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IMUNOLOGI

- Sel B dan sel T


- Alternative dan Lectin
pathway dari komplemen

Mekanisme pertahanan tubuh

Imunitas bawaan
imunitas alamiah,
imunitas non spesifik,
innate immunity
natural immunity.

Imunitas didapat
imunitas adaptif,
imunitas spesifik,
acquired immunity
adaptive immunity

IMUNITAS BAWAAN
IMUNITAS BAWAAN
BARIER ANATOMI

BARIER HUMORAL

BARIER SELULER

FAKTOR MEKANIS

KOMPLEMEN

NETROFIL

FAKTOR KEMIS

KOAGULASI

MAKROFAG

FAKTOR BIOLOGIS

LAKTOFERIN &
TRANSFERIN

SEL NK & LAK

INTERFERON

EOSINOFIL

LISOZIM
INTERLEUKIN

IMUNITAS DIDAPAT
IMUNITAS DIDAPAT
IMUNITAS SELULER
(LIMFOSIT T)
SEL T KILLER
SEL T HELPER
SEL T SUPRESSOR
SEL T MEMORY

IMUNITAS HUMORAL
(LIMFOSIT B)

SEL PLASMA
SEL B MEMORY

IMUNITAS SELULER (oleh Limfosit T)


Saat makrofag (imunitas bawaan) menelan antigen dan membunuhnya
merangsang limfosit T mengenal antigen.
Semua sel tertutup oleh berbagai substansi yaitu Cluster of differentiation (CD)
yang jenisnya >160 cluster. Ada 100.000 molekul pada permukaan Sel T
dan sel B.
Sel B tertutup oleh CD21, CD35, CD40, CD45, dan molekul non CD.
Sel T tertutup oleh CD2, CD3, CD4, CD28, CD45R dan molekul non CD.
Molekul pada permukaan limfosit menyebabkan pembentukan reseptor
yang bervariasi (ada 1018 macam reseptor)
Sel T awalnya dari timus melalui 2 proses seleksi.
Seleksi positif: hanya sel T yang cocok dengan reseptor yang dapat
mengenal molekul MHC yang bertanggungjawab terhadap pengenalan
self.
Seleksi negatif: dimulai ketika sel T yang dapat mengenal molekul MHC
bergabung dengan peptide asing dikeluarkan dari timus.

IMUNITAS SELULER (oleh Limfosit T)


Ada beberapa macam sel T:
Sitotoksik atau Sel T Killer (CD8+)
mengeluarkan limfotoksin yang menyebabkan lisis sel.
Sel T Helper (CD4+)
pengelola, mengarahkan respon imun.
mengeluarkan limfokin yang merangsang sel T Killer dan sel B
untuk tumbuh dan membelah diri,
memicu netrofil,
memicu makrofag untuk menelan dan merusak mikroba.
Sel T Supressor
menghambat produksi sel T Killer jika tak dibutuhkan lagi.
Sel T Memory
mengenal dan merespon patogen

Sistem Imun Tubuh

Respon Imun
Ada 4 jenis sel-sel imun yang berbeda dapat
membunuh target in vitro maupun in vivo.
1. Sel pembunuh alami (Natural Killer (NK)
Cell),
2. Cytolytic thymus dependent Lymphocytes
(CTLs),
3. Lymphokine-activated killer cells (LAK cells),
4. Macrophages

Sel B dan sel T :


Sel B

Plasma Cells

Sel T

CD8+ T cells
CD4+ T cells

Gamma/Delta Sel T
Lymphocyt merupakan salah satu dari lima komponen dari
sel darah putih (leukocytes), yang beredar dalam darah.
Meskipun leukosit yang matang tampak hampir serupa akan
tetapi fungsinya sangatlah berbeda dan bermacam-macam.
Limfosit yang terbanyak adalah :
Limfosit B (B cells) dan
Limfosit T (T cells).

Sel B diproduksi di sumsum tulang (bone marrow).


Prekursor sel T juga diproduksi di sumsum tulang akan
tetapi mengalami pematangan di kel. Thymus.

Setiap sel B dan sel T cell adalah spesifik terhadap antigen.


Tertentu, dimana ke spedifikan itu terdapat pada bagian
reseptor dari sel tsb. Reseptor sel B ( BCR) dan reseptor sel T
(TCR),.
Masing-masing BCR dan TCR mempunyai sifat yang sama sbb:
Mereka di kodekan oleh gen yang disusun oleh berbagai
kombinasi segmen-segmen DNA.
Mereka merupakan integral membrane proteins.
Mereka terdapat dalam beribu macam kopi yang identik yang
diekspose di permukaan sel..
Mereka dibuat sebelum sel itu bertemu dengan antigen.
Mereka mempunyai situs pengikatan yang khas..
Situs itu terikat pada bagian dari antigen yang disebut
antigenic determinant atau epitope.
Ikatan seperti itu menyerupai ikatan antara enzyme dan
substrat-nya yg tergantung pada komplemen pada permukaan
reseptor dan permukaan dari epitope.
Iktannya merupakan ikatan non-covalent forces , apalagi bila
dilengkapi dengan sinyal-sinyal tambahan, yg akan
menghasilkan :
Stimulasi sel untuk meninggalkan fase G0 dan memasukki siklus sel.

