Complement Cascade Flashcards
3 functions of complement cascade
- anaphylatoxin production, inflammatory mediators that activate vascular epithelium and recruit phagocytes
- opsonization
- formation of MAC
alternative pathway
innate, first to be activated
lectin pathway
innate, second to be activated
classical pathway
acquired (has an innate function as well), last to be activated
T/F all complement components produced by liver in inactive form
true
C3bBb
C3 convertase of the alternative pathway
C4bC2a
C3 convertase of lectin and classical pathway
Importance of C3b deposition
- it’s a component of the C5 convertase which is necessary for formation of the MAC
- opsonin
C3a
anaphylatoxin
C3b2Bb
C5 convertase-important for generation of the MAC
Formation of C3bBb
C3b binds pathogen, then factor B binds that, then factor D cleaves resulting in the C3 convertase C3bBb
C3b
opsonin
C5 convertase
Cleaves C5 into C5a and C5b
C5a
anaphylatoxin, IMPORTANT chemotactic factor for neutrophils (along with IL-8)
C5b
first component of the MAC
MAC formation
C5b joins with C6 and C7 which then joins with C8 which then recruits 10-16 of C9 resulting in the production of a pore in the bacterial cell membrane resulting in disintegrity and death
MBP/MBL
mannose binding protein of the lectin pathway, binds mannose residues of the bacteria
MASP-1/2
MBP recruits these, they bind and then result in the cleavage of C4 and C2 which results in the formation of the C4aC2b convertase of the lectin pathway (C3 convertase does the same thing as in the alternative path)
Classical pathway involves ____
antibodies
Classical pathway initiation
when complement component C1 binds to antibody that is bound to its cognate antigen
C1 molecule
has 6 C1q stalks with C1r and C1s. When C1 binds to an antigen-engaged antibody C1r cleaves C1s which then cleaves C4 and C2 to create the C4aC2b convertase of the classical pathway (C3 convertase does the same thing as in the other two pathways)
C4a
anaphylatoxin
C2b
anaphylatoxin
Most efficient isotopes for initiation classical complement cascade?
IgM and IgG3
Deposition of C3b leads to
- uptake and destruction of pathogen by phagocytes that have receptors for C3b
- creation of the MAC
C4b2a3b
C5 convertase
T/F Alternative pathway amplifies the other two pathways
true
Innate classical pathway
C reactive protein produced by the liver during septic bacterial infections binds to phosphocholine residues on bacteria and mimics the IgM antibody and thus recruits the C1 molecule and initiates the classical complement cascade
Complement is important for encapsulated bacteria because____
phagocytes can’t recognize PRRs on them bc they’re covered by the capsule but complement factors can be deposited on their surface which leads to phagocytic activity
T/F there are no Fc receptors for IgM
true
CR1
found on phagocytes
recognizes C3b and results in phagocytosis
CR1 on RBCs
clearance of immune complex-IMPORTANT-if not cleaned up they cause vasculitis and kidney disfunction
CR3 and CR4
found on phagocytes
recognize iC3b, breakdown of C3b and stimulate phagocytosis
CR2
B cell co-receptor
it increases the signaling that results from B cell receptor binding to cognate antigen, decreasing the amount of costimulation signal needed from helper T cells
C3a and C5a
role in activating mast cells
anaphylatoxins
2 forms of regulation of complement
- passive
2. active
passive regulation
hydrolization of thioester bonds
C1 inhibitor
binds C1r:C1s and causes them to disassociate from C1q so they cannot cleave C4 and C2
Deficiency of C1 inhibitor (HANE)
results in the overproduction of anaphylatoxins (which remember can stimulate mast cells) and cause angioedema episodes
C4 binding protein
binds to the C4b component of the classical pathway C3 convertase, causing a displacement of the C2b fragment and making the C4 fragment susceptible to cleavage by factor I, permanently disabling that copy of the C3 convertase enzyme
factor H
H binds to C3b, making it susceptible to cleavage by factor I. Once C3b is cleaved to form iC3b, it can no longer serve as a template for factor B binding, so that copy of C3b can never become part of a functional C3 convertase of the alternative pathway
factor I
protease that cleaves C4b once C2 has been dissociated from it by C4-binding protein and it cleaves C3b that has been bound by factor H
Factor I deficiency
this leads to depletion of C3, preventing activation of the complement cascades when they are really needed
also results in deficiency of iC3b
decay accelerating factor (CD55)
a membrane-bound protein that gets its name from its ability to dissociate C3 convertase enzymes
MCP
MCP binds to either C3b or C4b, they become susceptible to cleavage by factor I
membrane bound
CR1
membrane-bound protein that binds to C3b and C4b, making them susceptible to factor I cleavage.
CD59/protectin
prevents membrane attack complex formation on host cells by binding to the C5b,6,7,8 complex and preventing C9 from binding to the complex
paroxymal noctural hemoglobulinuria
the inability to produce a phospoinositol glycolipid tail that anchors decay accelerating factor and CD59 (or protectin) into the membrane of host cells
results inperiodic episodes of intravascular erythrocyte lysis
