Regal Complement Flashcards
Order of complement numbers:
1 4 2 3 5 6 7 8 9
What are 6 special functions of complement?
- lysis of pathogens
- opsonization of antigen –> uptake by phagocytes
- mediates inflammatory response
- solubilization and clearance of immune complexes
- augments stimulation of B-cells
- clearance of apoptotic cells
Complement molecules of the Classical pathway:
C1q – C1r2 — C1s2
Most abundant form of complement?
C3
C3 convertase is:
C4b2a
C5 convertase is:
C4b2a3b
Mannose binding pathway is activated by _________ and uses ____, ______, and ______ in place of C1q, C1r, and C1s to get to C4/2 stage.
Polysaccharides on microbes
MBL (mannose binding lectin), MASP-1, MASP-2
Alternative pathway is activated by ________ and uses _____, _____, and _____ to get to C3.
LPS, carbohydrates, etc.
Factor B
Factor D
Properdin
What is common to all pathways?
C3
What are the components unique to the terminal lytic pathway (MAC-major attack complex)?
C5, C6, C7, C8, C9
Small fragments are denoted by “a” and float away to act like cytokines, large fragments are denoted by “b” and bind to cell for next activation step. What is the exception to this?
C2a is the larger C2 fragment
Antigen binding to 2 _____ or ______ trigger the classical pathway/
IgG, IgM
What type of bond do C4b and C3b attach to cell surface via?
COVALENT, thioester
C1 esterase (C1qr2s2) does what? And is inhibited by what?
cleaves C4 into C4a (small) and C4b (big)
inhibited by C1INH
When C4b covalently binds to activating surface what can it do?
interact with CR1 (complement receptor) on white cells
What happens when C4b is bound to active surface and C2 comes along?
C1s cleaves it and leaves C2a (remember this is bigger) bound to make C4b2a —-> classical pathway C3 convertase
With C4b2a molecules bound to active surface, what happens when C3 comes along?
gets cleaved by C4b2a and C3b stick around to bind covalently and C3a float away.
*now we have C4b2a3b —> C5 convertase
How does the mannose binding lectin pathway get rolling?
Binds to cell active surface WITHOUT antibody involvement
- a C4 float by and gets cleaved leaving C4b
- then a C2 float by leaving a C2a
- now at same stage as classic pathway with a C4b2a bound to the cell surface waiting for a C3
Oldest C3 activating pathway and does not require antibody for activation?
Alternative patheway
Major activator of Alternative pathway?
LPS from Gram - bacteria
What do human cells have that protects them from activation of alternative pathway?
sialic acid
In the alternative pathway what comes to bind with C3b first?
Factor B
Once Factor B is bound to C3b, what happens next?
Factor D comes along and cleaves off Ba (little, just like 3a, 4a, 2b), and leaves Bb bound
Now you have C3bBb—just like C4b2a of classic pathway
What is the Alternative pathways equivalent of C3-convertase?
C3bBb
What stabilizes C3bBb?
Properidin
What are the two types of C5 convertase and what pathways are they associated with?
C4b2aC3b —- classical and Mannose
C3bBbC3b — Alternative
Activation of the complement system by antibody coated Strep pneumo leads to formation of a C3 convertase enzyme. The subunit composition of this enzyme is most likely:
A. C3bBbC3b
B. C4bC2a
C. C1qr2s2
D. C3(H2O)Bb
E. C3bBb
B. C4bC2a (i think you can also drop the second C and it means the same)
Which of the following complement proteins covalently binds to surfaces after enzymatic cleavage and exposure of an internal thioester bond?
A. C1qr2s2
B. C4b
C. C2a
D. Factor B
E. Factor D
B. C4b
Excessive complement activation in immune complex disease would most likely lead to the depletion of which of the following components?
A. C4
B. MBL
C. Factor B
D. Factor D
A. C4
What activates the terminal lytic pathway?
Cleavage of C5 into C5a and C5b by C5 convertase (either classical or alternative)
– C5b meets up with C6 then C7, C8, C9
– this creates a hole in the membrane and causes lysis and cell death
What are the components of the membrane attack complex?
C5b, C6, C7, C8, C9
What can prevent completion of the MAC?
When C5b-7 bind to S protein
Can lysis via MAC occur without C9?
yes, but it is slower
Two proteins that can interact with CR’s on white cells?
C3b, C4b —> CR’s 1-4
Two major limiting factors of complement activation?
- short enzymatic half life
2. properties of non-activator surfaces (sialic acid)
Control protein that binds to C1s/r in plasma so C4 not cleaved?
C1-INH
Control protein binds to soluble C5b-7 in the plasma?
S protein
Control protein that inhibits binding of C9 on human cell membranes?
CD59 aka Protectin
Control protein that can accelerate the decay of C3bBb so it can’t cleave C3?
Factor H
Factor H can bind to a membrane if ______ is present?
sialic acid
Protein that can degrade C3b with Factor H as a co factor?
Factor I
C1 Inh deficiency leads to:
HAE (hereditary angioedema)
*uncontrolled complement activation leads to consumption of C4 and C2
Treatment for C1 Inh deficiency:
Anabolic steroids to increase synth of C1 Inh
purified C1 inh
Kallikrein inhibitors and B2 receptor inhibitors
Control protein with wide distribution on “self” membranes that accelerates the decay of C3 convertase?
CD55 aka DAF (decay accelerating factor)
Cofactor on self membranes that has activity against C3b and C4b?
CD46 aka MCP (membrane cofactor protein)
Deficiency in DAF (CD55) and Protectin (CD59)?
increased RBC lysis by MACs
intravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH)
**also tx with Ig to C5 (eculizamab) reduces hemolysis and increases susceptibility to Neisseria
C3a and C5a function after they float away?
Inflammatory mediators
What’s an anaphylatoxin?
C3a and C5a can bind to C3a and C5a receptors and trigger an inflammatory response that can mimic anaphylaxis
** chemotaxis, smooth muscle contraction, increased vascular permiability, degranulation of mast cells
Opsonins of this system are?
C3b and C4b
Solubilization and clearance of immune complexes occur via _______ receptors.
CR1 (CD35)
Augmentation of humoral immunity occurs via ________ receptors.
CR2 (CD21)
Whats an important cell that transports immune complexes via CR1?
RBCs
Major cell (and two others) with CR2s?
B-cells
also activated T-cells and epithelial cells
CR2 has a high affinity for which virus?
EBV
Numerous C3b molecules are deposited on the surface of bacteria X. The C3b favors the phagocytosis of the bacteria by neutrophils by binding to which of the following?
A. anaphylatoxin receptor
B. CR1
C. CR2
D. Decay accelerating factor
B. CR1
Where do immune complexes attached to RBC CR1s go from there?
transferred to CR1s on macrophages in the reticuloendothelial system (ie. spleen, liver)
