Complement Flashcards
Where are complement proteins located?
mostly in the plasma (but also in secretions and interstitial fluid)
Does complement work on it’s own, or in tandem with humoral immunity?
both
What are the 6 functions of complement?
- lysis of invaders
- opsonization of antigen
- source of mediators for the inflammatory response
- solubilization and clearance of immune complexes
- clearance of apoptotic cells
- augment stimulation of the B cell to increase the humoral immune response
What are the three complement pathways?
- classical
- lectin
- alternative
Which of the three pathways requires antibody?
classical
What is the order of complement protein activation?
C1, 4, 2, 3, 5, 6, 7, 8, 9
If you have a complement deficiency in the classical pathway, what sort of disease are you at higher risk for?
Immune complex diseases
If you have a complement deficiency in the alternative pathway, what sort of disease are you at higher risk for?
infection - especially meningococcal infections
Where are the complement proteins synthesized for the most part?
the liver hepatocytes and by tissue macrophages (but also epitheliual cells, fibroblasts and monocytes)
What complement protein has the highest concentration in the plasma?
C3
What sort of reactions occur with complement 1-5? What reactions happen with C5-C9?
at first it’s all proteolytic cleavage, after C5, it’s all protein-protein interactions
Usually, the larger, active subunit after cleavage is derived as the #b unit. What’s the exception?
C2 - C2a is the bigger active subunit
What will trigger the classical pathway?
Antigen binding to antibody: either 2 IgG or 1 IgM
Is the binding of C4b and C3b to the surface ionic or covalent? With what type of bonds?
covalent - thioester bonds
What’s the first complement protein to bind the surface after the C1q interacts with the antibodies?
C4 (technically C4b)
C2 will be cleaved by C1s and interact with C4b to form what?
C4bC2a, which is the C3 convertase
THrough interactions, the C4bC2a and C3b form what?
the C5 convertase
What’s the primary constituent of the MBL pathway?
the plasma protein mannose binding lectin
What is the main trigger for the MBL pathway?
polysaccharide structures of microbes - specifically the NAG of LPS on salmonella, listeria, neiserria, candida, etc.
What proteins does MBL interact with to form a reaction similar to the C1qr2s2?
MASP1 and MASP2
What does the MLB/MASP complex do?
It cleaves C4, which then cleaves C2, so you get the same C4bC2a complex as in the classical pathway which acts as the C3 convertase here too
What are some of the things that trigger the alternative pathway?
It’s the most promiscous - it doesn’t take much: gram negative and gram positive bacteria, LPS, Teichoic acid, fungal and yeast cell walls, viruses, viral infected cells, tumor cells, parasites, human IgA, IgG and IgE complexes, anionic polymers (dextran sulfate0, pure carbs (agarose ,insulin)
The classical pathway relies on constitutive what?
“C3 tickover” - it’s a slow, but constant spontaneous conformational change of a few C3 molecules with water, forming a C3(H2O)
What happens to C3(H2O)
It gets bound to Factor B, which is then cleaved by Factor D to form C3bBb
What is C3bBb?
Another C3 convertase just like C4bC2a was!
What factor helps to stabilize C3bBb?
properdin - factor P
FOr the alternative pathway, surfaces rich in ___ and deficient in ___ tend to be the best activators?
high in carbs, low in sialic acid (which is why it doesn’t hurt our cells)
How does amplification occur?
A single C3 convertase can cleave many C3 molecules and a single C5 convertase can cleave many C5 molecules - increasing the provability that you will form a complete MAC
Excessive complement activation in immune complex disease would most likely trigger the depletion of what complement protein?
C4
If bound to a membrane, C5,6,7, will bind interact with what? If in the fluid phase, C567 will bind what?
membrane - will interact with C9, forming the MAC
fluid - will interact with protein S, which doesn’t cause lysis
Can lysis occur in the absence of C9?
Yes, but it’s much slower
What are some inherent aspect of the complement system and out cells that limit it’s activation?
- short half life of the complement enzymes
- We don’t usually make antibodies to our own cells
- We have sialic acid on our cells
- then there’s the inhibitors: fluid phase and membrane bound
What inhibitor will bind to C1s and C1r so that C4 is not cleaved?
C1 INH (C1 inhibitor)
What does S protein do specifically?
It binds to soluble C5b-7 and blocks its integration into membranes
What does CD59 (or protectin) do?
It inhibits the binding of C9 and its polymerizaiton, thus inhibiting the MAC
What does Factor H do? 2 things…
- It’s a fluid phase inhibitor that binds to C3bBb and causes the Bb to dissociate, thus inactivating its C3 convertase activity
- still bound to the C3b, it will act as a cofactor for Factor I to break down the C3b
WHEN does Factor H break down C3bBb?
When it sees it bound to the surface of a cell with sialic acid (our own cells)
What happens in C1 inhibitor deficiency?
You get hereditary angioedema - recurrent episodes of localized edema due to uncontrolled complement activation
What is the treatment for hereditary angioedema?
Attenuated androgens to increase C1 INH transcription
Anabolic steroids to increase synthesis of C1 inhibitor
purified C1 inhibitor
Kalikrein inhibitos and B2 receptor inhibitors
What happens in a deficiency of DAF (Cd55) and CD59?
you don’t get inhibition of MAC formation, so your erythroblasts are susceptible to lysis - this is paroxysmal nocturnal hemoglobinuria
What is the treatment for a CD55 and CD59 deficiency?
eculizumab - an antiboydy against C5, so you can’t form MACs - it makes you susceptible to infection thoguh too
Through what receptor does complement increase the solubility and clearance of immune complexes?
CR1
Through what receptor does complement augment humoral immunity?
CR2
C3a and C5a are examples of what? What can they do?
Anaphylatoxin - they interact with receptors fo mimic inflammation and anapylaxis, causing chemotaxis, smooth muscle contraction, increased vascular permeability, degranulation of mast cells, etc.
C3b are not the only forms of C3 that can interact with ocmplement receptors to have an effect. WHat are some others?
C3bi (inactivated C3b), C3d, C3dg
What CR1 do? Mainly through what cell?
It interacts with C3b and C4b primarily on RBCs and induce the transport of immune complexes by RBCs
also promotes phagocytsosis and blocks formation of C3 convertase
What does CR2 do? Mainly through what cell?
on B cells primarily, it forms an additional signal with antibody to augment the stimulation of B cells to increase the humoral response
What virus uses CR2 to enter B cells?
EBV
What does CR3 do?
It interacts with iC3b to increase cell adhesion and bind immune complexes
Immune complex disease occurs in individuals whoa re deficient in what?
C1, C4, C2, and C3
How do RBCs help with the removal of ICs?
RBCs have the majority of the CR1s, so they bind the ICs that are covered in C3b and bring them to the RES cells in the spleen, where they transfer the ICs to the CR1s on macrophages
