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Komplemen

(Complement)
Dr.Edhie Djohan Utama, SpMK
Dr. Tetty Aman Nasution, M.Med.Sc
28 Oktober 2007

Jules Bordet

(1870-1961),
discoverer of complement
National Library of Medicine
Complement refers, historically, to
fresh serum capable of lysing antibody
(Ab)-coated cells.
+

Complement
in fresh serum

Cell lysis

This activity is destroyed (inactivated)


by heating serum at 56 degrees C for
30 minutes.
(Jules Bordet)

Komplemen
Salah satu sistem enzim serum yang berfungsi
dalam inflamasi, opsonisasi partikel antigen, dan
kerusakan membran sel2 yang terinfeksi.
Merupakan molekul sistem imun nonspesifik
yang larut dan dalam keadaan tidak aktif.
Jika teraktivasi enzim utk reaksi berikut,
enzim pengontrol, & bbp tanpa aktivitas enzim.

EFEK BIOLOGIK SISTEM KOMPLEMEN

Akibat aktivasi sistem komplemen :


1.Reaksi inflammasi
2.Kemotaksis dan opsonisasi (mempermudah
terjadinya phagositosis)

3.Aktivitas sitolitik
(Cell lysis : cell bacteria, allograft dan cell tumor.)

4. Menghasilkan mediator (e.g. histamine)

REAKSI INFLAMASI
Reaksi tubuh terhadap masuknya benda
asing, invasi mikroorganisme atau
kerusakan jaringan.
Usaha pertama tubuh, mengerahkan
elemen2 sistem imun ke tempat dimana
benda asing dan mikroorganisme yang
masuk tubuh atau jaringan yg rusak tsb

Proses inflamasi ada 3 hal :


1. Peningkatan persediaan darah ke tempat benda
asing, mikroorganisme yang masuk atau jaringan
yang rusak
2. Peningkatan permeabilitas kapiler (pengerutan sel
endotel molekul yg lebih besar spt antibodi &
fagosit bergerak keluar pembuluh darah) dan sampai
di tempat tsb
3. Leukosit, terutama fagosit PMN dan makrofag
dikerahkan dari sirkulasi dan bergerak ke tempat
benda asing, mikroorganisme yang masuk atau
jaringan yang rusak.

Mediator yg dilepas saat komplemen diaktifkan

C1qrs meningkatkan permeabilitas vaskular


C2 mengaktifkan kinin
C3a & C5a kemotaksis mengerahkan lekosit
juga sbg anafilatoksin mempengaruhi
mastosit
C3b opsonin & adherens imun
C4b opsonin
C 5-6-7 kemotaksis
C 8-9 melepas sitolisin menghancurkan
sel

Inflammation
anaphylotoxins

C3a, C4a---increased
vascular permeability

C5achemoattraction
C3a, C4a----activation

The acute inflammatory response is characterized by symptoms of redness, pain,


swelling, and heat due to the action of C4a, C3a, C5a, and histamine.
Inflammation's primary goal is to set into motion a series of events that result in the
elimination of foreign and damaged cells. This response can be mediated by the
anaphylatoxins and their byproducts.

The main activity of C3a and C5a is anaphylaxis. These cause histamine release from
mast cells and basophils, which can affect the activity of smooth muscle.
Spasmogenicity, accounts for the ability of these molecules to induce an anaphylactic
response in animals. In addition to spasmogenicity, histamine release induced by the
anaphylatoxins as effects on inflammation. The cellular responses of neutrophils and
monocytes to C5a include (1) degranulation and lysosomal enzyme release, (2) cell

C3a dan C5a merupakan anafilatoksin


ANAFILATOKSIN : bahan dengan BM kecil
degranulasi mastosit atau basofil,
pelepasan histamin.

Histamin
= meningkatkan permeabilitas vaskular
dan
= kontraksi otot polos menimbulkan
gejala2 lain pada reaksi Allergi,
seperti asthmatis (serangan sesak napas)

Peningkatan permeabilitas vaskular


menimbulkan oedem.
Yaitu akumulasi cairan dalam jaringan yg
mengandung lbh byk antibodi & komponen
komplemen meningkatkan lagi pelepasan
anafilatoksin memperluas reaksi.
Dlm proses inflamasi, byk lekosit
dihancurkan, kemudian makrofag lain
memasuki daerah tsb mengakhiri reaksi
inflamasi.

