Lecture 2: The Complement System Flashcards
What is complement?
inactive plasma proteins (often pro-enzymes), activated (by proteolysis) to carry out various immunological functions
Where is complement found?
widely distributed in tissues and body fluids
What does complement do?
promotes lysis of bacteria, infected cells, transplanted cells etc. promotes opsonisation (i.e. phagocytosis of targeted cells) promotes inflammation (i.e. recruitment of leukocytes)
How many complement proteins are there and what are they produced by?
there are more than 30 complement proteins and they are produced by liver cells (hepatocytes), monocytes, macrophages and some epithelial (skin) cells
What does complement activation involve? When do proteins carry out their function?
an enzyme “cascade”
many active proteins exist but will not carry out their function until a trigger is fired e.g. first inactive protein in the “cascade” is activated
What are the terms given to cleaved products of enzyme cascade?
“a” for smaller fragment and “b” for larger fragment e.g. C3 cleaved to C3a and C3b
What is the trigger for the complement cascade?
C1 (inactive) -> C1 (active)
Where does activation of the complement system occur?
on the surface of pathogens (or other cells)
How do the products of complement activation bind to cell surfaces?
either alone, or bound to antibody
Why do host cell surface proteins regulate complement activation?
to minimise host damage
these proteins are found on normal (healthy) cells and are absent on microbes (e.g. bacteria)
What is the state of soluble complement components?
they are often inactive or transiently active
What are the stages of complement action?
pattern recognition trigger -> protease cascade amplification / C3 convertase -> inflammation / phagocytosis / membrane attack
What does the classical pathway of the complement system involve?
antigen-antibody complexes
- > IgM and IgG
- > formally an “effector mechanism of humoral immunity”
What does the alternative pathway of the complement system involve?
directly involves pathogen (bacterial surfaces)
antibody independent
part of the innate response
What does the lectin pathway of the complement system involve?
mannan binding lectin
How is the complement cascade initiated?
three pathways for activation which utilise different but often homologous components, e.g. C4 and C3, C2 and B
results in formation of different but homologous C3 convertases for classical/lectin and alternative pathways
What are the early common stages of the complement cascade?
up to (including) cleavage of C3 -> can be by C3 convertase
What are the late steps (effector phase) of the complement cascade?
after C3 cleavage, C5 convertases are formed, and C5 hydrolysis results in pore formation, cell lysis and inflammation
Which processes and proteins are involved in the common steps of the complement cascade?
proteolysis of C3 to C3a (inflammatory mediator) + C3b
binding of C3b to microbe surface
C3 activated by enzyme complex
C3 convertases form the C5 convertases
How does C3b act as an opsonin?
reactive thioester groups exposed on C3b bind amino and hydroxyl groups on microbial surfaces
What is C3 convertase in the different pathways of the complement system?
lectin pathway - C4b2a
classical pathway - C4b2a
alternative pathway - C3bBb
fluid phase - C3(H2O)Bb
What is C3 convertase in the different pathways of the complement system?
lectin pathway - C4b2a
classical pathway - C4b2a
alternative pathway - C3bBb
fluid phase - C3(H2O)Bb
What is C5 convertase in the different pathways of the complement system?
lectin pathway - C4b2a3b
classical pathway - C4b2a3b
alternative pathway - C3b2Bb
How is the alternative pathway of the complement system activated?
C3 undergoes spontaneous hydrolysis to C3(H2O), which binds to factor B, allowing it to be cleaved by factor D into Ba and Bb -> the C3(H2O)Bb complex is a C3 convertase, cleaving more C3 into C3a and C3b -> factor B binds noncovalently to C3b on a cell surface and is cleaved by Bb by factor D
What happens to C3 before cleavage by C3 convertase?
the thioester bond within TED is protected from reacting -> allows thioester bond to react with a chemical group on the pathogen surface
What is the role of properdin?
stabilises the C3bBb complex
properdin = factor P
What are the proteins of the alternative pathway of complement activation?
C3b (binds to pathogen surface; binds B for cleavage by D; C3bBb is a C3 convertase and C3b2Bb is a C5 convertase), Ba, Bb, D and P
How is the alternative pathway amplified?
C3b deposited by classical or lectin pathway C3 convertase -> C3b binds factor B -> bound factor B is cleaved by plasma protease factor D into Ba and Bb -> C3bBb complex is a C3 convertase, cleaving many C3 molecules to C3a and C3b
How do mannose-binding lectins allow for the death of bacterial cells and not human cells?
they bind to mannose which is only found on bacterial cells -> activation of complement proteins
What is C1?
a “pathogen sensing complex” which is found in the classical pathway of the complement system
How can C1q be activated?
by binding antibodies (IgG, IgM) that have bound pathogens and CRP that can bind phosphocholine residues on bacterial surfaces
What does C1q binding induce C1r to cleave?
C1s to create an active serine protease
What must happen in order for C1 activation to occur?
antibodies must bind to a surface
this is because C1q cannot bind to “free” IgM and must bind to at least 2 IgG’s
What does binding to multimeric cell surface antigen lead to?
- > conformational change of IgM which results in “exposure” of Fc region involved in C1q binding and activation of C1 complex
- > binding of multimeric IgG which results in activation of C1 complex
What are the proteins of the classical pathway of complement activation? What does C1q bind to and allow?
C1q, C1r, C1s, C4b, C4a, C2a, C2b, C3b, C3a
binds directly to pathogen surfaces or indirectly to antibody bound to pathogens, thus allowing auto-activation of C1r
How is C5 cleaved?
C3b binds to both C4b2a and C3bBb, forming the active C5 convertases C4b2a3b and C3b2Bb -> C5 binds to the C3b component of the C5 convertase enzyme -> C5 is cleaved by C2a or Bb to form C5b and C5a
What happens when C5 is cleaved?
initiates the pathway for the membrane attack complex
