Complement System Flashcards
How is the classical pathway activated?
Antigen-antibody complexes
How is the alternative pathway activated?
Pathogen surfaces
How is the lectin pathway activated?
lectin binding to pathogen surfaces
Outcomes of complement
Recruitment of inflammatory and immunocompetent cells, opsonization, killing of pathogen
How does complement recruit adaptive immune cells?
- opsonization by APCs allows for presentation of antigens to adaptive cells
- B cells have complement receptors which enhance B cell response to complement-coated microbes
Activation of classical complement pathway
Mainly potentiated by IgM and IgG binding to antigen. 2 C1q heads will bind adjacent Fc regions of antibodies. C1q binding activates C1r which cleaves itself into its active form so it can cleave C1s into an active form. Active C1s cleaves C4 to C4a and b. C4b attaches to the surface of the microbe.
C1s also cleaves C2 into C2a and b (here C2a is the larger fragment). C2a binds C4b forming C4b2a aka C3 convertase of the classical pathway. Once this is formed, C3b will eventually attach to the microbe surface and tags it for phagocytosis.
C3b also forms a complex with C3 convertase making C4b2a3b aka C5 convertase. C5 convertase allows the formation of C5b which will associate with C5 convertase and help form the MAC.
Ways C1q can bind pathogen surface
Main: binding antigen-antibody complex
Binding to CRP (bound to bacterial polysaccharides), binding directly to bacterial components (lipoteichoic acid)
Carbohydrate-binding proteins in lectin pathway
MBL, ficolins
Function of C3a
inflammation mediator
Function of C3b
main effector of complement system
Activation of alternative pathway
Usually begun by spontaneous cleavage of C3, which in the presence of a microbe will begin the cascade. C3b will bind the bacterial surface, and Factor B will come along and bind this C3b forming C3bB.
C3bB is cleaved by Factor D, making the active C3bBb which is the alternative pathway C3 convertase. This C3 convertase is highly active and creates a lot o C3b as well as an amplification loop. This C3 convertase is stabilized by Properdin or Factor P.
C3b cleaved by C3bBb will associate to C3 convertase forming C3bBb3b aka alternative C5 convertase. This will cleave C5 to form MAC
Activation of lectin pathway
mannose binding lectin will recognize different carbohydrate moieties on the pathogen surface and undergo a conformational change. This leads to activation of MASPs which cleave C4 and C2. C4b and C2a will associate to make C3 convertase (C4b2a) on the microbe surface.
C3 convertase will form C3b which will associate with C4b2a to make C5 convertase. This will lead to formation of the MAC
What happens if C3b binds a host cell?
It is rapidly degraded. Degradation occurs due to sialic acid residues promote C3b binding to Factor H, which will degrade inappropriately bound C3b along with Factor I. Bacterial membranes will not have sialic acid.
How MAC forms
C5b settles on the microbe surface and recruits C6 and C7 which all form a complex. C8 binds this complex and wedges itself into the microbe’s plasma membrane. C9 (10-16x) can then insert into the membrane and form a pore that leads to osmotic lysis
Regulation of complement system
done by complement control proteins - can stop or downregulate the complement response.
These proteins either inhibit protease activity or facilitate degradation of activated complement complexes/convertases
