Complement system
Classical Complement pathway
Alternative Complement Pathway
Lectin Pathway
requires antigen for initial activation
Complement system is a series of proteins that act in a sequential cascade
many proteins are pro-enzymes that require proteolytic cleavage to activate enzyme
Act in three different pathways
Complements act non specifically
regulation using inhibitory components is crucial
antibody complex for activation is triggered by C1 complex
Dependent on specific carbohydrate moieties like mannan which is on the surface of microbes
Mannose-binding lectin ( MBL) or ficolins initiate activation of pathway
The binding of MBL to mannose residues on the pathogen activating the MBL-associated serine proteases MASP-1 and MASP-2.
Ficolins are homologous to MBL and function via MASP but react to other carbohydrates than mannose.
activation via C3 hydrolysis
continuously activated at a low level
allows for spontaneous C3 hydrolysis ensuring prompt response of alternative pathways
All three pathways result in formation of
homologous variants of protease C3 convertase
this cleaves C3 to form C3a and C3b
C3b is part of C5 convertase that cleaves C5
leads to formation of Membrane attack complex ( MAC)
Lead to formation of soluble terminal complement complex (sTCC)
Four main functions
lysis of infectious organisms
activation of inflammation
opsonization
enhancing phagocytosis of antigens
Antibody complex interaction with serum C1 complex or immune aggregates containing IgG or IgM triggers classical complement pathway
Once antibody is attached, it leads to a conformational change in C1 complex leading to C1s and C1r serine protease subunits
Activated C1 cleaves C4 resulting in reactive C4b
reactive C4b covalently binds to proteins or polysaccarides at surface in close proximity to C1
Bound C4b binds to C2, allowing C2 to be available for proteolysis by C1
The C4b2a complex is formed
it is a CP C3 convertase
C3 convertase is responsible for important cleavage into C3a and C3b
Regulated by binding of membrane bound DAF which increases decay of C3 convertase
Factor I and Factor H are regulatory
Native C3b is able to covalently bind to surfaces near the C3 convertase, resulting in CPC5 convertase ( C4b2a3b)
The formation of C5 convertase is the final step of the lytic complement pathways
it cleaves C5 to C5a and C5b
The C5b complex is the first component of the self assembly of MAC or sTCC which initiates cell destruction
Identical to classical pathways except for the initiation of complement cascade
Opsonization via MBL or Ficolins
MBL binds to mannose residues on microbes
activates MASP1 and MASP2
MBL/ Ficolins in complex with MASPs can cleave C4 to C4a and C4b
MBL/ Ficollins can cleave C2 into C2a and C2b
functionally C4b and C2b form the C3 convertase, later joining with C3bto make C5 convertase
The C5 convertase will then form an assembly portion of the MAC complex or sTCC which initiates cellular lysis.
Is not triggered by antibodies or specific structures on microbes
spontaneous hydrolysis of C3 which is abundant in the plasma of the blood
causes a conformational change allowing for serine protease Factor B to bind
This in trun is cleaved by Factor D to form Ba and Bb respectively
Ba is released into a solution
Bb forms a complex, C3(H2))Bb which is the initial C3 convertase
The C3Bb is a proteolytic complex that initiates amplification process by formation of more C3b molecules building MORE C3bBb convertases resulting in surface deposition of C3b molecules
Surface C3b is shortlived which restricts AP activation to be a localized event
The C3b complement has several binding sites for multiple complement components
The newly formed C3v can do two things
generate C3 convertase which can interact with Factor B, D and properin
C3b is inactivated through control mechanism involving several inhibitory components like MCP and Factor H
Binding another C3b- fragment to C3 convertase creates C5 convertase(C3b2BbP) analogous with the lectin and classical pathways
The formation of C5 convertase initiates the final lytic process
The AP can act as a powerful amplifier of both CP and LP
C3b formed bby Classical and lectin pathways fuel the formation of both C3 convertase and c5 convertase thus forming an amplification loop
Active C3b binds to cell wall components and lipopolysaccharides and the constant low level of spontaneous C3b formation ensures that C3b cn bind to invading ells and trigger the rest of the alternative pathways
This pathways is kept in check by Factor H anf I in order to inactivate C3b enzyme in solution
The C5a is released and act as a potent anaphylatoxin
The C5b is the first step in self assembly of MAC or TCC
MAC is composed of
C5b
C6
C7
C8
several molecules of C9
Step one is C6 and 7 binding with C5b
this changes the structure of C7, allowing the whole complex to be inserted into the target cells membrane
this serves as the receptor for the C8, and then the whole complex binds to serveral molecules of C9 resulting in a transmembrane MAC lesion