The Complement system Flashcards
what are the three pathways of the complement system?
classical, alternative, lectin.
What is the complement system?
Helps protect against early infections and comes into both innate and adaptive immune response. It is a system of the humoral branch. It is a highly regulated enzymic cascade with an antigen clearance and inflammatory response.
What are main roles of the complement system?
1) opsonise antigens - almost like a coating that makes them more likely to be phagocytosed
2) small fragments of the complement system recruit phagocytes and regulate inflammatory response
3) some products activate B cells
4) generates the membrane attack complex (MAC) wich equals lysis of the pathogen.
What triggers each of the pathways?
Classical - initiated by antigen - antibody complexes
Alternative - triggered by some pathogen surfaces
lectin - initiated by acute phase proteins that bind glycoproteins or carbs on microorganisms.
What do all pathways generate?
C3 convertase
What arm of the immune system does each pathway correspond too?
Classical - we need antibodies, which is part of the adaptive response
Lectin - mannose binding protein (host protein made by liver) binding to pathogen surface, which is part of the innate response.
Alternative - the local surface of the pathogen creates an environment to start the cascade of the complement system - innate.
What is the first component of the classical pathway?
C1 is a complex made of C1q, C1r, C1s - 2 protein molecules of C1r and C1s each bind to the C1q molecule.
The C1q molecule extends from the C1r and C1s, and it has 6 globular heads. Each of the globular heads have a specific antibody binding site, and can bind to 1 Fc domain on the antibody. At least 2 globular heads must bind to 2 Fc domains for activation of C1q. C1q can either bind to two or more IgG, or a singular IgM antibody. The binding of C1q and its activation causes conformational change, revealing a proteolytic site on C1r. C1r now has enzymatic activity, will cleave C1s to generate a serine protease enzyme.
What complement proteins are involved with what pathways?
Classical - C1 (C1q, C1r, C1s); C4 and C2.
Alternate - Factor D, factor B, PROPERDIN (factor P).
Both - C3.
Terminal components - C5, 6, 7, 8, 9.
What is the second component of the classical pathway, once C1s has been cleaved and serine protease enzyme has been generated?
C1s now acts on the next two components of the classical pathway, cleaving C2 and C4.
C1s cleaves C4 into C4a and C4b. C4b binds covalently to the pathogen surface. C2 then binds to C4b on the antigen surface. C2 is then cleaved by the adjacent C1s, leaving the C4b2a complex (aka C3 convertase). C3 convertase is an active enzyme which has the role of cleaving large numbers of C3 molecules to C3b and C3a.
What is the third component of the classical pathway (C3)?
C3 is cleaved into C3a and C3b. By having lots of C3b on the surface of the pathogen, this means opsonisation and phagocytosis of the pathogen by cells with complement receptors. C3b can also activate the alternative pathway.
The C3a fragment is essentially a signalling molecule that attracts other phagocytes to the area.
What type of bond binds C3b to the pathogen surface?
Thioester bond which is exposed after the cleavage of C3 to C3a and C3b. If it doesn’t immediately bound, it is rapidly hydrolysed and become inactive.
What is the fourth component of the classical pathway? (C56789)
A C5 molecule will bind to the C4b2a3b complex on the pathogen surface (aka C5 convertase). This cleaves C5 into C5a and C5b. C5b binds to the pathogen surface and also binds C6 (C5bC6). This complex then binds to C7 (C5bC6C7). This results in a conformational change in C7 and inserts into the lipid bilayer of the pathogen wall.
DONT NEED TO KNOW - C5bC6C7 binds C8 which is a complex of C8β + C8α-γ.
C8β binds to C5b which allows the binding of C8α-γ. C8α-γ inserts into the lipid bilayer also and induces polymerization of 10-16 molecules of C9 -> forming a ring structure.
What is the C5b6789 structure?
MAC - membrane attack complex
What is the effect of the MAC?
- displaces cell membrane phospholipids
- this causes a channel where water can get in
- this causes cell lysis and death
What is the start of the alternate pathway?
A different C3 convertase undergoes spontaneous hydrolysis and splits into C3a and C3b again. C3b binds to the surface of the pathogen. Factor B binds to C3b, and factor B is cleaved by factor D. This forms C3bBb (Bb comes from the splitting of factor B by factor D into two subunits). This complex is stabilised by Factor P.
