Complement Flashcards
fxns of C’
triggering and amplification of inflammation rxns
chemotaxis for phagocytes
clearance of immune complexes
direct microbial killing
classical C5 convertase
C4b2a3b
alternative C5 convertase
C3bBb3b
activation of classical C’ pathway
Ab binding Ag
activation of alternative C’ pathway
independent of Ab
constant “trickle” of activated C’ for surveillance
activation of lectin C’ pathway
binding of a serum mannose binding protein to bacteria
diagram classical C’ pathway
1) C1q/2C1r/2C1s (C1) binds to multiple Fc of immune complex -> C1qrs
2) C1qrs + C4 -> C4b + C4a
3) C4b clusters near bound Ab, attracts C2
4) C1qrs + C2 -> C2a + C2b
5) C2a associates w/ C4b -> C4b2a (C3 convertase)
6) C3 convertase + C3 -> C3a + C3b
7) C3b deposits on non-self surfaces or associates w/ C4b2a -> C4b2a3b (C5 convertase)
8) C5 convertase + C5 -> C5a + C5b
9) C5b + C6 + C7 -> C5b67
10) C5b67 inserts into membrane, forms small pore -> slow lysis of target cell
11) C8 associates w/ C5b67, recruits 10-16 C9
12) C9 polymerizes, forms large pore in membrane -> osmotic lysis
diagram alternative C’ pathway
1) C3 -> C3a + C3bi (spontaneous!)
2) C3bi binds to membranes w/ low levels of sialic acid
3) Factor B binds C3bi
4) Factor D + Factor B -> Ba + Bb
5) C3bi + Bb -> C3bBb (C3 convertase)
6) properdin (P) + C3bBb -> C3bBbP (increases half-life of C3 convertase)
7) C3bBbP + C3b -> C3bBb3bP (C5 convertase)
8) C5 convertase + C5 -> C5a + C5b
9) C5b + C6 + C7 -> C5b67
10) C5b67 inserts into membrane, forms small pore -> slow lysis of target cell
11) C8 associates w/ C5b67, recruits 10-16 C9
12) C9 polymerizes, forms large pore in membrane -> osmotic lysis
diagram lectin C’ pathway
1) mannose binding lectin (MBL) or ficolin binds mannose
2) MBL/ficolin bind MBL-associated serine proteases (MASPs); structurally similar to C1 complex
3) MBL/MASP + C4 + C2 -> C4a + C4b + C2a + C2b
4) C4b clusters near bound Ab, attracts C2a
5) C2a associates w/ C4b -> C4b2a (C3 convertase)
6) C3 convertase + C3 -> C3a + C3b
7) C3b deposits on non-self surfaces or associates w/ C4b2a -> C4b2a3b (C5 convertase)
8) C5 convertase + C5 -> C5a + C5b
9) C5b + C6 + C7 -> C5b67
10) C5b67 inserts into membrane, forms small pore -> slow lysis of target cell
11) C8 associates w/ C5b67, recruits 10-16 C9
12) C9 polymerizes, forms large pore in membrane -> osmotic lysis
C’ regulation - component half-life
many C’ components undergo spontaneous inactivation as they diffuse away from the site of activation
C4b/C3b hydrolyze rapidly -> limits C4b/C3b deposition to nearby cells, limits formation of C3/C5 convertases
C’ regulation - C1inh (C1 inhibitor) - MOA
binds to C1r, C1s and MASP molecules
dissociates them from C1q/MBL complex
C’ regulation - Factor I - MOA
also C3b inactivator
cleaves C4b or C3b, prevents formation of C3/C5 convertases
requires co-factors
C’ regulation - C4-bp - MOA
binds C4b, prevents association w/ C2a
causes C4b to dissociate from C3 convertase
C4b/C4-bp targeted for digestion by Factor I
C’ regulation - complement receptor 1 (CR1) - MOA
also CD35
binds C3b molecules, allows cleavage by Factor I
mechanism for distinguishing btw self and non-self
C’ regulation - membrane co-factor protein (MCP) - MOA
also CD46
co-factor for Factor I
binds C4b/C3b
MCP is found on self membranes, helps distinguish btw self and non-self
C’ regulation - Factor H - MOA
analogous to C4-bp but binds C3b
prevents formation of C5 convertase
Factor H/C3b complex targeted by Factor I
describe the protected site concept
Factor H binding only occurs if C3b has been deposited on surface of self cell
deposition of C3b on microorganism means it is “protected” from Factor H -> activation of alternative C’ pathway
C’ regulation - decay-accelerating factor (DAF) - MOA
also CD55
promotes dissociation of C3 convertase (C2a from C4b, Bb from C3b)
C’ regulation - CD59 - MOA
blocks C9 binding to C5b678 complex
C’ regulation - vitronectin (S protein) - MOA
binds to fluid phase C5b67, prevents binding to membranes
does NOT prevent association w/ C8 and C9
MAC has no effect since it is not within a membrane
major opsonins of opsonization
C3b: due to abundance
C4b
C5a (anaphylatoxin): increases expression of C’Rs on surface of phagocytes
how are immune complexes removed from circulation?
1) IC opsonized w/ C3b/C4b
2) IC binds CR1 on RBC
3) IC transported to hepatic macrophage, becomes bound to it
4) IC/RBC bond broken -> RBC returns to circulation
5) liver metabolizes IC
how are self cells protected from MAC?
nucleated cells are more resistant to C’-mediated lysis
require formation of multiple MACs to destroy cell
many nucleated cells can endocytose MAC (including cancer cells)
single MAC can lyse RBC (anucleate)
anaphylatoxins - fxns
C5a is most potent mediator
bind to receptors on mast cells and basophils -> induce degranulation
induce smooth muscle contraction -> increased vascular permeability
induce monocytes and neutrophils to adhere to vascular endothelium -> increased extravasation
produces edema through cleavage to kinin by plasmin
C2b (prokinin)
C3 deficiency - effects; similar conditions?
life-threatening
severe, recurrent infxns soon after birth
Factor H/I deficiencies mimic -> unregulated C3b generation by C3 convertase completely exhausts C3 from serum
MAC deficiencies (C5-C9) - effects
generally healthy individuals
increased infxn w/ *Neisseria gonorrhoeae *and Neisseria meningitidis
C2 deficiency - effects
most commonly identified form of C’ deficiency
high degree of systemic lupus erythematosis (SLE) -> may arise from failure to efficiently clear circulating ICs
IC deposition on endothelium -> activation of C’ -> inflammation -> possible breakdown of tolerance to self Ags -> autoimmunity
C1inh deficiency - effects
C4 and C2 levels chronically low
hereditary angioneurotic edema (HANE): swelling attacks w/ no obvious cause; commonly involves extremities, face and GI tract; tx w/ androgens has produced near-normal levesl of C1inh in some pts
DAF deficiency - effects
paroxysmal nocturnal hemoglobinuria (PNH) (most pts wake up in the morning and urinate blood)
spontaneous episodes of hemolysis
RBCs, WBCs and platelets have increased sensitivity to C’ lysis
tx: EPO
viruses that use C’ components to increase infectivity
Epstein-Barr: uses CR2 as receptor for attachment
measles: uses MCP (CD46) as receptor for attachment
West Nile: C3b coats viral particle, enters cells via CR3 receptor
