4. The complement system Flashcards
where are complement proteins produced
the liver
what is opsonization
coating of the pathogen with antibodies for recognition by phagocytic cells
complement proteins in circulation
circulate in their inactive forms, “activated” in the presence of pathogens or antibodies bound to pathogens
3 different proteolytic pathways that lead to complement activation
first to act = alternative pathway
second to act = lectin pathway
third to act = classical pathway
many complement proteins are proteases and zymogens, what does this mean
complement proteins are synthesized as their inactive forms (zymogens) and successively cleave each other to become activated (proteases)
stages of complement activation
- pattern recognition trigger
- protease cascade amplification/C3 convertase
- 1 of 3 effector pathways (inflammation, phagocytosis or MAC)
outcome of complement activation: inflammation
C3a and C5a recruit and activate leukocytes at site of infection
outcome of complement activation: opsonization
C3b bound to microbe surface is recognized by C3b receptor on phagocyte which destroys the pathogen
outcome of complement activation: membrane attack complex
insertion of complement proteins C5b-C9 into the pathogen membrane forms pores which disrupts the osmotic balance across the membrane and promotes pathogen death
exceptions in complement protein nomenclature
- C2 product C2a is a larger fragment than C2b
- C1q, C1r and C1s are not cleavage products but distinct proteins that compose C1
extra proteins in the alternative pathway
factor B (Ba and Bb) and factor D
complement proteins were named by…
their order of discovery (C1-4-2-3-5…)
* C4 acts before C2 and 3 but it was discovered first
which complement proteins are NOT in the alternative pathway
C1, 4 and 2
which complement protein is NOT in the lectin pathway
C1
lectin pathway initiation
initiated by mannose-binding lectin and ficolins
bind to carbohydrate structures on microbial surfaces
MASPs trigger the cleavage of complement routines (since there is no C1)
classical pathway initiation
initiated when C1 either recognizes a microbial surface via CRP or directly binds to antibodies already bound to a pathogen
alternative pathway activation
initiated by spontaneous hydrolysis and activation of C3
which complement pathway boosts the adaptive immune system
classical pathway (involves antibodies)
where do all 3 complement pathways converge
the generation of C3 convertase - C3 is cleaved leaving C3 bound to the microbial surface and releases C3a to trigger inflammation
role of C3a and C3b
C3a: an anaphylatoxin - activates inflammatory response by triggering degranulation of cells that cause inflammation
C3b: covalently attaches to the pathogen surface and marks it for destruction (more susceptible to phagocytosis)
when C3 convertase creates C3a and C3b it exposes a…
highly reactive thioester bond in C3b
composition of C3 convertase in the different complement pathways
lectin and classical: C4b2a
alternative: C3bBb
composition of C5 convertase in the different complement pathways
lectin and classical: C4b2a3b
alternative: C3b2Bb
how to MBL and ficolins initiate the lectin pathway
- they form complexes with serine protease and recognize carbohydrates on protein surfaces
- their associated MASPs cleave complement proteins to start the pathway
- MBL: binds to mannose and fructose residues
- ficolins: bind oligosaccharides containing acetylated sugars
how does C3 convertase result in the binding of many C3b to the pathogen surface
MASP-2 (or C1s) cleaves C4 into C4a and C4b - C4b binds to microbial surface
C2 comes and MASP (or C1s) cleaves it - C2a joins and the C4b2a complex is created
C4b2a is an active C3 convertase - can cleave up to 1000 C3 proteins
what is the role of each proteins that makes up C1
C1q: binds to pathogen surfaces at CRP or indirectly to antibody, allowing auto-activation of C1r
C1r: cleaves C1s to activate it
C1s: cleaves C2 and C4
what are the roles of Factor B and D in the alternative pathway
Factor D: protease that functions to activate factor B
Factor B: protease zymogen which when activated functions as a subunit of C3 convertase
why do we have the alternative pathway?
it is an amplification loop for C3b formation that is accelerated by properdin in the presence of pathogens
more C3b = more opsonization = more phagocytosis
what is properdin (factor P)
a plasma protein that enhances the activity of the alternative C3 convertase to aid in complement fixation
different complement receptors and their ligands
CR3 and CR4: ligand is C3b and iC3b
CR2: ligand is C3dg
what is Factor I
a serine protease that inactivates C3b through its cleavage into iC3b - cannot function as a component of C3 convertase
which complement receptor do macrophages express
CR1 - binds C3b to enhance recognition and phagocytosis
what plasma proteins regulate complement activation
Factor H and Factor I: regulate cleavage of C3b
how does factor H regulate complement activation
enhances the cleavage of C3b into iC3b by factor I
binds to cell membranes by interacting with sialic acid which inhibits complement activation
what membrane proteins regulate complement activation
- DAF: breakdown the alternative C3 convertase
- MCP: binds to C3b and enhances its cleavage to inactive iC3b by factor I
*these proteins are expressed by human cells to inhibit C3b fixation because it would destruct the cell
what is the membrane attack complex
complement proteins C5b-C9 work together to form holes in bacterial and eukaryotic membranes
how is the MAC regulated
plasma proteins: S protein, clusterin and factor J inhibit C6 and C7 from binding to the membrane
human cell-surface proteins: CD59 and HRF prevent C9 from binding to the membrane