BCR dan TCR berbeda pada struktur, gen yg mengkodenya dan


tipe epitop yang diikatnya

Jaringan Lymphoid

Primary
(Responsible for
aturation of Ag-reactive
cells)

Thymus (T
cell
maturation
)

(T-cell
maturation)

Secondary
(Sites for Ag contact and response)

Bone
marrow

Lymph nodes

Spleen

(B-cell
maturation
)

(Expansion of lymphatic
system, separate from blood
circulation.
Deep cortex harbors mostly T
-cells, superficial cortex
harbors mostly B -cells)

(Similar to lymph
nodes but part of
blood circulation.
Collects blood-borne
Ags)

LEKOSIT

CELLS OF THE IMMUNE RESPONSE


Cell group

Surface components

B-lymphocytes

Surface immunoglobulin (Ag recognition)


Immunoglobulin Fc receptor
Class II Major Histocompatability Complex
(MHC) molecule (Ag presentation)

Function
Direct antigen recognition
Differentiation into antibody-producing plasma cells
Antigen presentation within Class II MHC

CD3 molecule
T-cell receptor (TCR, Ag recognition)

Involved in both humoral and cell-mediated responses

Helper T-cells (TH)

CD4 molecule

Recognizes antigen presented within Class II MHC


Promotes differentiation of B-cells and cytotoxic T-cells
Activates macrophages

Suppressor T-cells
(TS)

CD8 molecule

Downregulates the activities of other cells

Cytotoxic T-cells
(CTL)

CD8 molecule

Recognizes antigen presented within Class I MHC


Kills cells expressing appropriate antigen

Accessory cells

Variable

Phagocytosis and cell killing

T-lymphocytes

Macrophages

Immunoglobulin Fc receptor
Complement component C3b receptor
Class II MHC molecule

Dendritic cells

Class II MHC molecule

Polymorphonuclear
cells (PMNs)

Immunoglobulin Fc receptor
Complement component C3b receptor

Killer cells

Variable

Bind Fc portion of immunoglobulin (enhances


phagocytosis)
Bind complement component C3b (enhances
phagocytosis)
Antigen presentation within Class II MHC
Secrete IL-1 (macrokine) promoting T-cell differentiation
and proliferation
Can be "activated" by T-cell lymphokines
Antigen presentation within Class II MHC
Bind Fc portion of immunoglobulin (enhances
phagocytosis)
Bind complement component C3b (enhances
phagocytosis)

Direct cell killing

Unknown

Kills variety of target cells (e.g. tumor cells, virusinfected cells, transplanted cells)

K cells

Immunoglobulin Fc receptor

Bind Fc portion of immunoglobulin


Kills antibody-coated target cells (antibody-dependent
cell-mediated cytotoxicity, ADCC)

Mast cells

High affinity IgE Fc receptors

Bind IgE and initiate allergic responses by release of


histamine

NK cells

KOMPONEN KOMPONEN SISTEM IMUN


Innate immune system

Adaptive immune system

Response is non-specific

Pathogen and antigen specific response

Exposure leads to immediate maximal


response

Lag time between exposure and maximal


response

Cell-mediated and humoral components

Cell-mediated and humoral components

No immunological memory

Exposure leads to immunological memory

Found in nearly all forms of life

Found only in jawed vertebrates

Asosiasi antara sel T dengan MHC kelas I atau MHC


kelas II dengan antigen (yang berwarna merah)

Formation of Antigen
MHC Molecules Complexes

Minor lymphocyte populations with limited receptor diversity Are not clonally
expanded following antigen recognition Interact with nonclassical MHC like
molecules

Coreceptors on B Cells

B Cells :

BCRs bind soluble antigens (like diphtheria toxoid,


the protein introduced into your body in the
DTP vaccine ).
The bound antigen molecules are engulfed into the B
cell by receptor-mediated endocytosis .
The antigen is digested into fragments
which are then displayed at the cell surface nestled
inside a class II histocompatibility molecule .
Helper T cells specific for this structure (i.e., with
complementary TCRs) bind the B cell and
secrete lymphokines that:
stimulate the B cell to enter the cell cycle and develop, by
repeated mitosis, into a clone of cells with identical BCRs;

T Cells:
The surface of each T cell also displays thousands of
identical T cell receptors (TCRs).
There are two types of T cells that differ in their TCR:
alpha/beta () T cells. Their TCR is a heterodimer of an
alpha chain with a beta chain. Each chain has a variable (V)
region and a constant (C) region. The V regions each
contain 3 hypervariable regions that make up the
antigen-binding site. [Link]
gamma/delta () T cells. Their TCR is also a heterodimer
of a gamma chain paired with a delta chain.
The discussion that follows now concerns alpha/beta T cells.
Gamma/delta T cells, which are less well understood, are
discussed at the end .
The TCR (of alpha/beta T cells) binds a bimolecular complex
displayed at the surface of some other cell called an
antigen-presenting cell (APC). This complex consists of:
a fragment of an antigen lying within the groove of a
histocompatibility molecule

The complex has been compared to a "hot dog in a bun".


