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What is the definition of the complement system?
System of proteins largely produced by the liver and mostly found in blood
Where are complement proteins found?
Mostly blood, but can be found at other sites, including inside cells
What outcomes come from the cascade of active enzymes and accessory proteins in the complement system?
Lysis - direct destruction of bacteria
Inflammation - release of anaphylatoxins to increase local inflammation and fight infections
Opsonization - coating a surface with C3b and C4b to increase uptake by phagocytic cells
What three pathways are activated by compliment?
alternative
lectin
classical
In the classical pathway, what binds to the antigen-antibody complex to activate C4?
C1qC1rC1s
C1q binds to _______ antibodies
multiple
What is the complement cascade initiation of the classical pathway?
globular head of C1q binds to antibodies
C1r undergoes conformational change & cleaves C1r and C1s
Active C1s cleaves C4 to C4a + C4b
C4b binds C2 which is cleaved to C2a/b by C1s
C4b/C2a bind to C3 and cleave it to C3a and C3b
What two components make C3 convertase in the classical and lectin pathway?
C4b and C2a
What cleaves C4 to create C4a and C4b in the classical pathway
Active C1s
What are the first antibodies of the classical pathway?
IgM
What is the complement cascade initiation of the lectin pathway?
Globular heads of MBL bind to bacterial carbohydrates
MASP1/2 undergo conformational change-cleaves MASP1 and MASP2
Active MASP1/2 cleaves C4 to C4a and C4b
C4b binds C2 which is cleaved to C2a/b by C1s
C4b/C2a bind C3 and cleave it to C3a and C3b
What cleaves C4 to create C4a and C4b in the lectin pathway
MASP1/2
What is the complement cascade initiation of the alternative pathway?
C3 is hydrolyzed by water in the blood-creating pseudo-C3b
Factor B binds to C3(H2O)
Factor D cleaves Factor B to Ba and Bb
C3(H2O)Bb bind to C3 and cleave it to C3a and C3b
C3b/Bb attaches to a surface
Properdin stabilizes the C3 convertase
C3bBb binds to C5 and cleaves it into C5a and C5b
What create C3 convertase in the alternative pathway?
C3H2O and Bb
What role does Factor B play in alternative pathway?
stabilization
For all 3 pathways there are 2 stages. What are they and what shows which is which?
Initiation
Amplification
It goes from initiation to amplification once C3 is bound to C3 convertase
All 3 pathways lead to one common factor that brings them together. What is this?
C5
What does MAC stand for?
Membrane Attack complex
Where can cascade happen?
Anywhere compliment activates
_______ increases inflammation
Anaphylatoxins
C3a and C5a will bind to what in a transmembrane protein to activate anaphylatoxin signaling?
C3aR or C5aR
Anaphylatoxin signaling and inflammatory response is carried out by what?
Macrophage - chemotaxis, phagocytosis, cytokine
Basophil - degranulation
Eosinophil - degranulation,chemotaxis
Neutrophil - degranulation, chemotaxis, phagocytosis
Mast cell - degranulation, chemotaxis
What increases phagocytic uptake?
Opsonization
What is opsonization?
when opsonins coat a pathogen with macrophages and neutrophils to “tag” it for destruction by phagocytes
Other than bacteria, what can compliment opsonize?
deposited immune complexes, viruses, apoptotic cells, host cells
What will happen is C1/C2/C4 had a deficiency?
Failure to clear ICs, apoptotic cells
What will happen is C3 had a deficiency?
Lack bacterial clearance
What will happen is C5-C9 had a deficiency?
Loss of bacterial lysis
What will happen is MBL had a deficiency?
No binding lectins
What will happen is Factor B & D had a deficiency?
Loss of AP
What will happen is properdin had a deficiency?
X-linked
What are examples of CR1s?
Erythrocytes, neutrophils, monocytes, macrophages, eosinophils, FDCs, B cells, some T cells
What are examples of CR2s?
B cells and FDCs
What are examples of CR3s?
Monocytes, macrophages, neutrophils, eosinophils, NK cells, T cells, FDCs
What are examples of CR4s?
Monocytes, macrophages, neutrophils, dendritic cells, NK cells, T cells
CD59 does what to regulate compliment?
protection
CD55 does what to regulate compliment?
decay accelerator
CD46 does what to regulate compliment?
membrane cofactor
What occurs during displacing C1 proteases?
C1q binds to antigen-antibody complex to activate C1r and C1s. C1 inhibitor dissociates C1r and C1s from the active C1 complex
What occurs during inactivating C4?
C4b2b is the active C3 convertase. DAF,C4BP, and CR1 displace C2b from the C4b2b complex. C4 bound by C4BP or MCP is cleaved by soluble protease 1 to inactive forms of C4c and C4d
What occurs during inactivating C3?
C5 is cleaved into C5a and C5b. CR1 and H displace C3b. Cr1 and H act as cofactors in the cleavage of C3b
What stops the MAC?
CD59 prevents final assembly of the membrane attack complex at the C8 to C9 stage
What in the cell cleaves and chops up C3 and C5
lysosome
Pathogens can take advantage of ____ for cell entry
CD46