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SISTEM KOMPLEMEN
Imunologi
Semester Gazal 2015/2016
Hariyanto IH.,M.Si.,Apt

Tujuan Instruksional
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1. Mahasiswa mampu menjelaskan mediator komplemen
2. Mahasiswa mampu menjelaskan reseptor komplemen
3. Mahasiswa mampu menjelaskan 3 cara aktivasi komplemen
4. Mahasiswa mampu menjelaskan regulator komplemen
5. Mahasiswa mampu menjelaskan efek biologik dari komplemen

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 as heat-labile component of normal plasma

that augments the opsonization and
killing of bacteria by antibodies.
Complement the antibacterial activity of
antibody
As an Effectors arm of the antibody response
Jules Bordet
(1870-1961)

Complement can also be activated early in

infection in the absence of antibody
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Like blood
coagulation
process

is a complex system of serum proteins which

interact in a cascade,
which activate each other sequentially.
The system refers to a series of proteins circulating in the
blood and bathing the fluids surrounding tissues.
The

proteins circulate in an inactive form, but in response

to components of microorganism, they become
sequentially actived

Working in a cascade where in the binding of one protein

promotes the binding of the next protein
in the cascade.
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Component of the complement system

Proteins, glycoproteins, synthesized
- mainly by liver hepathocytes,
- monocytes,
- macrophages and epithelial cells of GIT and
genitourinary tracts
Designated by:
- numerals: C1 C9
- letter symbols : factor D, Properdin, factor B, factor I
- trivial names: homolog restriction factor (HRF)

Most circulate in the serum in functionally inactive form as

proenzymes or zymogens, which are inactive until
proteolytic cleavage which removes an inhibitory
fragment and exposes the active site.

Components of the complement system

Complement components constitute approximately 15% of the globulin protein
fraction in plasma, and their combined concentration can be as high as 3 mg/mL.

The complement reaction sequence starts with an enzyme cascade.

Peptide fragments formed by activation of a component are
denoted by small letters :
a for smaller fragment : diffuse from the site and initiates
localized inflammatory responses by binding to the specific receptor

b for larger fragment: bind to the target near the site of action

Except only for C2 C2a as larger fragment ,

C2b as smaller fragment
The complement fragments interact one another to form functional
complexes. These complexes that have enzymatic activity are
designated by a bar over the number or symbol,
e.g., C4b2a, C3bBb

Proteins Involved in the Complement System

1. Initiator complement components
Inititators (C1q, MBL, ficolins)

2. Enzymatic mediators
Convertase activators (C1r, C1s, C4b, C2a) and enzymatic
mediators (C3 convertase, C5 convertase)

3. Membrane-binding components or opsonins.

4. Inflammatory mediators
Anaphylatoxins (e.g. C3a, C5a, and C4a)

5. Membrane attack proteins

The proteins of the membrane attack complex (MAC) insert
into the cell membranes of invading microorganisms and punch
holes that result in lysis of the pathogen.
The complement components of the MAC are C5b, C6, C7, C8,
and multiple copies of C9.

6. Complement receptor proteins.

CR1 bind to complement components such as C3b on the
surface of pathogens, triggering phagocytosis of the
C3-bound pathogen.
Binding of the complement component C5a to C5aR receptors
on neutrophils stimulates neutrophil degranulation and
inflammation.

7. Regulatory complement components.

Host cells are protected from unintended complementmediated lysis by the presence of membrane-bound as well as
soluble regulatory proteins.
These regulatory proteins include:
- factor I, which degrades C3b,
- Protectin, which inhibits the formation of the MAC on host
cells.

10

Component of the complement system

~ 30 components
Symbol: C called C1 (q, r, s), C2, C3, C4, C5, C9
Where components are proteolytically cleaved, the
products are referred to a or b as C3a + C3b etc.
Factor B,
Properdin
involve in Alternative Pathway or in
Factor H
regulating complement activity
Factor D
Factor I, etc.

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Sistem Komplemen
Tergolong dalam sistem imun bawaan humoral
Merupakan sekumpulan protein plasma yang bersikulasi di
dalam tubuh dan dalam kondisi normal inaktif
Bersifat non-spesifik dalam eliminasi patogen dan bekerja
seperti sistem cascade
Komponen : C1-C9, faktor D, properdin, faktor B, faktor I
Interaksi dengan imun bawaan selular : membantu
aktivasi sel-sel fagositik yang merupakan sistem imun
bawaan selular
----- C5a, C4a, C3a : anafilatoksin mengaktivasi sel-sel
fagosit
----- C5a, C3a : kemotaktik faktor, mengaktivasi basofil dan
sel mast degranulasi histamin

There are 3 complement pathways that make up

the complement system:

- the lectin pathway,

- the alternative pathway,
- the classical pathway.
The pathways differ in the manner in which they are
activated and ultimately produce a key enzyme called
C3 convertase:
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SCHEMATIC OVERVIEW OF THE COMPLEMENT CASCADE

Classical

MB-Lectin

Ag-Ab complex

Lectin binding to
pathogen surfaces

Alternative .
Pathogen surfaces

Complement activation

Recruitment of
inflammatory cells
(C3a, C5a)

Opsonization of
pathogens
(C3b)

MAC

Killing of pathogens
(C5b6789)
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maria immaculata iwo, sf itb

Jalur Komplemen
A. Jalur Lektin
Pemicu : polisakarida pada membran sel patogen yang dapat berikatan
dengan lektin
Jalur :
Infeksi hati

produksi

MBL/MBP
(Mannose Binding
Lectin/Protein)

MASP I

C4 & C2 convertase
MASP II

mannose-associated serine protease 1 (MASP-1)

mannose-associated serine protease 2 (MASP-2)