Most of the T cells in the body belong to one of two
subsets. These are distinguished by the presence on their
surface of one or the other of two glycoproteins
designated:
CD4
CD8
Which of these molecules is present determines what types
of cells the T cell can bind to.
CD8+ T cells bind epitopes that are part of class I
histocompatibility molecules. Almost all the cells of the
body express class I molecules.
CD4+ T cells bind epitopes that are part of class II
histocompatibility molecules. Only specialized antigenpresenting cells express class II molecules.
These include:
dendritic cells
like macrophages and
B cells!

MHC dan CD8+ T Cells

CD8+ T cells
The best understood CD8+ T cells are cytotoxic T
lymphocytes (CTLs).
They secrete molecules that destroy the cell to which they
have bound
This is a very useful function if the target cell is infected
with a virus because the cell is usually destroyed before it
can release a fresh crop of viruses able to infect other cells.
In general, the role of the CD8+ T cells is to monitor all the
cells of the body, ready to destroy any that express foreign
antigen fragments in their class I molecules. In general, the
role of the CD8+ T cells is to monitor all the cells of the
body, ready to destroy any that express foreign antigen
fragments in their class I molecules.

Activation of Cytotoxic T Cells

CYTOLYTIC THYMUS-DEPENDENT LYMPHOCYTES


(CTLs) = Cytotoxic T cells
CTL,
- dapat membunuh sel asing setelah dipresentasikan oleh MHC kelas I.
- sebagai sel-sel efektor utama dalam penolakan sel=sel asing
- CTLs dapat membunuh sel-sel target melalui 2 pathway :
1. Pathway pertama, yang melibatkan sekresi protein dan protease
serin alami yang keduanya ada dalam granula unik pada CTLs
2. Pathway kedua, memerlukan cross-linked ligands permukaan
pada CTLs dengan reseptor permukaan spesifik pada sel-sel
sasaran untuk merangsang apoptosis sel-sel itu (program
kematian sel).

CD4+ T cells
CD4+ T cells bind an epitope consisting of an antigen fragment
lying in the groove of a class II histocompatibility molecule .
CD4+ T cells are essential for both the cell-mediated and
antibody-mediated branches of the immune system:
cell-mediated immunity
These CD4+ cells bind to antigen presented by antigenpresenting cells (APCs) like phagocytic macrophages and
dendritic cells. The T cells then release lymphokines that
attract other cells to the area. The result is inflammation : the
accumulation of cells and molecules that attempt to wall off
and destroy the antigenic material (an abscess is one example,
the rash following exposure to poison ivy is another).
antibody-mediated immunity
These CD4+ cells, called helper T cells, bind to antigen
presented by B cells (as shown above ). The result is the
development of clones of plasma cells secreting antibodies
against the antigenic material.
AIDS provides a vivid and tragic illustration of the importance of CD4+ T cells in
immunity. The human immunodeficiency virus ( HIV) binds to CD4 molecules and thus is
able to invade and infect CD4+ T cells. As the disease progresses, the number of CD4+ T
cells declines below its normal level of about 1000 per microliter (l). (A partial
explanation for this may be the unceasing efforts of the patient's CD8+ T cells to destroy
the infected CD4+ cells.

Helper T- Cells

Aktivasi Sel T spesifik - antigen

: T cells
Unlike adaptive T cells, have a TCR
composed of a heterodimer of : chains
as opposed to the common : molecules
Two types: circulating cells/lymphoid
tissues and resident cells found in the
epithelium. Circulating cells have a diverse
TCR (similar to adaptive T cells), while
intraepithelial : T cells express a limited
repertoire.
Resident : T cells recognize antigens
directly, not in the context of MHC
presented molecules. Presumed to have
evolved tissue specific Antigen recognition
(MHC class 1b).

Lymphokine-Activated
Killer cells (LAK cells)
LAK cells,
Subset null lymphocyte berbeda dari
sel-sel NK dan CTLs.
Dapat dihasilkan in vitro, caranya
mengkultur sel-sel limfosit + interleukin-2, konsentrasi IL-2 tinggi
Memiliki aktivitas anti tumor (membunuh
sel tumor).

Killer T cells

SEL NK (natural killer) & LAK (lymphokine activated killer)


Secara non spesifik membunuh virus dan sel-sel tumor.
Bukan bagian dari respon radang.