Fagositosis komponen penting pada


inflamasi
FAGOSITOSIS : proses menghancurkan
patogen dalam sel tanpa kerusakan
jaringan sekitarnya.
Proses ini tjd bila neutrofil, monosit,
makrofag, dan eosinofil kontak dgn sasaran
inflamasi (bakteri, parasit, bahan asing,
dsb)

Fagosit akhirnya memakan benda


asing, mikroorganisme atau jaringan yg
rusak.
Selama proses tsb, enzim lisosom
dilepas oleh makrofag ke luar sel shg dpt
merusak jaringan sekitar. (phagolispspm)
Akibat kerja sama sistem imun non
spesifik dan spesifik dapat terjadi reaksi
tubuh spt panas, bengkak, sakit dan
kerusakan jaringan (tanda2 inflamasi)

Sel PMN lbh sering ditemukan pada


inflamasi akut.
Proliferasi monosit ditemukan pada inflamasi
kronik
Eosinofil kurang berfungsi sbg fagosit
dibanding dg neutrofil. Sasaran eosinofil
biasanya parasit ukuran besar.

KEMOTAKSIS DAN OPSONISASI


KEMOTAKSIS : gerakan fagosit ke tempat infeksi
respons thd berbagai faktor spt produk bakteri &
faktor biokimiawi yg lepas pd aktivasi komplemen.
Jaringan yg rusak atau mati dpt juga melepas faktor
kemotaksis.
Sel PMN bergerak cepat berada di tempat
infeksi dalam 2-4 jam
Monosit bergerak lbh lambat perlu waktu 7-8
jam untuk sampai di tujuan
C3a, C5a dan C5-6-7 mempunyai efek kemotaksis

CHEMOTAXIS :
Adalah
pergerakan
bakteri akibat
ketarikannya
(attraction)
oleh bahan
kimia yang
terdapat
didalam
lingkungannya

Opsonization / Phagocytosis

C3b or iC3b

CR1, CR3, or CR4

opsonized bacteria

OPSONIN : molekul yg dpt diikat oleh


partikel yg hrs difagositir dan oleh
reseptor fagosit.
Sehingga opsonin merupakan jembatan
antara 2 protein reaktif tersebut di atas.

AKTIVITAS SITOLITIK
Eosinofil dan sel PMN mempunyai reseptor utk C3b dan
IgG C3b dpt mengaktifkan sitotoksisitas sel efektor
ADCC (Antibody Dependant Cellular Cytotoxicity)
kerjanya bergantung pd IgG
Sel darah merah yg disensitisasi C3b dpt dihancurkan
oleh makrofag tanpa fagositosis, disebut kerusakan
kontak (contactual damage).
Akhir aktivasi komplemen, C8-9 merusak membran
sebagai akibat lisis osmotik

Dapat mengaktifkan komplemen melalui


jalur klasik :
kompleks imun (IgG dan IgM)
agregat antibodi (IgG1,IgG2, IgG3)
lipid A dari endotoxin
protease
kristal urat
polinukleotide
membran virus tertentu
CRP

OPSONISASI : proses melapisi partikel


antigen oleh antibodi dan/atau oleh
komponen komplemen sehingga lebih
mudah dan cepat dimakan sel fagosit.
Hal ini oleh karena ada reseptor pd fagosit utk
fraksi Fc dr IgG, C3b dan CRP (C-Reaktif
Protein) yg berfungsi sbg opsonin.

Opsonization.
Facilitated phagocytosis is
referred to as opsonization. In this
process, C3b, which coats the
particle, is known as an opsonin.
This process occurs when cells,
viruses, or immune complexes are
made ready for enhanced
phagocytosis by becoming coated
with C3b or C4b.
This leads to binding of bacteria to
phagocyte C3 receptors and the
subsequent clearance of the
bacteria by phagocytosis.
It can either take place in the
presence or absence of
antibodies.

The Membrane Attack


Pathway

MAC

The MAC is especially important for the immune response against


Neisseria spp. Membrane proteins (CD59, HRF) prevent MAC
formation on host cells.

