18 - complement Flashcards
what is the complement system?
an enzyme cascade
protection in early infections
leads to antigen clearance and inflammatory response
roles of the complement system?
some activated proteins bind covalently to bacteria opsonising them
some small fragments recruit phagocytes to the site
some products activate B cells
terminal component of the system generates membrane attack complex (MAC)
what does the membrane attack complex (MAC) do?
leads to lysis of pathogen
puts holes and pouches in the pathogen so that it bursts and is destroyed
what are the 3 pathways that activate the initiation of the cascade?
the classical pathway
the lectin pathway
the alternative pathway
how is the classical pathway activated?
by antigen-antibody complexes
how is the alternative pathway activated?
triggered by some pathogen surfaces
how is the lectin pathway activated?
by acute phase proteins that bind glycoproteins or carbohydrates on microorganisms
what enzyme do all 3 pathways generate?
C3 convertase
what is C3 convertase and what does it do?
a potent enzyme that is made of components of the complement system
enzymes converts C3 into its 2 components: C3a and C3b
• C3a is good for inflammation
• C3b is good at opsonising antigens
complement proteins in the classical pathway
C1q, C1r, C1s, C2, C3, C4
complement proteins in the alternative pathway
C3, factor D, factor B, properdin (factor P)
terminal components in complement
C5, C6, C7, C8, C9
what is the first step in the classical pathway?
the activation of C1
what are the 5 components of C1?
2 molecules of C1r and 2 molecules of C1s bind to each C1q
what is C1q attached to?
globules which bind to antibodies
what are the 5 classes of antibodies?
Ig : M, A, D, G, E
how does IgM go around?
in 5s - a pentamer
they bind to antigens on bacterial surface and adopt ‘staple’ form
C1q binds to a single IgM molecule to activate complement
how does IgG go around?
individually - monomers
bind to antigens on the bacterial surface
C1q binds atleast 2 of these in order to activate complement
what does the binding of C1q to either IgM or IgG lead to?
leads to a conformational change in C1q which reveals a proteolytic site on the C1r
C1r can noe cleave C1s to generate a serine protease enzyme C1s
what does C1s do?
C1s cleaves C4 to C4a and C4b
C4b binds covalently to the pathogen surface
C2 then binds to C4b on the pathogen surface
C2 is cleaved by C1s leaving the C4b2a complex
C2 is cleaved into C2a (bigger) and C2b (smaller)
what is the C4b2a complex also called?
C3 convertase
what does C3b do?
has a reactive thioester bond which is exposed after cleavage allowing it to bind covalently to the pathogens surface
if it doesn’t bind almost immediately it is rapidly hydrolysed by water and becomes inactive
what happens after C3 convertase has been cleaved?
C3b joins C4b2a complex to form C4b2a3b (C5 convertase)
C5 binds to the C4b2a3b complex and cleaves into C5a and C5b
C5b binds to pathogen surface and binds C6 to make C5bC6
C5bC6 binds C7 to make C5b67
what happens after C5b67 has been formed?
leads to a conformational change and C7 inserts itself into the lipid bilayer of the pathogen wall
C5b67 then binds to C8
what is C8 made up of?
C8 beta
C8 alpha-gamma
what does C8 beta do?
binds to C5b
this allows binding of C8 alpha-gamma
what does C8 alpha-gamma do?
inserts in the lipid bilayer
induces polymerisation of 10-16 molecules of C9 forming a ring structure
this is C5b6789
what is C5b6789 also known as?
MAC
what are the inflammatory mediators of the classical pathway?
C3a, C4a and C5a
how is the alternative pathway different?
different C3 convertase: • C3 undergoes spontaneous hydrolysis • C3b binds to surface (thioester bond) • factor B binds C3b • cleaved by factor D to Ba and Bb • C3 convertase composed of C3b factor Bb - C3bBb • factor P stabilises the C3 convertase
what is the C3 composed of in the alternative pathway?
C3b and factor Bb
= C3bBb
what does factor P do in the alternative pathway?
stabilises the C3 convertase
how do we get C5 convertase in the alternative pathway?
add another C3b to the C3 convertase
C3b2Bb = C5 convertase
the lectin pathway
uses soluble receptors (acute phase proteins) made by the liver
recognises microbial surfaces
activates complement cascade
get complexes of mannose binding lectin and MBL-associated serine proteases - needed to activate the pathway
what MBL-associated serine proteases activate the pathway?
MASP-1 and MASP-2
what does MASP-2 do?
cleaves C4 followed by C2 to create a C3 convertase (C4b2a complex)
this is the same as the C3 convertase in the classical pathway but is produced used MASP-2 instead of C1