Sel NK
Sel-sel NK dapat membunuh sel-sel sasaran tanpa
mensintesa sebelumnya Antigen spesifik, aktivitasnya tidak memerlukan adanya MHC kelas I pada
sel-sel target.
Diperkirakan sel-sel NK ambil bagian dalam pengawasan tumor yang mulai timbul dan juga terhadap
pertumbuhan metastatik tumor.
Berkembang dalam bone marrow, kemudian diperoleh dalam peripheral blood, sel pit (sinusoid liver)
dan sinusoid limpa
Dapat mensekresi interferon gamma, dan secara
spontan membunuh sel yang diinfeksi virus dan
sel-sel tumor

Sel NK,
mungkin salah satu dari sel T Sitotoksik
Mempunyai reseptor yang berikatan dengan bagian
dari molekul IgG.
Saat berikatan, sel-sel NK memasukkan suatu protein
ke sel
target, menyebabkan sel target membengkak dan
pecah.
Markernya CD 16

NATURAL KILLER CELLS

NK cells
NK cells merupakan suatu grup yg
disebut "large granular lymphocytes".
Sel-sel ini bersifat non-specific, MHCunrestricted cells berperan untuk
eliminasi sel-sel neoplastik atau tumor,
Mekanisme bagaimana sel ini
mengenal
sel sasarannya belum diketahui secara
jelas.
Kemungkinan terdapat beberapa tipe
NK-determinant yg diekspresikan oleh
sel sasaran yg dikenal oleh reseptor
NK-receptor pd permukaan sel NK .
Begitu sel sasaran dikenali
pemusnahan mungkin sama dengan
cara kerja CTL.

Macrophages
Sel fagosit mono nukleus non limfosit
Ada pada jaringan dan dalam darah, derivat
dari
stem sel monositic.
Penting sebagai sel pelengkap pada respon
imun
Makrofag khusus ada pada beberapa lokasi, selsel
Kupffer dan histiosit.

MAKROFAG
Makrofag dan monosit yang baru
direkrut melakukan fagositosis serta
membunuh mikroorganisme di
dalam sel.
Makrofag juga mampu membunuh
secara ekstraseluler.
Makrofag mendukung perbaikan
jaringan dan beraksi sebagai
antigen-presenting cells (APC),
yang diperlukan untuk memicu
respon imun spesifik.

Fungsi Complement
Complement merupakan suatu grup protein serum yang berkerja sebagai
komplemen aktivitas antibodi untuk melenyapkan patogen.
Adalah suatu kaskade enzim yang membentu pertahanan tubuh thd
infeksi.
Complement bukan bersifat spesifik thd antigen dan komponennya
diaktifkan dengan segera bila terdapat patogen, sehingga digolongkan
dalam imunitas didapat (innate immunity). Akan tetapi adapula antigen
yang dapt mengaktifkan protein komplemen sehingga aktivasi komplemen
sebagian digolongkan pula dalam humoral immunity.
Complement menstimulasi inflamasi, memfasilitasi fagositosis antigen dan
lisis dari beberapa macam sel secara langsung.Karena merupakan suatu
agen inflamasi yang kuat maka aktivitasnya diregulasi secara ketat..
Complement protein diproduksi secara konstitutif oleh makrofag dan
hepatosit. Yg terdapat dalam sirkulasi merupakan sebagai molekul yg
belum aktif. Sebagian besar protein komplemen merupakan pro-enzyme
(zymogen) dan sebagian ditemukan pula pada permukaan sel..
Complement proteins occur in serum as inactive enzyme precursors
(zymogens); others reside on cell surfaces.

Sistem complement :
Sistem komplemen menjembatani antara innate
dan acquired immunity melalui :
Memperbesar respons antibody (Ab) responses dan
immunologic memory
Melisiskan selsel asing
Membersihkan kompleks imun dan sel yg mengalami
apoptosis.
Komponen- komponen komplemen mempunyai banyak
fungsi biologis (a,l. Stimulasi proses chemotaxis, memicu
degranulasi sel mast tanpa tergantung pada IgE).

Aktivasi komplemen: Terdapat 3 jalur pengaktifan


komplemen:

Classical
Lectin
Alternative

Classical pathway
Aktivasi dependen thd Ab, terjadi bila C1 berinteraksi
dengan Ag-IgM atau aggregated Ag-IgG complexes,
atau Ab-independent, yg terjadi bila polyanion (eg,
heparin, protamine, DNA dan RNA dari sel apoptotic),
gram-negative bacteria, atau terikat pada C-reactive
protein yg bereaksi langsung dengan C1.
Pathway ini diregulasi oleh C1 inhibitor (C1-INH).
Lectin pathway
Aktivasi adalah Ab-independent; yang terjadi bila
mannose-binding lectin (MBL), suatu protein serum,
terikat pada gugus manosa atau fruktosa pada dinding
sel bakteri, dinding sel ragi (yeast), atau virus.
Secara fungsionil dan struktural jalur ini menyerupai
jalur klasik.

