The Complement System Flashcards
What is the function of the complement system?
Innate recognition of non self, Abs, apoptotic cells
Opsonisation
Effector: lysis, Inflammation, phagocytosis.
Other functions: Chemotaxis, inflammatory cell adhesion, clears immune and apoptotic cells
What are the 3 pathways in the complement system?
- Antibody triggered (Classical)
- Presence of pathogen alone (Alternative)
- Lectin type protein activation (Lectin)
- 1 COMMON PATHWAY
-All pathways converge onto the terminal lysis pathway
What is the C1 complex?
Describe the classical pathway for the complement system
IgM binds to C1q more strongly than IgG
C1r activates, which activates C1s. This starts classical
C1s joins w C4–> splits into C4a and C4b
C4b covalently attaches to target cell by thioester bond.
If C4b doesn’t attach, C4b just dissociates from the cell wall (prevents self attachment).
C4b + C2a= C3 convertase!
C3 is split by C3 convertase into C3a and C3b.
C3b attaches to target cell by thioester bond. If C3b doesn’t attach, it dissociates. This must occur bc the alt pathway activates w just c3 (problem)
Thioester bond attaches c3b to target cell=opsonin
Describe the second part of the classical pathway for the complement system
C3 is split by C3 convertase into C3a and C3b.
C3b attaches to target cell by thioester bond. If C3b doesn’t attach, it dissociates. This must occur bc the alt pathway activates w just c3 (problem)
Thioester bond attaches c3b to target cell which keeps repeating=opsonin, acts as signal for macrophages and neutrophils
c4b +c2a + c3b is C5 convertase = the second part of classical pathway
C5 convertase acts on C5 and splits it into c5a and c5b (a v strong anaphyltoxin). c5 binds up to c6 c7 c8 c9
What is C4a, C3a, C5a and C5 convertase?
c4a = anaphylaxin, part of the inflam response.
C3a=anaphylaxin; involved in chemotaxis and inflam responses
c5a= strongest anaphyltoxin. Also helps make adhesion molecules
C5 Convertase recruits C6,7,8,9, which initiates the terminal pathway
What is the lectin pathway?
Exactly same as classical pathway — same molecules
Only diff is recognition: not done through Abs/pentraxins/lipids but instead via atypical glycosylation (sugars!) on pathogen surface
Describe specifically the types of recognition molecules for the lectin pathway
Mannose-binding lectin (MBL): recognizes and binds to mannose, N-acetylglucosamine, and fucose residues on microbe surfaces.
MBL is structurally similar to C1q and forms complexes w proteases (MASPs) to activate complement.
Ficolins: recognize and bind to acetyl groups present on microbe surface. Ficolins also associate w MASPs
MASP undergoes a conformational change and follows same pathway as classical after!
What is the alternative pathway activated by?
Alternative= slowly activated by hydrolysis of the internal C3 thioester bond
Also triggered by foreign proteins, lipids etc
Initiated by C3b that is generated by lectin / classical pathway
Explain the start of the alt pathway using the C3b recognition method
C3b produced by classcial/lectin attaches to target cell
Factor B (only in alt pathway) binds to C3b
Factor D splits B into Bb and Ba
C3b attaches to Bb= alt C3 convertase
C3 convertase= unstable here, so factor P (properdin) stabilises it.
Note factor P only attaches to pathogen cells, not host, to ensure convertase works on the pathogen surface
Explain the start of the alt pathway using the Tick over mechanism
Spontaneous cleavage of C3 in the plasma starts the tick over mechanism of the alt pathway:
C3 binds to water. Factor B binds to C3H20
Factor D splits B into Ba and Bb
C3H20Bb= fluid C3 convertase in the blood
C3 convertase splits C3 into C3a and C3b.
C3b attaches to the target cell
Because C3 spontaneously!! splits in the plasma, this is a tick over mechanism bc the above process keeps happening
How is the alternative pathway also an amplification loop?
Also mention F P
Amplification loop means it keeps going- c3b keeps attaching to target cell, getting more factor b and then alt pathway starts again
Alt pathway is powerful bc you dont need an antigen- bc the splitting of C3 in the plasma is spontaneous
Factor P is important in stabilising C3b and Bb. Another C3b attaches to this molecule–> forms C5 convertase
Describe and explain the terminal pathway
C3 convertase has made all C3b — coats pathogens
C5b recruits C6 C7 C8 C9 and makes a pore
18 c9 molecules in a pore — makes a membrane attack complex (MAC)
MAC inserts into Ag surface and punches holes into the pathogen — lysis part of the mechanism
Explain the regulation of complement using properdin
propredin will only attach to factor B and c3b if it is on the pathogen surface (does not act on host cells bc you dont wanna kill your own cells for no reason)
Explain how regulatory proteins regulate complement and its different mechanisms of action
Complement Regulatory proteins can b soluble or membranous. They prevent complement on host cells
Explain the mechanism of action of the control proteins of C1i, Factor I, C4bp, Factor H
Explain the mechanism of action of the control proteins CR1, DAF, MCP, CD59
Explain what AHUS is
Problem with factor H
What is PNH? = Paroxysmal Nocturnal Haemoglobinuria (PNH)
Mutation in PIG-A gene–> less gpi protein in host cell walls
This reduces anchoring of CD55 and CD59 control factors on erythrocytes
C3b accumulates on Erythrocyte surface, activating Terminal/Mac pathway and causing lysis
Variable symptoms: aches, pains, GI symptoms
Treatment- Eculizumab= monoclonal Ab against C5
