the complement system Flashcards
complement proteins are normally found in
plasma and among the plasma proteins that leak out of the capillaries into the tissue spaces
complement system
consist of approximately 20 heat- liable serum and cell surface proteins, many of which are enzyme precursors that must be cleaved to form active enzymes
complement proteins are synthesized by the
liver and macrophages
Juleus Bordet concluded that the lytic effect required two factors:
1) specific antibody
2) heat- liable component present in normal serum
Paul Ehrlich called the labile component _____, since it was thought to assist or complement the lytic function of antibodies.
complement
two main pathways for complement activation:
1) classical way
2) alternative pathway
classical pathway is initiated by:
antigen-antibody (IgM or IgG) complexes
alternative pathway is initiated by:
microbial surfaces
Both of the pathways for complement activation lead to the production of
C3b, the central molecule of the complement cascade
C3B can combine with other complement components to generate
C5 convertase
C5 convertase
this enzyme leads to the terminal pathway that produces the membrane attack complex (MAC)
when the complement system is _____, multiple products are formed that preform a variety of biological functions, including ___ ___ ___.
activated
cell membrane lysis
C3 is
the most abundant complement protein
the enzyme cascades are generated by the sequential ____ ____ of enzyme precursors (______ or ______) to generate enzymes with proteolytic activity. In the process, an inhibitory fragment (____(“a”)) is removed, exposing the active site on the ____ ____ (“b”).
proteolytic cleavage
proenzymes or zymogens
small fragment
major fragment
regulatory proteins present in serum and on host cell membranes ___ or ____ complement-mediated damage.
inhibit
minimize
T or F:
Since microorganisms lack these regulatory proteins, complement activation is allowed to occur on microbial surfaces.
T
proteins of the classical pathway
C1( C1qr2s2)
C2
C3
C4
proteins of the alternative pathway
C3
Factor B
Factor D
Properdin
the classical complement pathway
is initiated by binding of C1 to the Fc regions of IgM or IgG molecules that have bound to antigen
C1 is composed of 3 subunits:
C1q and two molecules each C1r and C1s held together by non-covalent and stabilized by calcium ions
C1q
- Cannot bind to free or soluble IgM or IgG
- six globes held on slender shafts that fuse into a common base
- globes are recognition unit
- when IgM or IgG binds to its antigen, its active site on the Fc region is exposed to C1q
each IgM or IgG Fc region possesses only ___ C1q-binding site, and each C1q molecule must bind to ___ Fc regions to be activated.
one
two
T or F:
IgM is a much more efficient complement-binding antibody than IgG
true
C1r
- serine protease
- binding of two or more of the globular heads of C1q to IgG or IgM induces a conformational change in C1r, converting C1r to an active protease enzyme that is able to cleve and activate C1s
C1s
- serine protease
- once it is activated it cleaves C4 into a larger C4b fragment adn a smaller C4a fragment
C4b fragment
- has an internal thioester bond that binds to the target cell membrane in the vicinity of C1
- when unbound decays in the medium
C4a fragment
is released into the fluid phase
C2
proenzyme binds to the exposed binding site on the cell- bound C4b to form C4bC2 complex; C2 is cleaved by a nearby C1s molecule into a soluble C2a fragment and C2b
classical C3 convertase
C2b remains bound to C4b to form an enzyme complex C4b2b
substrate modulation
C1s cannot act on C2 unless it is bound to C4b
C3
- activated by proteolytic cleavage
- C4b2b binds to and proteolytically cleaves C3 into C3b and a small C3a fragment
a single C3 convertase enzyme can generate more than ___ molecules of C3b, resulting in tremendous ____ at this step of the complement cascade.
200
amplification
there are 3 things that C3b can do:
- can bind to c3 convertase to form the C5 convertase
- can bind directly to cell membrane in the vicinity of C4b2b
- some diffuse away and coat immune complexes (antigen-antibody complexes) and particulate antigens, eg, bacteria, functioning as opsonin and promoting phagocytosis
C5 convertase
C3b cmponent of the complex binds C5 and alters it conformation, so that the C4b2b component can cleave C5 into C5a and C5b
C5a
is released into the fluid phase
C5b
remains attached to the C5 convertase, initiating the terminal pathway of the complement activation.