LECTIN PATHWAY
Mannose-binding lectin (MBL) cascade memerlukan sintesis
MBL oleh hati sebagai jawaban terhadap sitokin inflamasi dari
Jalur ini diinisiasi oleh ikatan MBL pada permukaan bakteri yg
mempunyai polisakarida yang mengandung manosa (mannans).
Ikatan antara MBL pada patogen menghasilkan dua macam
protease serin yaitu MASP-1 dan MASP-2 (= MBL-associated
serine proteases). MASP-1 and MASP-2 adalah sama dengan C1r
dan C1s, dan MBL adalah sama dengan C1q. Pembentukan
MBL/MASP-1/MASP-2 tri-molecular complex menhasilkan
pengaktifan dari kedua MASP dan pembelahan selanjutnya dari
C4 menjadi C4a dan C4b. Fragmen C4b terikat pada membran
dan fragmen C4a dibebaskan pada lingkungan mikro itu dan
aktivasi kedua MASP juga memecah C2 menjadi C2a dan C2b.
C2a kmdn terikat pada membran yg berasosiasi dengan C4b dan
C2b kemudian dibebaskan ke lingkungan mikro itu.
Kompleks C4bC2a yg terbentuk merupakan suatu C3 convertase,
yang berikutnya akan membelah C3 menjadi C3a dan C3b. C3b
akan terikat pada membran dalam asosiasi dengan C4b dan C2a
dan C3a akan dibebaskan pada lingkungan mikro tersebut.
Kompleks C4bC2aC3b yg terbentuj asalah suatu C5 convertase.
Pembentukan C5 convertase merupakan akhir dari lectin pathway.
Aktivitas biologis dan protein regulasi jalur lectin adalah
sama dengan jalur klasik.

Table 1. Proteins of the Complement system

Classical Pathway

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

Lectin Pathway

Mannan binding protein (MBP),


mannan-asociated serine
protease (MASP, MASP2)

Components underlined acquire enzymatic activity when activated.


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

Alternative Pathway

C3, Factors B & D*,


Properdin (P)
Factors I* & H, decay
accelerating factor (DAF),
Complement receptor
1(CR1), etc.
etc.

Lytic Pathway

C5, C6, C7, C8, C9


Protein S

Components of the Classical Pathway


Native
compon
ent

C1(q,r,s
)

Active
compone
nt(s)

Function(s)

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.

C2

C3

C4

Component cleavage
Enzymatic activity
Component assembly

Components of the Alternate Pathway


Native
compon
ent

Active
compone
nt(s)

Function(s)

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.

Properdi
n

Binds and stabilizes membrane


bound C3bBb.

C3

Factor B

Component cleavage
Enzymatic activity
Component assembly

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

Alternate pathway
Aktivasi terjadi bila komponen permukaan sel
mikroba (a.l., yeast walls, bacterial cell wall
lipopolysaccharide [endotoxin]) atau Ig (a.l.,
nephritic factor, aggregated IgA) memecah
sebagian kecil C3.
Jalur ini diregulasi oleh properdin, factor H, dan
decay-accelerating factor.
Ke 3 jalur itu kemudian akan mengerucut menjadi
suatu jalur final bersama bilamana C3 convertase
memecah C3 menjadi C3a dan C3b
Pemecahan C3 akan menghasilkan pembentukan
membrane attack complex (MAC), yg
merupakan komponen sitotoksik sistem
komplemen. MAC menyebabkan lysis dari sel-sel
asing.

Formation of the Membrane Attack Complex


(MAC):
Aktivasi komplemen stimulasi berbagai aktivitas antimikrobial.
Titik akhir adalah pembentukan membrane attack complex
(MAC), yg akan berinsersi ke pada lipid membran bakteri atau
sel eukariot dan menyebabkan lisis osmotik.
Begitu C3 convertase terbentuk baik dari jalur klasik atau
alternatif suatu seri kaskade enzimatik terjadi yg berakhir
dengan pembentukan Membrane Attack Complex (MAC).
Kaskade ini termasuk pengikatan sekuensial C'6 (complement
protein 6), C'7 dan C'8 pd permukaan sel asing.
Kompleks ini menginduksi polimerisasi jamak molekul C'9.
Protein-orotein ini akan menyusun diri pada membran plasma sel
sasaran dan membentuk sebuah pori yg akan menyebabkan air
dan molekul-molekul garam keluar dan akan merusak sel itu
melalui lisis osmotik.

Complement activation pathways.


The classical, lectin, and alternative pathways converge into a final common pathway when C3
convertase (C3 con) cleaves C3 into C3a and C3b. Ab = antibody; Ag = antigen; C1-INH = C1 inhibitor;
MAC = membrane attack complex; MASP = MBL-associated serine protease; MBL = mannose-binding
lectin; P = properdin. Overbar indicates activation.

