Complement -Regal Flashcards
Sequence of complement rxn:
C1, 4, 2, 3, 5, 6, 7, 8, 9,
Functions of Complement:
- Lysis of microorganisms (MAC)
- Opsonization of antigen
- Source of mediators of inflammatory response (C3a, C5a)
- Solubilization and clearance of immune complexes
- Augments stimulation of B cells (CR2 receptor)
What are C 1, 4, 2, 3, important for?
Clearance of immune complexes
C3b importance?
- amplifying adaptive immunity
- Opsonin
C5a importance?
Inflammation & T cell regulation
C5, 6, 7, 8, 9 Deficiencies? (they make MAC)
terminal lytic pathway
- think MENINGOCOCCAL infections
- NEISERRIAL infections : need MAC to lyse Neiserria to get rid of it.
Deficiencies in C3 and alternative pathway?
- Glomerulonephritis
- SLE
- recurrent infections
- Neisseria
Deficiencies in C1, 4, 2 or 3 ?
-Classical pathway?
High incidence of immune complex diseases like SLE, glomerulonephritis (IC’s are not solubilized and cleared)
- also role in tissue damage in IC disease like SLE (pathological complement activation)
- encapsulated bacterial infections or pyogenic infections
MBL deficiency?
Serious pyogenic infections
What is complement important for?
Where is it synthesized?
- Lysing bacteria
- Clearing immune complexes
- Made by liver hepatocytes and tissue macrophages
- It is a PLASMA protein system (C3 is 5% of plasma proteins)
What proteins covalently bind to bacteria?
C4b and C3b
-via thioester bonds
- can interact with complement receptors 1-4 on OUR cells
- Act as opsonins
The proteins get cleaved and for most the B part is active, what protein’s ‘a’ portion is most important?
C2a
-think because it is part of C4b2a enzyme!)
(C2b floats off)
C3 convertases?
C4b2a (classical, alternative, MBL pathways)
C3bBb (alternative pathway)
C5 convertase?
C3bBbC3b (Alternative pathway)
C4b2aC3b (classical)
*C3b at end =think C5 convertase :)
What pathway needs Abs/antigen to activate it?
What antibodies?
Classical! - makes C1qrs
IgG or IgM
What activates the MBL pathway?
The alternative pathway?
MBL: mannose
Alternative- LPS, carbohydrates, etc
What is common to all pathways?
C3
Activation of C1 in classical pathway?
- C1qr2s2 complex in plasma is usually inactive. but BOOM. it binds two IgG or 1 IgM and makes a conformational change
- C1r activates auto-catalytically and activates the second C1r; –> both activate C1s
- Active C1 esterase cleaves C4 that is covalently bonded to bacteria.
Activation of C4
C1 esterase cleaves it.
C4b covalently bonds with activating surface
C4b can act as opsonin
Activation of C2
C2 interacts with C4b
C1s cleaves it –> C4b2a is formed on surface
C4b2a == C3 convertase of classical pathway
C3 activation
C4b2a cleaves C3 –> C3b covalently binds to surface
C3b can be opsonin
Mannose Binding Lectin (MBL) pathway
- recognizes mannose/polysaccaride structure
- MBL, MASP-1, MASP-2 cleave C4 and C2 —> C4b2a =C3 convertase
- Independent of C1
- MBL interactions with MASP-1 & 2 are a lot like C1q interactions with C1r and C1s :)
Alternative Pathway
Cue Promiscuous Girl by Nelly
Trigger: complement recognizes foreign surface structures (LPS) itself. SELF activating pathway
Recognizes antigen/Ab complexes but DONT need specific Ig’s
Alternative Pathway–C3 tickover:
spontaneous conformational change of C3 –> water hydrolyzes the thioester bond –> C3(H20)
-always doing this
Alternative Pathway steps
- Spontaneous split of C3 by hydrolysis
- Factor B binds to C3b
- Factor D cleaves FB off –> C3bBb (C3 convertase)
- C3b gets bonded to cell surfaces
What’s the deal with sialic acid?
C3b is continuously deposited on surfaces of host cells and pathogenic organisms. Only get activated on right surface.