Complement
Definition
Overview
Classical Pathway
Alternative Pathway
Regulation
Deficiencies

Pokok bahasan / Key words

Complement (C) Definition :


Group of 30 different serum proteins which exist normally in an inactive form.
When activated, they can enhance aspects of innate immunity & some of the
biological effects of antibodies.
Sistem Komplemen terdiri atas lebih dari 25 protein yang secara normal dijumpai
didalam plasma dan serum darah hewan dan manusia di produksi oleh jaringan yang
berbeda, hepatocytes, macrophage dan epitel saluran pencernaan. Komponen dari
komplemen 2 itu ditulis dengan huruf C1 C9 sesuai dengan penemuannya.
Complement system is composed of more than 25 different proteins produced by
different tissues and cells including hepatocytes, macrophages and gut epithelial cells.
All components of the complement pathway are designated by letter C
followed by a number (C1-C9). Numbered in the order of their discovery

Komplemen terdiri dari 9 komponen protein yang disebut


C1 sampai dengan C9. C1 terdiri dari 3 fraksi yaitu C1q, C1r
dan C1s. Faktor B (serine protease) dan D (plasma serine
protease) serta Properdin

These proteins are activated by a variety of agents


and their activation proceeds in a cascade fashion
leading to lysis.
Classical Pathway of Complement Activation
The process of complement activation is a
cascade of enzyme linked reactions

Complements Protein Sources :


= Hepatocytes
= Epithelial cells of the GI

= Tissue macrophages
= Blood monocytes

Complement :
Heat Labile component of normal plasma
Augments opsonization of bacteria by abs.
Allows some antibodies to kill bacteria

Activity was said to complement antibacterial activity of antibodies


Consequently, an absence of one of the components in the pathway can disrupt the
cascade and terminate the reaction.

The effector functions of complement can be activated through 2 major


pathways :
= The Classical Pathway (Acquired Immunity)
= The Alternative Pathway (Innate Immunity)

Antigen

3 Main Consequences of Complement Activation


1. Opsonization of Pathogens: C3b
2. Acute Inflammation: C3a, C5a
3. Killing of Pathogens: pore formation

AKTIVASI KOMPLEMEN
Pada tahapan pengaktivan komponen itu dihasilkan satu enzim baru
yang dapat melibatkan beberapa molekul substrat berikutnya,
sehingga timbul reaksi yang cukup kuat untuk merusak dinding sel
(sel lisis).
Aktivasinya memerlukan ion Ca dan Mg dan tergantung dari pH
(7,2 7,4) dan suhu 30oC 37oC.
Antibodi yang dapat mengikat komplemen adalah IgG dan IgM,
sedangkan antibody jenis lain tidak mengikat komplemen.
Komplek Ab dengan Ag : misalnya Ab dengan sel eritrosit
berkemampuan untuk mengaktifkan beberapa komponen.

Efek dari komplemen


Cell lysis
: cell bacteria, allograft dan cell tumor.
Opsonisasi : mempermudah phagositosis
Menghasilkan mediator (e.g. histamine)
Komplemen terutama dihasilkan oleh hati, heat labile yaitu dapat diinaktivasi dengan memanaskan serum pada 56oC selama 30 menit.
Sedangkan pada suhu ini immunoglobulin tidak di-inaktivasi (tdk rusak).
Sebagian komplemen adalah proenzyme, yang bekerja menyebabkan
aktivasi enzyme.
Komplemen bisa diaktivasi oleh Ag-Ab kompleks (kompleks IgG atau
IgM) atau oleh molekul yg nonimmunologic seperti endotoksin.

COMPLEMENT CASCADE
Jalur klasik (classic pathway)
Jalur alternative (alternative pathway)
Jalur Lectin
Jalur Lytic (Membrane attack pathway)

Classic

Alternative

Lysis &
cytotoxicity

Antigen-Antibody
compexes

Microbial surfaces ( nonspecific


activators eg. Endotoxin)

Bind

Bind
C5b,6,7,8,9

C1
C8

C2

C4b,2b
( C3 convertase )
+
C2a,C4a

C9
C5b,6,7

C1 (protease)
C4

D (protease)
C7

C6
C3

C5a + C5b

C4b,2b,3b
C5
( C5 covertase )
+
C3a = anaphylatoxin

= Proteolytic cleavage

C3(H2O) + B

C3

C3b,Bb
( C3 convertase )

C3b,Bb,C3b
( C5 covertase )
+
C3a = anaphylatoxin
diatas huruf = enzymatic activity