Biologic activities:

Complement components have other immune functions that


are mediated by complement receptors (CR) on various cells.
CR1 (CD35) promotes phagocytosis and helps clear immune
complexes.
CR2 (CD21) regulates Ab production by B cells and is the
Epstein-Barr virus receptor.
CR3 (CD11b/CD18), CR4 (CD11c/CD18), and C1q receptors
play a role in phagocytosis.
C3a, C5a, and C4a (weakly) have anaphylatoxin activity: They
cause mast cell degranulation, leading to increased vascular
permeability and smooth muscle contraction.
C3b acts as an opsonin by coating microorganisms and
thereby enhancing their phagocytosis.
C3d enhances Ab production by B cells.
C5a is a neutrophil chemoattractant; it regulates neutrophil
and monocyte activities and may cause augmented adherence
of cells, degranulation and release of intracellular enzymes
from granulocytes, production of toxic oxygen metabolites,
and initiation of other cellular metabolic events.
Hereditary angioedema is due to a genetic deficiency of C1INH.

BIOLOGICALLY ACTIVE PRODUCTS dari AKTIVASI KOMPLEMEN


Aktivasi komplemen menghasilkan produksi sejumlah molekul biologis yang
aktif yg berkontribusi oada terjadinya resistance, anaphylaxis dan
inflammation..
Kinin production
C2b yg dihasilkan pd jalur klasik dari pengaktifan C merupakan suatu
prokinin yg akan menjadi aktif secara biologis setelah mengalami alterasi
enzimatik oleh plasmin. Kelebihan produksi C2b dicegah oleh pembatasan
aktivasi C2 activation oleh C1 inhibitor (C1-INH) yg dikenal pula sebagai
serpin yg menggantikan C1rs dari kompleks C1qrs.
Suatu defisiensi gene4tik dari C1-INH menyebabkan overproduksi dari C2b
dan menyebabkan hereditary angioneurotic edema. Keadaan ini dapat
diperbaiki dengan Danazol yg mempromosikan produksi C1-INH atau asam
-amino caproic yg dapat menurunkan aktivitas plasmin.
Anaphylotoxins
C4a, C3a dan C5a merupakan anaphylotoxins yg menyebabkan
basophil/mast cell degranulation dan smooth muscle contraction. Edek yg
tidak diinginkan dari peptida ini dapat dikontrol oleh pemberian
carboxypeptidase B (C3a-INA).
Chemotactic Factors
C5a dan MAC (C5b67) bersifat chemotactic. C5a juga merupakan aktivator
kuat dari neutrophils, basophils dan macrophages dan menyebabkan
induksi molekul adhesi dan sel-sel endotel vaskuler..
Opsonins
C3b dan C4b pada permukaan mikroorganisme akan menempel pada Creceptor (CR1) pada sel phagocytic dan menyebabkan phagocytosis.

Biologically active products dari aktivasi C


Degradaei produk C3 (iC3b, C3d and C3e) juga dapar
terikat pada berbagai macam sel oleh reseptor khusus
dan akan memodulasi fungsi dari sel itu.
Juga terdapat defisiensi genetik pada individu tertentu
pada komponen komplemen C, dan ditemukqan pula
diantaranya defisiensi C3 gengan akibat serius dan
fatal. Defisiensi komplemen juga ditemukan pada
immune complex diseases (e.g., SLE) acute dan
chronic bacterial, viral dan parasitic infections.

Ringkasan : sistem komplemen berperan


pada resistensi spesifik maupun nonspesifik dan menghasilkan berbagai
produk biologis dan patofisiologis yang
signifikan

Table 4. Activities of Complement Activation Products and their Control Factors


Fragment

Activity

Effect

Control Factor (s)

C2a

Prokinin, accumulation of fluids

Edema

C1-INH

C3a

Basophil and mast cells degranulation; enhanced


vascular permeability, smooth muscle
contraction

Anaphylaxis

C3a-INA

C3b

Opsonin, phagocyte activation

Phagocytosis

Factors H and I

C4a

Basophil and mast cells degranulation; enhanced


vascular permeability, smooth muscle
contraction

Anaphylaxis
(least potent)

C3a-INA

C4b

Opsonin

Phagocytosis

C4-BP and Factor I

Basophil and mast cells degranulation; enhanced


vascular permeability, smooth muscle
contraction

Anaphylaxis
(most potent)

C5a

C3a-INA
Chemotaxis, stimulation of respiratory burst,
activation of phagocytes, stimulation of
inflammatory cytokines

Inflammation

Chemotaxis

Inflammation

C5bC6C7

Protein S (vitronectin)
Attaches to other membranes

Tissue damage

Complement deficiencies and disease


Pathway/Component

Disease

Mechanism

C1INH

Hereditary angioedema

Overproduction of C2b (prokinin)

C1, C2, C4

Predisposition to SLE

Opsonization of immune complexes help keep them soluble, deficiency results in


increased precipitation in tissues and inflammation

Susceptibility to bacterial
infections in infants or
immunosuppressed

Inability to initiate the lectin pathway

Factors B or D

Susceptibility to
pyogenic (pus-forming)
bacterial infections

Lack of sufficient opsonization of bacteria

C3

Susceptibility to bacterial
infections

Lack of opsonization and inability to utilize the membrane attack pathway

C5, C6, C7 C8, and C9

Susceptibility to Gramnegative infections

Inability to attack the outer membrane of Gram-negative bacteria

Properdin (X-linked)

