9. complement (reuploaded)

8/13/2019 9. Complement (Reuploaded)

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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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9. complement (reuploaded)

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