Complement Cascade Flashcards
what systems does complement “complement”?
humoral and innate immunity
C’
complement
complement is central to what?
inflammatory reactions
triggering and amplifying inflammation, attraction of phagocytes, clearance of immune complexes, cellular activation, direct microbial killing, and important in development of the humoral responses
larger and smaller fragment of complement?
a - smaller
b - larger
b binds and a diffuses
anaphylotaxins
a fragments of complement
are chemotactic peptides
role of anaphylatoxins
play a role in initiating a localized inflammatory response
all pathways of complement end where?
formation of the MAC
classical pathway
activated by antigen binding to antigen
assists in the humoral response
alternative pathway
not necessary for a prior exposure
-doesn’t need antibody
plays a role in surveillence
more primitive than classical
lectin pathway
activated by binding of mannose binding protein in bacteria
initiation of classical pathway?
IgG or IgM antibody is bound and results in the binding of C1
-C1 binds to Fc portion of antibodies
overview of classical complement pathway
most efficient and fast
1) IgG and IgM antibodies bind antigen and Fc portion binds C1
-binds to C1q domains (cleavage of C1r and C1s)
enzymatically active C1qrs
structure of C1
one hexamer C1q subunit, two C1r, and two C1s subunits
forms a large complex
what activates C1?
cleavage of C1r and C1s
-yields active C1qrs
*the C1 is a C1q hexamer, two C1r, and two C1s subunits
how many of each antibody to activate classical pathway?
IgM is a pentamer
-only requires one to initiate cascade
IgG is a monomer
-requires at least two to initiate cascade
activity of enzymatically active C1qrs?
cleaves C4
-release C4a and C4b
C4b attaches to the cell membrane which form clusters around the area of the antibody interaction
C4a diffuses away
also cleaves C2
activity of C4b?
recruits C2, which is also cleaved by C1qrs
-C2a diffuses away and C2b binds to C4b
what is the C3 convertase of classical pathway?
C4b2b
-cleaves C3
C3b will opsonize and also associate with the C3 convertase
-forms the C4b2b3b (C5 convertase)
importance of C3
responsible for the distinction between self and non-self
self surfaces limit the deposition of C3b
-C3b rapidly associates with non-self surfaces
C5 convertase of the classical pathway?
C4b2b3b
initiates the formation of the MAC complex
C5b associates with C6 and C7 which inserts into the membrane
-forms pore - which will lead to slow lysis
C8 then bind the C5b67 which
-forms C5b678 which recruits 10-16 copies of C9
forms the MAC
what is the MAC complex?
C5b6789
creates large pores in the membrane
-results in more rapid osmotic lysis of the cell
alternative pathway of complement?
slow and less efficient
surveillence system
initiation of alternative pathway?
spontaneous conversion of C3 to C3b
-important in recognizing self from non-self
how is C3b involved in the recognition of self membrane?
sialic acid levels are high on the self membranes
-result in the inactivation of C3b
bacterial and viral envelopes have low sialic acid
-C3b remains associated with membrane
C3 convertase of the alternative pathway?
factor B binds to C3b and is cleaved
-factor D cleaves factor B
forms C3bBb (alternative C3 convertase) results in the cleavage of C3 (amplifies process)
Factor B
binds to membrane associated C3b
cleaved by Factor D
Factor D
cleaves factor B bound to C3b
-results in C3bBb (C3 convertase of the alternative pathway)
properdin
binds the C3 convertase of alternative pathway and stabilizes it
*increases its half-life
C5 convertase of alternative pathway?
C3bBbP3b
Properdin is stabilizing the C5 convertase
C5 convertase cleaves C5 and formation of MAC complex occurs
lectin pathway?
antibody-independent
involves the lectin
-MBLs and MASPs
activation of the lectin pathway?
