by soluble protease I to inactive forms C4c and C3d
regulation of C’: CR1 (2)
- displace C3b
- act as cofactors in cleavage of C3b by protease I
how have pathogens reacted to the complement system
- evolved ways to combat the complement system at various stages