Levinson & Jawetz, 2000, Ed.6th, page 381

Pathways of Complement Activation

Jalur klasik (classic pathway)


C1q, C1r dan C1s terikat satu dengan lainnya dengan perantaraan ion
Ca (calcium). Setelah C1q terikat pada antibodi (Ig), maka fraksi C1s
bersifat sebagai enzim protease yang mengaktipkan C4 dan C2
membentuk kompleks C4b2b (enzyme) .
Komplek C4b2b akan memecah C3 menjadi C3a dan C3b
C3a adalah anafilatoksin. C3b membentuk kompleks C4b2b3b yang
menghasilkan enzim baru yang merupakan convertase C5 (C4b2b3b)
yang memecah C5 menjadi C5a dan C5b (C5a adalah anafilatoksin &
faktor khemotaksis).
C5b terikat pada C6 dan C7 membentuk kompleks yang berinteraksi
dengan C8 dan C9 dan membentuk MAC = membrane attack
complex (C5b6789) yang menyebabkan sel lisis, karena terjadi pori
pori (lubang2) pada membrane sel sehingga sel lisis sebab kehilangan
air.
C3b yang terikat pada kompleks antibody dan menempel pada dinding
sel.

Classical Pathway
Component cleavage

Enzymatic act.

Component asemb.

CLASSICAL PATHWAY
Classical pathway normally requires a suitable Ab bound to antigen (Ag),
complement components 1, 4, 2 and 3 and Ca++ and Mg++ cations.

C1 activation
Binding of C1qrs (a calcium-dependent complex), present in normal serum, to AgAb complexes results in autocatalysis of C1r. The altered C1r cleaves C1s and this
cleaved C1s becomes an enzyme (C4-C2 convertase) capable of cleaving both C4
and C2.

C4 and C2 activation (generation of C3 convertase)


Activated C1s enzymatically cleaves C4 into C4a and C4b. C4b binds to the Agbearing particle or cell membrane while C4a remains a biologically active peptide at
the reaction site. C4b binds C2 which becomes susceptible to C1s and is cleaved
into C2a and C2b. C2a remains complexed with C4b whereas C2b is released in the
micro environment. C4b2a complex, is known as C3 convertase in which C2a is the
enzymatic moiety.

C3 activation (generation of C5 convertase)


C3 convertase, in the presence of Mg++, cleaves C3 into C3a and C3b. C3b binds to
the membrane to form C4b2a3b complex whereas C3a remains in the micro
environment. C4b2a3b complex functions as C5 convertase which cleaves C5 into
C5a and C5b. Generation of C5 convertase marks the end of the classical pathway.

Components of the Classical Pathway


C1(q,r,s)

C2

C3

C4

C1q

Binds to antibody that has bound antigen, activates C1r.

C1r

Cleaves C1s to activate protease function.

C1s

Cleaves C2 and C4.

C2a

Unknown.

C2b

Active enzyme of classical pathway; cleaves C3 and C5.

C3a

Mediates inflammation; anaphylatoxin.

C3b

Binds C5 for cleavage by C2b.


Binds cell surfaces for opsonization and activation of
alternate pathway.

C4a

Mediates inflammation.

C4b

Binds C2 for cleavage by C1s. Binds cell surfaces for


opsonization.

Jalur alternative (alternative


pathway)
Komplemen aktivasi juga terjadi melalui jalur
alternatip dimana terjadi by pass dan untuk
menstimulasi jalur ini reaksi antigen antibody tidak
perlu. Properdin, suatu serum protein, berfungsi
dalam proses ini.
Jalur alternatip diinisiasi (diawali) oleh berbagai
bahan (substances) seperti lipopolisakarida bakteri
(endotoksin), dinding fungi, dan envelope virus.
Diawali dengan terikat C3(H2O) & faktor B.
Kompleks ini menjadi C3bBb oleh enzim protease,
seperti konvertase yang memecah C3 dan
membentuk C3b & C3a.

Proteins of the Alternative Pathway


C3 : C3b terikat pada permukaan mikroba,
berfungsi sebagai opsonin dan sebagai
komponen dari C3 dan C5 convertase.
Factor B : Bb adalah serine protease dan
mengaktipkan C3 dan C5 convertase.
Factor D : Plasma serine protease,
memecah (cleaves) faktor B dan terikat
pada C3b.
Properdin : menstabilkan C3 covertase
(C3bBb) pada permukaan mikroba.