Susceptibility
meningococcal
meningitis

Lack of opsonization of bacteria

Factors H or I

C3 deficiency and
susceptibility to bacterial
infections

Uncontrolled activation of C3 via alternative pathway resulting in depletion of C3

Classical Pathway

Lectin Pathway
MBL
Alternative Pathway

Cytokines

Cytokine
Cytokine merupakan protein sekresi kecil yang berperan memediasi
dan pengaturan imunitas, inflamasi dan hematopoiesis. Protein ini
dihasilkan de novo sebagai respons stimulus imun.
Umumnya berperan pada jarak dekat dan mempunyai half life yg
pendek dan terdapat dalam konsentrasi kecil.
Mereka bertindak dengan mengikat reseptor spesifik pada membran
yg kemudian memberi sinyal pada sel itu melalui second
messengers, umumnya tyrosine kinase, untuk mengubah ekspresi
gen
Respons thd cytokine termasuk peningkatan atau penurunan
ekspresi protein membran termasuk juga reseptor cytokine,
proliferasi, dan sekresi effector molecule..
Cytokine merupakan nama umum dan sering juga disebut
lymphokine (cytokines yg dibuat lymphocyte), monokine
(cytokines dibuat oleh monocyte), chemokine (cytokines dgn
chemotactic activities), dan interleukin (cytokines dibuat oleh
leukocyte dan berperan thd leukosit lainnya). Cytokines dapat
bekerja pada sel yg menghasilkannya (autocrine action), pd sel
lain yg dekat (paracrine action), atau pada sel lain yg letaknya
jauh dari tempat dihasilkan =melalui pemb.darah- (endocrine
action).

Cytokine Activities
Cytokine activities are characterized using
recombinant cytokines and purified cell populations in
vitro, or with knock-out mice for individual cytokine
genes to characterize cytokine functions in vivo.
Cytokines are made by many cell populations, but the
predominant producers are helper T cells (Th) and
macrophages.
The largest group of cytokines stimulates immune cell
proliferation and differentiation. This group includes
Interleukin 1 (IL-1), which activates T cells; IL-2,
which stimulates proliferation of antigen-activated T
and B cells; IL-4, IL-5, and IL-6, which stimulate
proliferation and differentiation of B cells; Interferon
gamma (IFNg), which activates macrophages; and IL3, IL-7 and Granulocyte Monocyte Colony-Stimulating
Factor (GM-CSF), which stimulate hematopoiesis.

Selected Immune Cytokines and Their Activities*


Cytokine

Producing Cell

Target Cell

Function**

GM-CSF

Th cells

progenitor cells

growth and differentiation


of monocytes and DC

IL-1
IL-1

monocytes
macrophages
B cells
DC

IL-2

Th1 cells

IL-3

Th cells
NK cells

IL-4

IL-5

IL-6

Th cells

co-stimulation

B cells

maturation and
proliferation

NK cells

activation

various

inflammation, acute
phase response, fever

activated T and B cells,


NK cells

growth, proliferation,
activation

stem cells

growth and differentiation

mast cells

growth and histamine


release

activated B cells

proliferation and
differentiation
IgG1 and IgE synthesis

Th2 cells

Th2 cells

monocytes
macrophages
Th2 cells
stromal cells

macrophages

MHC Class II

T cells

proliferation

activated B cells

proliferation and
differentiation
IgA synthesis

activated B cells

differentiation into
plasma cells

plasma cells

antibody secretion

stem cells

differentiation

IL-7

marrow stroma
thymus stroma

stem cells

differentiation into
progenitor B and T cells

IL-8

macrophages
endothelial cells

neutrophils

chemotaxis

IL-10

Th2 cells

IL-12

macrophages
B cells
cells

activated Tc cells

IFN-

leukocytes

various

viral replication
MHC I expression

IFN-

fibroblasts

various

viral replication
MHC I expression

various

Viral replication

macrophages

MHC expression

IFN-

Th1 cells,
Tc cells, NK cells

macrophages
B cells

NK cells

activated B cells
Th2 cells
macrophages

cytokine production
activation
differentiation into CTL
(with IL-2)
activation

Ig class switch to IgG2a


proliferation
pathogen elimination

MIP-1

macrophages

monocytes, T cells

chemotaxis

MIP-1

lymphocytes

monocytes, T cells

chemotaxis

monocytes, macrophages
TGF-

T cells, monocytes

activated macrophages

IL-1 synthesis

activated B cells

IgA synthesis

various
TNF

TNF-

macrophages, mast cells,


NK cells

Th1 and Tc cells

chemotaxis

macrophages

proliferation
CAM and cytokine
expression

tumor cells

cell death

phagocytes

phagocytosis, NO
production

tumor cells

cell death

* CTL: cytotoxic T lymphocytes; DC: dendritic cells; GM-CSF: GranulocyteMonocyte Colony Stimulating Factor; IL: interleukin; IFN: Interferon; TGF:
Tumor Growth Factor; TNF: Tumor Necrosis Factor.
** Italicized activities are inhibited.

