8 Complement Flashcards
Innate Immune response – recognition
Bacterial cell surface induces cleavage and complement activation
One complement fragment covalently binds to bacterium, other attracts an effector cell
Complement receptor on effector cell binds to complement fragment on bacterium
Effector cell engulfs bacterium, kills it and breaks down
Stages of complement action
Pattern recognition trigger
Protease cascade amplification/C3 convertase
Inflammation, phagocytosis, membrane attack
can complement kill
complement can directly kill through the membrane attack complex
Complement pathways
antibody dependent
antibody independent
Antibody dependent complement pathways
classical pathway
Antibody independent complement pathways
lectin pathway and alternative pathway
when is the lectin pathway activated
activated as soon as antigen in body – direct recognition of pathogen
when is the alternative pathway activated
once complement is activated even more complement is activated
when is the classical pathway activated
pathogen has to be recognised, producing antibodies
what do the three pathways lead to
Three pathways all lead to activation of C3 and generation of C5 convertase
Activation of C5
what happens in the classical pathway
antibodies bind to specific antigen on pathogen surface
what happens in the lectin pathway
mannose-binding lectin binds to pathogen surface
what happens in the alternative pathway
pathogen surface creates local environment conductive to complement activation
what does the C3 molecule lead to
All lead to C3 molecule – which in the end leads to the membrane attack complex
Physiological consequences of complement activation
Bacteria = lysis Phagocyte = chemotaxis Bacteria = opsonization
what is lysis
forming holes in membrane – membrane attack complex
what is opsonization
tagging of pathogen to see something foreign in the body
Components of lectin pathway
Mannose groups
Mannose Binding Lectin
C4
C2
what are the enzymes in the lectin pathway
Enzymes: MASP2 and MASP1
serine proteases
what do the enzymes in the lectin pathway do
switch on the process when activated
what activates the enzymes in the lectin pathway
When mannose bind lectin binds to the mannose groups on surface = activation of MASP1 and MASP
what does MASP1 do
activates MASP2
what does MASP2 do
cleaves C4 into C4a and C4b
how is C3 convertase made in the lectin pathway
C2 cleaved into C2a and C2b
C2a joins onto pathogen surface with C4a = C3 convertase
how is a C5 convertase generated in lectin pathway
one molecule of C4b2a can cleave C3 to C3b, C3b bind to microbial surface (deposition on pathogen surface)
C4b2a3b = C5
C5 convertase leads to membrane attack complex
Components of classical pathway
C1, C2, C3, C4
what is C1 complex
made of C1q and C1r and C1s (serine proteases C1r and C1s – to activate need to be bound to two IgG or IgM = conformational change)
how is the classical pathway initiated
Pentameric IgM molecule binds to antigens on bacterial surface and adopts ‘staple’ form
C1 binds to single IgM molecule
IgG molecules bind to antigens on bacterial surface
C1q binds to two or more IgG molecules
how is a C3 convertase generated in classical pathway
Activated C1s cleaves C4 to C4a and C4b. some C4b binds covalently to microbial surface
Activated C1s also cleaves C2 to C2a and C2b
how is a C5 convertase generated in the classical binding pathway
C2a binds to surface C4b forming classical C3 convertase, C4b2a
what does the C4b2a do in the classical pathway
binds C3 and cleaves C3a into C3b
what does C3a do
causes inflammation, mast cells to degranulate
what does the C3b made in the classical pathway do
binds covalently to microbial surface
Components of the alternative pathway
C3b
factor b
factor d
properdin
what does factor b do in the alternative pathway
binds to C3b makes alternative pathway C3b
what does factor d do in the alternative pathway
plasma serine protease, cleave B when it is bound to C3b to Ba and Bb
how is C3 generated in alternative pathway
C3bBb = C3 convertase of alternative pathway
C3b deposited by classical or lectin pathway C3 converase
C3b binds to factor B = C3bB
Bound factor B is cleaved by plasma protease factor D into Ba and Bb
C3bBb complex is C3 convertase, cleaving many C3 molecules to C3a and C3b
what is C3a needed for
mast cell activation
what is C3b needed for
C3b to get more C3a
C5 function in the membrane attack complex
on activation the soluble C4b initiates assembly of MAC in solution
C6 function in the membrane attack complex
binds to and stabilises C5b, forming C7 binding site
C7 function in the membrane attack complex
binds to C5b, 6 and exposes a hydrophobic region that permits attachment to cell membrane
C8 function in the membrane attack complex
binds to C5b, 6, 7 and exposes a hydrophobic region that inserts into cell
C9 function in the membrane attack complex
polymerization on C5b, 6, 7, 8 complex, form membrane-spanning channel that disrupts cell’s integrity and can cause cell death
what does opsonization and phagocytosis do
C3b and C4b of complement binds tagging for phagocytosis
Cellular recruitment and activation
Increased vascular permeability
Vasodilation
C5a and C3a activates mast cell= cellular recruitment and inflammation
Chemo-attractive properties = chemotaxis
what leads to inflammation
C3a and C5a
what do mast cells lead to
C3a, C5a, PAMPs damage
what are the complement functions
host benefit
host detriment
complement - Host benefit
- opsonization to enhance phagocytosis
- phagocyte attraction and activation
- lysis of bacteria and infected cells
- regulation of antibody responses
- clearance of immune complexes
- clearance of apoptotic cells
complement - Host detriment
- inflammation (through C3a/C5a and mast cells)
- anaphylaxis