Classic

Alternative

Lysis &
cytotoxicity

Antigen-Antibody
compexes

Microbial surfaces ( nonspecific


activators eg. Endotoxin)

Bind

Bind
C5b,6,7,8,9

C1
C8

C2

C4b,2b
( C3 convertase )
+
C2a,C4a

C9
C5b,6,7

C1 (protease)
C4

D (protease)
C7

C6
C3

C4b,2b,3b
( C5 covertase )
+
C3a

= Proteolytic cleavage

C3(H2O) + B

C5a + C5b

C3

C5

C3b,Bb,C3b
( C5 covertase )
+
C3a

C3b,Bb
( C3 convertase )

diatas huruf = enzymatic activity

Levinson & Jawetz, Ed.6th,2000, page 381

Alternate Pathway

Components of the Alternate Pathway


C3a

Mediates inflammation; anaphylatoxin.

C3b

Binds cell surfaces for opsonization and activation of


alternate pathway.

Binds membrane bound C3b. Cleaved by Factor D.

Ba

Unknown.

Bb

Cleaved form stabilized by P produces C3


convertase.

Factor D

Cleaves Factor B when bound to C3b.

Properdin

Binds and stabilizes membrane bound C3bBb.

C3

Factor B

LECTIN PATHWAY
C4 activation can be achieved without antibody and C1
participation by the lectin pathway.
This pathway is initiated by three proteins: a mannanbinding lectin (MBL), also known as mannan-binding
protein (MBP) which interacts with two mannan-binding
lectin-associated serine proteases (MASP and
MADSP2), analogous to C1r and C1s.
This interaction generates a complex analogous to
C1qrs and leads to antibody -independent activation of
the classical pathway.
C1q can also bind to a number of agents including some
retroviruses, mycoplasma, poly-inosinic acid and
aggregated IgG, and initiate the classical pathway.

Table 1. Proteins of the Complement system


Classical Path
way
Activation Proteins:
C1qrs, C2, C3, C4
Control Proteins:
C1-INH, C4-BP

Lectin Pathway

Alternative
Pathway

Mannan binding protein


C3, Factors B &
(MBP), mannanD*, Properdin
asociated serine
protease (MASP,
MASP2)
Factors I* & H,
(Mannan = Mannose) DAF, CR1, etc.

Lytic
Pathway

C5, C6, C7,


C8, C9
Protein S

Components underlined acquire enzymatic activity when activated.


Components marked with an asterisk have enzymatic activity in their native form.

Roitt et al. Immunology (5th ed.), chapter 4

LYTIC PATHWAY
The lytic (membrane attack) pathway involves the C5-9 components.
C5 convertase generated by the classical or alternative pathway
cleaves C5 into C5a and C5b. C5b binds C6 and subsequently C7 to
yield a hydrophobic C5b67 complex which attaches quickly to the
plasma membrane (slide 22, 23 & 24).
Subsequently, C8 binds to this complex and causes the insertion of
several C9 molecules. bind to this complex and lead to formation of a
hole in the membrane resulting in cell lysis.
The lysis of target cell by C5b6789 complex is nonenzymatic and is
believed to be due to a physical change in the plasma membrane.
C5b67 can bind indiscriminately to any cell membrane leading to cell
lysis.
Such an indiscriminate damage to by-standing cells is prevented by
protein S (vitronectin) which binds to C5b67 complex and blocks its
indiscriminate binding to cells other than the primary target.

LYTIC PATHWAY

Classic

Lysis &
cytotoxicity

Antigen-Antibody
compexes

Alternative
Microbial surfaces ( nonspecific
activators eg. Endotoxin)

MAC

Bind

Bind
C5b,6,7,8,9

C1
C8

C2

C4b,2b
( C3 convertase )
+
C2a,C4a

C9
C5b,6,7

C1 (protease)
C4

D (protease)
C7

C6
C3

C4b,2b,3b
( C5 covertase )
+
C3a

= Proteolytic cleavage

C3(H2O) + B

C5a + C5b

C3

C5

C3b,Bb,C3b
( C5 covertase )
+
C3a

C3b,Bb
( C3 convertase )

diatas huruf = enzymatic activity

Levinson & Jawetz, Ed.6th,2000, page 381

Components of the Membrane-Attack Complex


Native
component

Active
component(s)

Function(s)

C5a

Mediates inflammation; anaphylatoxin,


chemotaxin.