alternative complement pathway
-described by pillemer
system for activating complement begining at C3, which does not involve an Ag-Ab reaction but by binding of complement protein C3b to the surface of a patogen
microbial structure that can activate the alternative pathway include:
lipopolysaccharide
teichoic acid
zymosan
viral envelopes
Alternative pathway is ____ important than the classical pathway the ___ time an individual or animal is infected by a microorganism, because the ___ or ___ required to trigger the classical pathway is not present
more
first
IgG
IgM
the thioester bond in C3 can be cleaved by:
plasmin
phagocyte
proteases
trypsin
C3b binding to host cell surfaces is inactivated by :
factor H and I
Factor H has an affinity for ___ constituents of host cell membrane glycoproteins and this ___ its binding to any C3b deposited on host cells
sialic acid
increase
some bacteria may express high levels of sialic acid on their cell surfaces or they may scavange sialic acid from the host and enzymatically transfer the sugar to their cell surface. this can ____ the alternative pathway by enhancing the binding of factor ___ to ___ on the bacterial membrane
inhibit
H
C3b
factor d
factor B binds to C3b undergoes substrate modulation and is cleaved by factor D to yield a soluble fragment, Ba and a larger fragment Bb that remains attached to C3b
C3bBb
is the alternative C3 convertase and it cleaves more C3 molecules, initiating anamplification sequence for C3b
extremely unstable unless bound to properdin
C5 convertase
C3b generated by C3 convertase can bind to the convertase.
his results in the formation of C3bBb3b complex, which functions as the alternative C5 convertase to cleave C5 and initiate the terminal pathway
cleaves C5 into a soluble C5a and C5b.
C5b67 complex
undergoes a conformational change, causing its release from the C5 convertase and exposing hydrophobic regions that enable the complex to bind to membrane phospholipids
when bound binds to C8
C5b678 complex
is responsible for slow membrane leakage. a fully active MAC is accomplished by the polymerizaion of up to 18 molecules of C9 to form a tubular pore in the cell membrane, allowing the entry of water and ions
complement receptors
cell surface proteins on various cells which recognize and bind to various complement fragments
this facilitates the effector functions of complement
most of the effector functions of the complement are mediated by binding of _____ fragments of complement proteins to various cell surface receptors.
proteolytic
only cell lysis is mediated by the
MAC
cells include:
erythrocytes, Gram negative bacteria, tumor cells, and enveloped viruses
__________ are not susceptible to the mAC because their cell membranes are protected by the thick peptidoglycan layer
Gram positive bacteria
chemotactic fragments include:
C5a, C3a, C5b67
chemotaxis of monocytes/macrophages and polymorphs
___,_____, and ___, bound to microbial surfaces can simultaneously bind to complement receptors on neutrophils and macrophages, stimulating engulfment and intracellular killing
C3b, C4b, iC3b
___>___>___ bind to mast cells and blood basophils and induce degranulation with the release of histamine and other vasoactive mediators. the mast cell reactions result in influxes of phagocytic cells and plasm proteins to the site of microbial invasion.
C5a, C3a, C4a (anaphylatoxins)
C5a and C3a
bind to their receptors on endothelial cells inducing the expression of P selectin and vascular permeability, events that promote leukocyte extravasation into tissue
P-selectin
promotes neutrophil binding
anaphylatoxins can also bind ___ to smooth muscle cells of the bronchioles and cause______.
directly
bronchospasm
activation of phagocytes involves:
- rearrangement of integrin adhesion molecules
- increased expression of CR1 and CR3
- stimulation of the respiratory burst and production of reactive oxygen intermediates
- release of inflammatory cytokines, proteases
Bb
activates macrophages, ausing them to adhere to and spread on surfaces, thus inhibiting macrophage migration from the site of antigen deposition
the central role of C3b
- binds to factor B, C5 and cellsurface proteins and polysaccharides
- nonspecific opsonin
- clearance of immune complexes from the circulation
- selection of B calls in germinal centers
- source of iC3b, C3d, etc
Uncontrolled activation of complement can:
- rapidly deplete complement proteins
- lead to formation of MAC on normal host cells
- result in excessive generation of inflammatory mediators
regulation of complement is mediated by:
circulating and cell surface proteins
spontaneous decay of activated complement components include:
time and temperature dependent dissociation of the active complexes such as C4b2b, C3bBb and C5b67
soluble C1 inhibitor
covalently binds to active C1r2 and C1s2 and dissociates them from C1q, thus stopping activation by the classical pathway
membrane-bound decay- accelerating factor
displaces Bb from c3bBb or C2b from C4b2b, the alternative and classical pathway c3 convertases
soluble anaphylatoxin inactivator
proteolytically removes terminal arginine residues and inactivates the anaphylatoxins
fluid phase Factor I
cleaves cell-associated C3b and C4b. C3b is cleaved to yield iC3b, C3c, C3d, C3f, and C3dg. this factor is active only in the presence of regulatory proteins or cofactors
soluble factor H
cofactor for cleavage of C3b by factor I
s protein
binds to C5b67 complex, preventing the complex from inserting into cell membranes
Cd59
formation of the MAC is inhibited by a widely distributed cell membrane protein on normal host cells called CD59. this works by binding to C5b678 on the cell surface and preventing C9 olymerization