Other groups of cytokines include interferons and


chemokines.
Interferons IFNa and IFNb inhibit virus replication
in infected cells, while IFNg also stimulates antigenpresenting cell MHC expression.
Chemokines attract leukocytes to infection sites.
Chemokines have conserved cysteine residues that
allow them to be assigned to four groups. The
groups, with representative chemokines, are C-C
chemokines (RANTES, MCP-1, MIP-1a, and MIP-1b),
C-X-C chemokines (IL-8), C chemokines
(Lymphotactin), and CXXXC chemokines
(Fractalkine).
Some cytokines are predominantly inhibitory. For
example, IL-10 and IL-13 inhibit inflammatory
cytokine production by macrophages. : to stimulate
cellular immunity and inflammation, and to
stimulate B cells to produce

Cytokine Receptors
Cytokines act on their target cells by binding specific membrane receptors.
The Helper T cells have two important functions antibody. Two functionally
distinct subsets of T cells secrete cytokines which promote these different
activities. Th1 cells produce IL-2, IFNg, and TNFb, which activate Tc and
macrophages to stimulate cellular immunity and inflammation. Th1 cells
also secrete IL-3 and GM-CSF to stimulate the bone marrow to produce
more leukocytes. Th2 cells secrete IL-4, IL-5, IL-6, and IL-10, which
stimulate antibody production by B cells.
T cells are initially activated as Th0 cells, which produce IL-2, IL-4 and
IFNg. The nearby cytokine environment then influences differentiation into
Th1 or Th2 cells. IL-4 stimulates Th2 activity and suppresses Th1 activity,
while IL-12 promotes Th1 activities. Th1 and Th2 cytokines are
antagonistic in activity. Th1 cytokine IFNg inhibits proliferation of Th2 cells,
while IFNg and IL-2 stimulate B cells to secrete IgG2a and inhibit secretion
of IgG1 and IgE. Th2 cytokine IL-10 inhibits Th1 secretion of IFNg and IL2; it also suppresses Class II MHC expression and production of bacterial
killing molecules and inflammatory cytokines by macrophages. IL-4
stimulates B cells to secrete IgE and IgG1. The balance between Th1 and
Th2 activity may steer the immune response in the direction of cellmediated or humoral immunity. receptors and their corresponding
cytokines have been divided into several families based on their structure
and activities.

KELUARGA SITOKIN
Hematopoietin family receptors are dimers or trimers
with conserved cysteines in their extracellular domains and
a conserved Trp-Ser-X-Trp-Ser sequence. Examples are
receptors for IL-2 through IL-7 and GM-CSF.
Interferon family receptors have the conserved cysteine
residues but not the Trp-Ser-X-Trp-Ser sequence, and
include the receptors for IFNa, IFNb, and IFNg.
Tumor Necrosis Factor family receptors have four
extracellular domains; they include receptors for soluble
TNFa and TNFb as well as membrane-bound CD40
(important for B cell and macrophage activation) and Fas
(which signals the cell to undergo apoptosis).
Chemokine family receptors have seven transmembrane
helices and interact with G protein. This family includes
receptors for IL-8, MIP-1 and RANTES. Chemokine
receptors CCR5 and CXCR4 are used by HIV to
preferentially enter either macrophages or T cells.

ANTAGONIS SITOKIN ;
Cytokine activity can be blocked by antagonists,
molecules which bind cytokines or their receptors.
IL-1 has a specific antagonist that blocks binding
of IL-1a and IL-1b to their receptor.
During immune responses, fragments of
membrane receptors may be shed and then
compete for cytokine binding.
Microbes also influence cytokine activities. For
example, Vaccinia virus (Smallpox and Cowpox)
encodes soluble molecules which bind IFNg, while
Epstein-Barr virus (Infectious Mononucleosis)
encodes a molecule homologous to IL-10 that
suppresses immune function in the host.

The TNF receptor family molecules CD40 and Fas


bind cell surface ligands on effector T cells: CD40L
and FasL. CD40 is expressed on B cell and
macrophage plasma membranes.
T cell CD40L binding to B cell CD40 stimulates B cell
proliferation and isotype switching. T cell CD40L
binding to macrophage CD40 stimulates
macrophages to secrete TNFa and become much
more sensitive to IFNg. T cell FasL binding to Fas
leads to the activation of caspase proteases that
initiate apoptosis of the cell expressing membrane
Fas.
Activated lymphocytes express Fas, so that FasLpositive Tc cells can regulate the immune response
by eliminating activated cells. An immune deficiency
disease linked to expression of a mutant Fas is
characterized by over-proliferation of lymphocytes.