C5b

Initiates assembly of the membrane-attack


complex (MAC).

C6

C6

Binds C5b, forms acceptor for C7.

C7

C7

Binds C5b6, inserts into membrane, forms


acceptor for C8.

C8

C8

Binds C5b67, initiates C9 polymerization.

C9

C9n

Polymerizes around C5b678 to form


channel that causes cell lysis.

C5

Classical Pathway
Component cleavage

Enzymatic act.

Component asemb.
Lytic Pathway

Alternate Pathway
Lytic Pathway

The complement system. Activation of either wing of the system leads to the
formation of peptide fragments that function on leukocytes and forms the
membrane attack complex.

Late Steps of Complement Activation

Hereditary C Deficiencies
C3 Deficiency
recurrent bacterial infections
described in canines (Brittany spaniel colony)

Porcine factor H deficiency


Inhibits binding of C3b to Bb
failure to thrive
Die of renal failure

BIOLOGICALLY ACTIVE PRODUCTS


OF COMPLEMENT ACTIVATION (1)
Activation of complement results in the production of several
biologically active molecules which contribute to resistance,
anaphylaxis and inflammation.

Kinin production

C2b generated during the classical pathway of C activation is


a prokinin which becomes biologically active following
enzymatic alteration by plasmin. Excess C2b production is
prevented by limiting C2 activation by C1 inhibitor (C1-INH)
also known as serpin which displaces C1rs from the C1qrs
complex.

A genetic deficiency of C1-INH results in an overproduction of


C2b and is the cause of hereditary angioneurotic edema.
This condition can be treated with Danazol which promotes
C1-INH production or with -amino caproic acid which
decreases plasmin activity.

BIOLOGICALLY ACTIVE PRODUCTS


OF COMPLEMENT ACTIVATION (2)
Anaphylotoxins

C4a, C3a and C5a (in increasing order of activity) are all
Anaphylotoxins which cause basophil/mast cell degranulation and
smooth muscle contraction. Undesirable effects of these peptides
are controlled by carboxypeptidase B (C3a-INA).

Chemotactic Factors

C5a and MAC (C5b67) are both chemotactic. C5a is also a potent
activator of neutrophils, basophils and macrophages and causes
induction of adhesion molecules on vascular endothelial cells.

Opsonins

C3b and C4b in the surface of microorganisms attach to C-receptor


(CR1) on phagocytic cells and promote phagocytosis.

Other Biologically active products of C activation

Degradation products of C3 (iC3b, C3d and C3e) also bind to


different cells by distinct receptors and modulate their functions.

The main activity of C3a and C5a is anaphylaxis. These cause histamine release from
mast cells and basophils, which can affect the activity of smooth muscle.
Spasmogenicity, accounts for the ability of these molecules to induce an anaphylactic
response in animals. In addition to spasmogenicity, histamine release induced by the
anaphylatoxins as effects on inflammation. The cellular responses of neutrophils and
monocytes to C5a include (1) degranulation and lysosomal enzyme release, (2) cell

The acute inflammatory response is characterized by symptoms of redness, pain,


swelling, and heat due to the action of C4a, C3a, C5a, and histamine.
Inflammation's primary goal is to set into motion a series of events that result in the
elimination of foreign and damaged cells. This response can be mediated by the
anaphylatoxins and their byproducts.

Opsonization.
Facilitated phagocytosis is
referred to as opsonization. In this
process, C3b, which coats the
particle, is known as an opsonin.
This process occurs when cells,
viruses, or immune complexes are
made ready for enhanced
phagocytosis by becoming coated
with C3b or C4b.
This leads to binding of bacteria to
phagocyte C3 receptors and the
subsequent clearance of the
bacteria by phagocytosis.
It can either take place in the
presence or absence of
antibodies.

In summary, the complement system takes part


in both specific and non-specific resistance and
generates a number of products of biological
and pathophysiological significance.
There are known genetic deficiencies of most
individual C complement components, but C3
deficiency is most serious and fatal.
Complement deficiencies also occur in :
immune complex diseases (e.g., SLE) and
acute and chronic bacterial, viral and parasitic
infections.

