1=the Complement

7/31/2019 1=the Complement

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The Complement System

Complement refers, historically, to fresh serum capable oflysing antibody (Ab)-coated cells. This activity isdestroyed (inactivated) by heating serum at 56 degreesC for 30 minutes.

The complement system plays amajor role in host defenseand the inflammatory process (through innate andacquired immunity).

It consists of complex series of at least 25 plasma proteinsproduced by different tissues and cells includinghepatocytes, macrophages and gut epithelial cells arenormally functionally inactive.


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liver MQfibroblast Synthesisby


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Complement functions

Host benefit: opsonization to enhance phagocytosis

phagocyte attraction and activation lysis of bacteria and infected cells

clearance of immune complex

Host detriment:

Inflammation, anaphylaxis


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Pathways of Complement Activation

Alternative

(properdin)Classical


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Pathways of complementactivation

CLASSICALPATHWAY

ALTERNATIVEPATHWAY

activationof C5

LYTIC ATTACKPATHWAY

antibody

dependent

antibody

independent

Activation of C3 andgeneration of C5 convertase


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Components of the ClassicalPathway

C4C3

C1 complex


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Classical PathwayGeneration of C5-convertase

C4bC3b

________

C4b2a3b is C5 convertase;it leads into the MembraneAttack Pathway


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Classical pathway

Normally requires a suitableantibody (Ab) bound to an

antigen (Ag), complementand3and2,4,1components.Ca++ and Mg++ cations


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C1 activation

Binding of C1 (C1q, C1r & C1s complex),present in normal serum, to Ag-Abcomplexes results in the autocatalysis of

C1r. The altered C1r cleaves C1s and thiscleaved C1s functions as C4-C2convertase capable of cleaving both C4

and C2.


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C4 and C2 activation (generation

of C3 convertase)

Activated C1s enzymatically cleaves C4 intoC4a and C4b. C4b binds to the Ag-bearingparticle or cell membrane while C4a

remains a biologically active peptide at thereaction site


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C4b binds C2 that becomes

susceptible to C1s and is cleavedinto C2a and C2b. C2a remainscomplexed with C4b whereas C2b

is released.C4b2a complex is known as C3

convertase.


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C3 activation (generation of C5

convertase): C3 convertase, in the

presence of Mg++, cleaves C3 intoC3a and C3b. C3b binds to themembrane to form C4b2a3b

complex; C3a is released.

4b2a3b complex functions as C5convertase that cleaves C5 intoC5a and C5b.


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C3 activation (generation of C5

convertase)

C3 convertase, in the presence of Mg++,cleaves C3 into C3a and C3b. C3b bindsto the membrane to form C4b2a3b

complex; C3a is released.

4b2a3b complex functions as C5convertase that cleaves C5 into C5a and

C5b


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C4b

_____

C4b2a is C3 convertase


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C4bC3b

________

C4b2a3b is C5 convertase;it leads into the MembraneAttack Pathway


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Alternative Pathway


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begins withAlternative pathway

the activation of C3 andrequires Factors B and D and

Mg++ cation, all present innormal serum.


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Components of thealternative pathway

C3


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Spontaneous C3 activation

C3 i

Generation of C3 convertase

C3iBb complex has a very short half life

b C3b


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Spontaneous activation of C3:(C3i) is generated by slow

hydrolysis of native C3.C3i binds factor B that is cleaved

by Factor D to produce C3iBb.C3iBb acts as C3-convertase and

cleaves native C3 into C3a and

C3b


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C3b binds factor B, which is againcleaved by Factor D to produceC3bBb complex (C3 convertase).

This C3 convertase will continue toact on C3


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Spontaneous C3 activation

C3 i

Generation of C3 convertase

C3iBb complex has a very short half life

b C3b


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Generation of C5 convertaseleads to the activation of the

Lytic pathway

Lytic pathway


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Components of the lytic pathway

C6

C9

C7


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Lytic pathwayC5-activation

C3bC4b

b


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Lytic pathwayC5-activation

C3bC4b

b


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Lytic pathwayassembly of the lytic complex

b

C6

C7


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Lytic pathway:insertion of lytic complex into cell membrane

b

C6

C7

C9

C9

C9

C9C9

C9 C

9C9

C9


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The lytic pathway involves the

C5-C9 components. C5convertase, generated by one ofthe pathways described above,

cleaves C5 into C5a and C5b.C5b instantaneously binds C6

and subsequently C7 to yield

C5b67 complex that attachesquickly to plasma membrane


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Subsequently, C8 binds to this

complex and causes the insertionof several C9 molecules. The

insertion of C8(9)n complexcauses formation of a hole in the

membrane and cell lysis.


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Lytic pathwayassembly of the lytic complex

b

C6

C7


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Lytic pathway:insertion of lytic complex into cell membrane

b

C6

C7

C9

C9

C9

C9C9

C9 C

9C9

C9


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Biologic activities of

complementTriggering inflammation (C5a> C3a>C4a)

Chemotactically attracting phagocytes to the infectionsite (C5a)

Promoting the attachment of antigens tophagocytes via enhanced attachment oropsonization (C3b>C4b)

Removing harmful immune complexes from the

body(C3b>C4b)


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Biological Role of Complement

Inflammation

Phagocyte attraction and activation

Opsonization to enhance phagocytosis Lysis of bacteria and infected cells

Clearance of immune complexes


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Functions

C5a

1- cytotoxicityC5aC3aC4a

C3bC4b

4- anaphylatoxins

MAC

2-chemotaxis

3- opsonisation

5- remove immunecomplexes


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The biologic functions of complement:

b)4b, C3Opsonization and phagocytosis (C-1


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The biologic functions of complement(cont.):

) and chemotaxis5,3,2,4Anaphylatoxins (Ca-2a)5(C


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The biologic functions of complement(cont.):

mediated cytotoxicity-Complement-3


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Regulatory mechanisms

C1inhibitor

Factor I Protein H

C1qrs

Unstable complex

C3

C3c C3d

No factor Bbinding

No C3b production


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Regulation of complement activation

Mammalian cells express regulatory proteins that inhibitcomplement activation, thus preventing complement-mediated damage of host cells.

Examples:

1- C1 inhibitor (C1 INH):

Stops complement activation early , at the stage ofC1 activation.

Deficiency of C1 INH hereditary angioneuroticedema.


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C1-inhibitor deficiency:angioedema


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Regulation of complement activation:

Examples:(cont.)

2- Factor I:

inhibits production of C3b3- Factor H:

prevent production of C3 convertase (C3bBb)


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Indication ofDisease activity

Diagnosis&mgmt of

-recurrent infections-allergy-autoimmunity

estimation of compl.Components is used in


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Documents

1=the Complement