Low sialic acid =Bacterial surface
Our cells have lots of sialic acid so we are safe :)
So C3b is bound to cells…what inactivates it?
Factor H and Factor I
===C3bi
*this happens on non-activator surface (aka high sialic acid)
Amplification is so awesome:
Where, why, how?
-In all 3 pathways!
C3 convertase cleaves a bunch so we get lots of C3b deposits on surfaces
C5 convertase cleaves lots of C5 so we increase the likelihood of forming a complete MAC
Properdin?
Stabilizes the alternative pathway C3 convertase so it won’t decay as fast!
If antibody is activating complement, what C3 convertase is being used?
C4bC2a
Excessive complement activation in immune complex disease would most likely result in depletion of what components?
C4
-keeps getting covalently bound to immune complexes. Happens more quickly thank the making of C4
If C5b-9 don’t form a pore, what else than they do?
C5b-7 can bind to S protein in fluid phase. No lysis===Keeps it all local/confined.
Key points of MAC:
- after C5 cleavage, its just conformational changes
- Lysis can still happen without C9 (slower)
How do we control Complement activation?
- Short half life of enzymes
- our cells have high sialic acid levels
- Inhibitors:
- Fluid phase inhibitors
- Membrane bound inhibitors
Fluid phase inhibitors?
Fluid: so active fragments don’t go too far
ex: Factor H (inhibitor of C3 convertase) if it sees C3bBb floating around it binds and dissociates the Bb (alternative pathway)
Protein S
Membrane bound inhibitors?
Membrane: on OUR membranes
-keeps C3b and C4b from attaching and lysing our cells :) thanks so much!
C1 Inhibitor Deficiency
HAE=Hereditary angioedema
-recurrent episodes of localized edema in skin, GI tract, larynx
Normally, inhibits C1 esterase (and MASP) so C4 doesn’t get cleaved
Uncontrolled activation —> consumption of C4 and C2 so you can’t get rid of immune complexes
Secondary Deficiency
Using up proteins faster than you can make them.
Kinda a secondary autoimmune diseases b’c you can’t fight other infections
C1 Inhibitor Deficiency
Tx:
- Anabolic steroids to increase sythesis of C1 INH
- purified C1 INH
- Kallikrein inhibitors and B2 receptor inhibitors
Deficiency in DAF (CD55) & CD59
-Something is wrong with the anchor that binds these to membrane.
CD55= decays C3 convertases
CD59=stops C9 from inserting on membrane
Increased susceptibility of erythrocytes to MAC mediated lysis
Tx: antibody to C5 (anti C5)
What are the inflammatory mediators produced by complement activation?
C3a
C5a
Receptors for these on neutrophils, B cells, endothelial cells..
–>anaphylaxis (chemotaxis, smooth muscle contraction, increased vascular perm, degranulation of mast cells)
Other functions of complement:
Solubilization/clearance of immune complexes by…..
Augmentation of humoral immunity by…
…. CR1 receptor
……..CR2 receptor (CD21) –C3d tags bad things and takes it to lymphocytes to tell them to make antibodies.
CR1 (CD35)
- On RBC - makes each RBC a carrier for immune complex –> spleen for degradation
- Binds C3b, C4b
- CR1 also blocks formation of C3 convertase
- Promotes PHAGOCYTOSIS (neutrophils/macs)
Decays acceleration of C3 convertases
CR2 (CD21)
On B cells -augment stimulation of B cells to increase humoral immune response
-binds C3d, C3dg, iC3b
-CR2 has high affinity for Epstein Barr virus –>allows virus to enter the B cell.
CR3 and CR4
On WBCs
*Cell adhesion and phagocytosis
Binds IC3b
How does complement prevent formation of insoluble immune complexes?
- C3b binding with CR1 interferes with lattice formation and keeps it soluble.
–if allowed to aggregate it could cause damage to organs like kidneys
Factor H
Makes C3bBb decay faster
-Cofactor to Factor I for C3b inhibition (cleaves Bb off C3bBb so FI can –> C3bi
Works with alternative pathway