Protein Fasa
Akut

Patogen

Protein fasa akut

berikatan dengan
karbohidrat pada
membran sel patogen

17

C4
C4a

C4b

C4b2a
aktivasi

aktivasi

C3

C2
C2a

Stabilisasi oleh
Mg2+

C3 konvertase
(C4b + C2a)

C2b

C3a

C3b + C4b2a

C4b2a3b
C5 konvertase
C5

C5b6789

C9
Menempel di membran patogen
menyebabkan lisis patogen
(MAC/Membran Attack Complex)

C8

C7

C6

C5b

C5a

MBL has been showed to bind to:

yeasts such as Candida albicans

viruses such as HIV and influenza A
many bacteria including Salmonella and Streptococci
parasites like Leishmania

The subsequent complement cascade catalyzed by

C3 convertase results in creating a
membrane attack complex, which causes lysis of
the pathogen that MBL bound to.

maria immaculata iwo, sf itb

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B. Jalur Alternatif
Pemicu : dinding sel/materi lain pada permukaan patogen, proteolysis by
enzymes derived from bacteria, blood clotting enzymes, injury
Komponen bakteri

aktivasi

C3a

Faktor D

Ba

C3

aktivasi

Faktor B

C3b

Bb
C3 konvertase
(C3b + Bb)

C3bBb
+ C3b

C3bBb3b
C5 konvertase

Stabilisasi oleh
properdin (serum
protein)

C. Jalur Klasik
Sebenarnya membutuhkan imun adaptif (kompleks antigen-antibodi) untuk
aktivasinya (sebagai trigger)
Namun ada teori yang menyatakan bisa aktif tanpa imun adaptif natural
antibody
Natural antibody

OR

Antigen-Antibodi
Complex

C1q

C1r

C1s
C4 konvertase

REGULATOR DALAM AKTIVASI KOMPLEMEN

1. C1
olehMaster
C1 inhibitor
(C1 INH) :
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Berikatan bebas dengan C1 dalam darah
Membatasi aktivasi C4 & C2 Dengan cara mengikat dan menginhibisa C1r and C1s proteases
2. Mengurangi waktu paruh C3 Convertases , oleh :
Decay Accelerating Factor (DAF)
C4 binding protein (C4bp) dan factor H, yang masing-masing bekerja pada C4b2b and
C3bBb.
3. C9 Dengan Menghambat polimerisasi C9, oleh :
CD59
Homologous Restriction Factor (HRF).

EFEK BIOLOGIK DARI SISTEM KOMPLEMEN

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1. OPSONISASI
2. INFLAMASI
3. LISIS
4. IMMUNE COMPLEX CLEARANCE

6 KEUNTUNGAN FUNGSI PERTAHANAN INNATE DARI

KOMPONEN-KOMPONEN SISTEM KOMPLEMEN
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1. Pemicu inflammation (C3a, C4a, C5a)
2. Kemotaktik sel fegosit ke lokasi infeksi (C5a)

3. Promosi pelekatan antigen ke sel fagosit (enhanced attachment or opsonization)

4. Lisis pada bakteri gram (-) dan sel manusia yang mengekspresikan epitop asing
5. Penghantar sinyal kedua dalam aktivasi Sel B-Naive (C3d)
6. Eliminasi kompleks imun yang berbahaya ke luar tubuh

COMPLEMENT RECEPTORS
CR1
CR1 binds C3b and C4b.
CR1 is found on erythrocytes, where it plays a vital role in
removing immune complexes from circulation.

It is also found on macrophages and neutrophils and can trigger

phagocytosis (only after activation of cells by other mediators
including C5a).

CR2
CR2 binds iC3b and C3d and is found on B cells where it plays an
important role in activating class switching and memory
formation.
The presence of bound C3d molecules enhances the response
to antigen by about 20-fold for each molecule of C3d bound
(at least up to 3).

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CR3 and CR4

CR3 and CR4 are related receptors which bind iC3b and
are found on monocytes/macrophages and neutrophils.
They trigger phagocytosis of opsonised particles, either
in concert with Fc receptors or independently.

Phagocytosis of microorganisms via CR3, and via CR1+FcR, is

the major defense mechanism against bacterial and fungal
infection.

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Distribution and function of receptors for

complement proteins on the surface of the cells
Receptor

Specificity

Functions

Cell type

Promotes C3b and

C4b decay, stimulates
phagocytosis,
erythroyte transport
of immune complexes

Erythrocyte,
Macrophages,
monocytes,
polymorphonuclea
r leokocytes, B cells,
FDC

CR1 (CD35)

C3b, C4b,
iC3b

CR2

C3d, iC3b,
Part of B-cell coC3dg,
receptor Epstein Barr
Epstein Barr virus receptor
virus

CR3
(Mac-1),
iC3b
(CD11b/CD18)

Stimulates
phagocytosis

B cells, FDC

Macrophages,
monocytes,
polymorphonuclea
r leokocytes, FDC

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DISTRIBUTION AND FUNCTION OF RECEPTORS FOR COMPLEMENT

PROTEINS ON THE SURFACE OF THE CELLS
Receptor Specificity
CR4
(gp150,95)
(CD11c/
CD18)

C5a
receptor

C3a
receptor

iC3b

Functions
Stimulates
phagocytosis

C5a

Binding of
C5a,
activates G
protein

C3a

Binding of
C3a,
activates G
protein

Cell type
Macrophages,
monocytes,
polymorphonuclear
leokocytes, dendritic cells
Endothelial cells, mast
cells, phagocytes

Endothelial cells, mast

cells, phagocytes
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