Biological Properties of C Activation Products and their


Regulatory Molecules
Component

Biological activity

Effect

C2b (prokinin)

Accumulation of body fluid

Edema

C3a
(anaphylatoxin)

Basophil and mast cell


Anaphylaxis
degranulation; enhanced
vascular permeability; smooth
muscle contraction

Controls
C1-INH
Carboxy
peptidase- B
(C3a-INA)

Induction of suppressor
T cells.

Immunoregulation

C3b and its


products

Opsonization;
Phagocyte activation

Phagocytosis

Factors H & I

C4a
(anaphylatoxin)

Basophil & mast cell


activation; smooth muscle
contraction; enhanced
vascular permeability.

Anaphylaxis

C3a-INA

Biological Properties of C Activation Products and their


Regulatory Molecules
Component

Biological activity

C5a
(anaphylatoxin;
Chemotactic
factor)

Basophil & mast cell


activation; enhanced
vascular permeability;
smooth muscle
contraction.

Effect
Anaphylaxis
Inflammation

C3a INA

Chemotaxis; neutrophil
aggregation; Oxidative
metabolism stimulation

C5b67

Controls

Stimulation of leukotriene
release

Delayed anaphylaxis

Induction of helper Tcells.

Immunoregulation

Chemotaxis; attachment to Inflammation; lysis


other cell membranes.
of bystander cells.

Protein-S

Table 1 : Proteins of the Classical Pathway of Complement


Protein

Structure

Serum conc.
(ug/ml)

C1(C1qr2s2) 750 kD

Function
Initiates the classical pathway

C1q

460 kD
hexamer

75-150

Binds to the Fc portion of antibody tgat


bound antigen

C1r

85 kD dimer

50

Serine protease, cleaves C1s to make it


an active protease

C1s

85 kD dimer

50

Serine protease, cleaves C4 dan C2

C4

210 kD trimer 300-600

C4b covalently binds to the surface of a


microbe or cell, where the antibody is bound
and complement is activated.C4b binds C2
for cleavage by C1s C4a stimulates
inflammation (anaphylatoxin)

C2

103 kD
monomer

C2a is a serine protease and functions as


the active enzyme of C3 and C5
convertase to cleave C3 and C5

C3

See table 2.

20

Abbas & Lichtman : Cellular and Molecular Immunology,2003, Ed. 5th page 331

Table 2 : Proteins of the Alternative Pathway


Protein

Structure

Serum conc.
(ug/ml)

C3

185 kD (alpha
1000-1200
subunit, 110 kD &
beta subunit 75
kD)

C3b terikat pada permukaan mikroba,


berfungsi sebagai opsonin dan sebagai
komponen dari C3 dan C5 cinvertase.
C3a menstimulasi inflamasi
(anaphylatoxin)

Factor B

93 kD monomer

200

Bb adalah serine protease dan


mengaktipkan C3 dan C5 convertase.

Factor D

25 kD monomer

1-2

Plasma serine protease, memecah


(cleaves) faktor B dan terikat pada C3b

Properdin Terdiri dari 4 buah 25


56 kD subunit

Function

menstabilkan C3 covertase (C3bBb)


pada permukaan mikroba.

Abbas & Lichtman : Cellular and Molecular Immunology,2003, Ed. 5th page 331

Table 3 : Proteins of the Late Step of Complement


Activation
Protein

Structure

Serum conc.
(ug/ml)

Function

C5

190-kD dimer

80

C5b initiates assembly of the MAC


C5a stimulates inflammation
(anaphylatoxin)

C6

110-kD monomer

45

Component of the MAC : binds to C5b


and accepts C7

C7

100-kD monomer

90

Component of the MAC : binds to C5b,6


and inserts into lipid membranes

C8

155-kD trimer of
64-, 64-, and 22 kD
chains

60

Component of the MAC : binds to C5b,6,7


and inisiates the binding and
polymerization of C9.

C9

79-kD monomer

60

Component of the MAC : binds to


C5b,6,7,8 and polymerizes to form
membrane pores.

Abbas & Lichtman : Cellular and Molecular Immunology. 2003, Ed. 5th page 331

Regulation of Complement Activation

Extracellular neutralization of virus by antibody. Antibody can reduce the


number of infectious particles by linking virions and thereby causing
aggregation. Antibody alone or with complement can also inactivate viruses .