(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
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.
3.Aktivitas sitolitik
(Cell lysis : cell bacteria, allograft dan cell tumor.)
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
Inflammation
anaphylotoxins
C3a, C4a---increased
vascular permeability
C5achemoattraction
C3a, C4a----activation
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
Histamin
= meningkatkan permeabilitas vaskular
dan
= kontraksi otot polos menimbulkan
gejala2 lain pada reaksi Allergi,
seperti asthmatis (serangan sesak napas)
CHEMOTAXIS :
Adalah
pergerakan
bakteri akibat
ketarikannya
(attraction)
oleh bahan
kimia yang
terdapat
didalam
lingkungannya
Opsonization / Phagocytosis
C3b or iC3b
opsonized bacteria
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
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.
MAC
Complement
Definition
Overview
Classical Pathway
Alternative Pathway
Regulation
Deficiencies
= Tissue macrophages
= Blood monocytes
Complement :
Heat Labile component of normal plasma
Augments opsonization of bacteria by abs.
Allows some antibodies to kill bacteria
Antigen
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.
COMPLEMENT CASCADE
Jalur klasik (classic pathway)
Jalur alternative (alternative pathway)
Jalur Lectin
Jalur Lytic (Membrane attack pathway)
Classic
Alternative
Lysis &
cytotoxicity
Antigen-Antibody
compexes
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
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.
C2
C3
C4
C1q
C1r
C1s
C2a
Unknown.
C2b
C3a
C3b
C4a
Mediates inflammation.
C4b
Classic
Alternative
Lysis &
cytotoxicity
Antigen-Antibody
compexes
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 )
Alternate Pathway
C3b
Ba
Unknown.
Bb
Factor D
Properdin
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.
Lectin Pathway
Alternative
Pathway
Lytic
Pathway
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 )
Active
component(s)
Function(s)
C5a
C5b
C6
C6
C7
C7
C8
C8
C9
C9n
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.
Hereditary C Deficiencies
C3 Deficiency
recurrent bacterial infections
described in canines (Brittany spaniel colony)
Kinin production
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
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
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.
Biological activity
Effect
C2b (prokinin)
Edema
C3a
(anaphylatoxin)
Controls
C1-INH
Carboxy
peptidase- B
(C3a-INA)
Induction of suppressor
T cells.
Immunoregulation
Opsonization;
Phagocyte activation
Phagocytosis
Factors H & I
C4a
(anaphylatoxin)
Anaphylaxis
C3a-INA
Biological activity
C5a
(anaphylatoxin;
Chemotactic
factor)
Effect
Anaphylaxis
Inflammation
C3a INA
Chemotaxis; neutrophil
aggregation; Oxidative
metabolism stimulation
C5b67
Controls
Stimulation of leukotriene
release
Delayed anaphylaxis
Immunoregulation
Protein-S
Structure
Serum conc.
(ug/ml)
C1(C1qr2s2) 750 kD
Function
Initiates the classical pathway
C1q
460 kD
hexamer
75-150
C1r
85 kD dimer
50
C1s
85 kD dimer
50
C4
C2
103 kD
monomer
C3
See table 2.
20
Abbas & Lichtman : Cellular and Molecular Immunology,2003, Ed. 5th page 331
Structure
Serum conc.
(ug/ml)
C3
185 kD (alpha
1000-1200
subunit, 110 kD &
beta subunit 75
kD)
Factor B
93 kD monomer
200
Factor D
25 kD monomer
1-2
Function
Abbas & Lichtman : Cellular and Molecular Immunology,2003, Ed. 5th page 331
Structure
Serum conc.
(ug/ml)
Function
C5
190-kD dimer
80
C6
110-kD monomer
45
C7
100-kD monomer
90
C8
155-kD trimer of
64-, 64-, and 22 kD
chains
60
C9
79-kD monomer
60
Abbas & Lichtman : Cellular and Molecular Immunology. 2003, Ed. 5th page 331