Complement Flashcards
What is complement?
A group of small, soluble, heat-sensitive proteins that can combine to create complexes with proteolytic activity (zymogens) which can activate other members of the complement family in a cascade-like manner
What are the 3 complement pathways?
Classical
Lectin
Alternative
What does complement do?
Recognises and tags the target
Brings in other cells
Attacks and removes the threat
How does complement recognise and tag targets?
Attaches to non-self pattern (innate recognition)
Recognises fixed antibody (humoral recognition)
Recognises apoptotic cells for removal without inducing inflammation
How does complement bring in other cells?
Initiated chemotaxis and activation of phagocytic cells
Increases blood vessel permeability and adhesion of inflammatory cells
Contracts smooth muscle cells (anaphylatoxic effect)
Releases inflammatory mediators from mast cells (degranulation)
How does complement attack and remove the threat?
Lyses microbes by hole formation in complement targeted membranes
Strengthens T and B cell responses
Describe the classical pathway
C1 complex is formed from C1q and a dimer of C1r and C1s
C1 complex is activated when recruited to multivalent attachment sites
Activated C1s recruits and cleaves C4 to C4a and C4b
C4b covalently attaches to cell surface
C4b recruits and cleaves C2 to produce C3 convertase + C2b
C3 convertase generates C3a+C3b
C3 convertase decorates microbe surfaces with multiple C3b
This creates a shell around the particle, leading to chemotaxis and phagocytosis
What further happens on the classical pathway?
C2a+C4b+C3b = C5 convertase which recruits C5
This generates C5a and C5b
Both C3b coating and C5a are required to activate phagocytosis
C5b recruits C6, C7, C8 and 18 copies of C9 to make membrane attack complex (MAC)
This leads to cell lysis
What signals initiate the classical pathway?
Binding Fc fragment of Ag-Ab complexes
Binding Lipid A in bacterial lipopolysaccharides
Binding to pentraxins which have bound bacterial phospholipid
What initiates the lectin pathway?
MBL or ficolin binding to N-acetyl-glucosamine
How do MBL and ficolin work?
Trimeric structures forming polypeptide clusters with MASPs that act like C1r2s2
What do MASPs do?
Recruit and activate C4 and C2 in the same manner as the C1 complex does in the classical pathway
Rest of the lectin pathway is the same as the classical (C3 and 5 recruitment then MAC formation)
How is the alternative pathway activated?
When C3b from the lectin or classical pathway feeds back into the alternative pathway and activates it
Or by ‘tick over’
What happens once the alternative pathway has been activated?
Soluble C3 hydrolysed to C3b and C3a
Factors B and D activate surface C3b to create C3b-Bb (C3 convertase)
Properdin stabilises binding of C3b-Bb to microbes like yeasts and N. gonorrhoeae but not host cells (keeps alternative pathway from damaging host cells)
C3 convertase binds C3 and another C3b to create C3bBb3b (C5 convertase)
Then recruitment of C5 leading to MAC formation
What is the common biochemical intermediate of all 3 pathways?
Binding of C3b
