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Assoc. Prof. Ma. Jennifer R. Tiburcio MSMTDepartment of Med TechUST Faculty of Pharmacy
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Complement
Group of nonimmunoglobulin plasmaproteins
More than 25 plasma proteins
Sequentially activated by Ag-Ab complexesDirectly by microbial constituents
Irreversible damage to membranes of the
target cells
Important functions related to hosts
defense mechanisms
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Synthesized in theLiver (except C1intestinal epithelial cells)
Adipose tissuefactor D
Monocytes, macrophages, neutrophils & Tcells - properdin & C7
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inactive precursors or zymogensnumbered sequentially from C1 to C9
activationhorizontal bar over the
designated C components
cleavage products:small cleavage producta
large cleavage productb
letter i inactive form
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additional proteins
Factor BC3 proactivator
Factor DC3 proactivator convertase
C3bBbC3 activatorCVFcobra venom factor
Pproperdin factor
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Activities of the Complement
1. Cell lysis
the later C component complexes disrupt
biologic membranes
2. Stimulation of an inflammatory response
the cleavage products of several C components
regulate the activities of cells & tissues through
chemotactic & anaphylatoxic fragments
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3. Opsonizationseveral C component fragments coat target cells
(opsonization) to make them more palatable tophagocytic cells, which carry receptors for some C
fragments
4. Removal of Ag-Ab (immune) complexes
C fragments reduce tissue-damaging immune
complexes to small , soluble aggregates while in the
circulation & faci l i tate clearance of circulating
immune complexes
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Classical Alternative
Immunologic activatorsIgM or IgG (3, 1, 2) or bound to
an antigen
Immunologic activatorsAggregated IgA in some instances
IgG4 & IgE
Non-immunologic activators
Apoptotic cellsStaphylococcal protein A,
CRP, Gram neg. bacteria
DNA
Non-immunologic activators
Bacterial & plant polysaccharideLPS, zymosan. Inulin, CVF,
viruses & tumor cells
Possess a recognition unit No recognition unit
Requires presence of calcium &
requires C1; C2 & C4 are utilized
for its activation
Lack of dependence on calcium
Activation immediately starts w/ C3
Other components are Factors B, D &
properdin
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Routes or Pathways of C activation
A. Classical
ini tiation (or recogni tion/activation phase)
C1 specif ical ly C1q
amplif ication (or enzymatic activation)
C4, C2 and C3
membrane attack leading to cell destruction
(membrane attack complex) C56789
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B. Alternate
normal serum proteins
ini tiation ofsoluble C3
Factor Banalogous to C2
Factor Dsimilar to C1s
Properdingamma globulin, whencomplexed w/ C3b stabilized the alternative C3convertase
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C. Lectin Pathway
activates C without Ab being present
MBL (mannose-binding lectin) binds to mannose or relatedsugars such as N-acetylglucosamine to initiate the pathway
resembles C1q
after MBL is bound to the surface of a cell, two MBL-associated
serine proteases (MASPs) become activated
MASP-1, homologous to C1r
MASP-2, homologous to C1s
Cleave C4 and C2
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interaction of MBL w/ a carbohydrate
on the surface polysacchar ide of microbes
to the formation of enzymatic complex
that binds and activates C4 and C2
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Fluid Phase Regulators
1. C1 inhibitor (C1INH)dissociates C1r
& C1s from C1q
2. Factor Hinhibits convertase activity by
binding to C3b, thus preventing the binding of
factor B3.Factor I (C3b inactivator)inactivates C3b
and C4b only when they are associated with factor
H
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4.C4 binding protein (C4BP)acts as cofactorfor factor I in the inactivation of C4b
5.S protein (vitronectin)interacts with the C5b67
complex & prevents binding to cell membranes
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Cell Bound Regulators
1. CR1(CD 35)binds C3b,iC3b & C4b thendegraded by Factor I
2. Decay Accelerating Factor (DAF)(CD55
dissociates both classical & alternative C3 convertases
3. Membrane Cofactor Protein (MCP)(CD46)
most eff icient cofactor for Factor I -mediated cleavage
of C3b & C4b, binding of C2 to C4b and of factor B
to C3b is inhibited4. Membrane inhibitor of reactive lysis
(MRL)(CD59) - blocks the formation of MAC
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Additional
1. AIanaphylatoxin inhibitor binds to
C3a, C4a, C5a
2. MAC INH
Homologous restr iction factor (HRF),
S protein
CD59
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S protein, vitronectin binds to soluble
(C5bC6C7) complexes preventing their
insertion into autologous membranes CD59
HRF bind to 8, preventing polymerization of C9& formation of MAC
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Biologic Manifestations of C Activation
1. Anaphylatoxins
increased vascular permeabil i ty,
contraction of smooth muscle & release of
histamine from basophils & mast cells
C3a, C4a & C4b, C5a(most potent)
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2. Chemotaxins
C5aserves as chemotaxins for neutrophi ls,
eosinophi ls , basophi ls & monocytes
3. Opsonization
C4b, C3b & iC3bbind w/ specif ic receptorson erythrocytes, neutrophi ls, monocytes, &
macrophages
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Congenital deficiencies
C1 esterase inhibitorhereditary angioedema
complement is activated by trauma
C1, C4, C2, or C3- increased susceptibility to
infections w/ pyogenic bacteriaC6, C7, C8 or C9Neisseria
C1, C2, or C4rheumatic diseases (impairedclearance of immune complexes)
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In Vitro Destruction of Complement1. Addition of chelating agent
2. I nactivation of serum at 56oC for 30 mins
3. Treatment wi th zymosan
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Assays for the classical pathway
Hemolytic titration (CH50) assay
Because all proteins from C1 to C9 are necessary
for this to occur, absence of any one component
wil l resul t in an abnormal CH50 essentially
reducing this number to zero
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C component Activity
C4, C2 Virus neutralization
C4a Some anaphylatoxin activity (induction of histamine release
leading to vasodilation & smooth muscle contraction)
C3a Anaphylatoxin activity, aggregation of platelets
C3b Opsonization; inhibits immune complex formation;
promotes clearance of immune complexes
C5a Anaphylatoxin activity, chemotaxis of neutrophils; immune
adherence to vascular endothelium through specificmacrophage receptors
Bb Migration inhibition; induction of monocyte & macrophage
spreading (nonspecific)
C5b-9 Membrane damage (lysis of target cell)
Biologic properties of C components &
activation products
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