MBL binds MASP on bacterial surface polysaccharides
this structure is similar to the C1q
-cleaves C4 and C2
forms C4b2b (C3 convertase of the classical pathway) -everything occurs as classical pathway forms the C3 convertase C4b2b
RCA proteins?
regulators of complement activation
two main function of RCA?
bind and cause dissociate
cause the proteolytic cleave of components
first level of control of convertases?
decay acceleration
decay acceleration
many of the components have short half lives
C3b is hydrolyzed rapidly**
C1inh
in both classical and lectin pathway
binds to the C1r and C1s to dissociate them from C1q
removes MASP enzymes from MBL complex
Factor I
plasma protein
cleaves C4b or C3b
has several cofactors - C4-bp, MCP, CR1
prevents formation of C3 and C5 convertases
- C3 - C4 degradation - C5 - C3 degradation
cofactors of Factor I
C4-bp, MCP, CR1
C4-binding protein
binds to C4b
- prevents its association with C2b - causes C4b to dissociate from the C3 convertase
C4-bp/C4b is target for digestion by Factor I
Complement Receptor I
binds C3b and allows for the cleavage by Factor I
**mechanism for distinguishing between self and non-self
(CR1;CD35)
Membrane Co-factor protein
MCP;CD46
co-factor for factor I
binds to either C4b or C3b
found on self membranes
*allows self vs. non-self recognition
Factor H
analagous to C4-bp
binds to C3b and prevents C5 convertase formation
Factor H/C3b is a target for factor I
protected site concept
factor H binding only occurs if the C3b has been deposited on surface of cell
decay-accelerating factor
DAF;CD55
promotes the dissociation of the C3 convertase
- C2b from C4b and Bb from C3b - in classical and alternative pathways
CD59
blocks C9 binding to C5b678 on cell surface
vitronectin (S protein)
binds to the fluid phase (C5b67)
-prevents binding to membrane
* *doesn't prevent C8 or C9 association - forming MAC, but they aren't in the membrane
opsonization
-major one in body?
major one is C3b
C4b is also an opsonin
Complement receptors on the phagocytic cells bind to the C3b or C4b
- increases phagocytosis - also the a fragments increase phagocytosis
activity of anaphylatoxins?
increase the number of complement receptors on the cell surface of phagocytes
greatly facilitate their phagocytosis of complement opsonized cells
waste management
removal of immune complexes from circulation
-antibodies bind extracellular antigens
antibody with bound C3b
- binds to erythrocytes complement receptor - taken to the spleen and liver (degradation) - erythrocytes offload the antibody/complement
MAC activity on erythrocytes?
only single MAC to lyse an RBC
nucleated cells and MAC?
usually requires several MACs
there are certain cells that can internalize the MAC and degrade it
complement and inflammation?
instrumental role
activation of complement results in influx of fluid
anaphylatoxins function?
increase inflammation
bind to receptors on mast cells and basophils - histamine
smooth muscle contraction - vascular permeability
monocytes and neutrophils to adhere to endothelial cells
C5a
most potent in mediating the processes of inflammation in response to complement cascade
C2a
prokinin
cleaved by plasmin to yield kinin
-results in edema
C3 deficiency
can lead to life-threatening situations
-noticed early after birth
can be mimicked by deficiency in factor H and factor I
**why?
MAC deficiency?
C5, 6, 7, 8, 9
generally healthy
except infection by Neisseria gonorrhoeae and N. meningitidis
deficiency in C1, 2, and 4
most common is C2
-patients have a high degree of systemic lupus erythematois
SLE
C1inh deficiency
HANE
chronic low levels of C4 and C2
swelling with no obvious cause
commonly involves the extremities
DAF deficiency
decay-accelerating factor
leads to paroxysmal nocturnal hemoglobinuria
hemolytic disorders
-degrades RBCs
treat with erythropoietin
viruses and complement?
use them to increase its infectivity
epstein-barr - CR2 as a receptor for attachment
measles - MCP as a receptor
West Nile virus - C3b to gain entry into cells via CR3 recepor
