BAB 2

INNATE IMMUNITY
Features of Innate Immune recognation.
Components of the Innate Immune system
Role of Innate Immunity in stimulating
Adaptive Immune Responses
Summary.
 Specificity of Innate and Adaptive Immunity

Innate Immunity Adaptive immunity

SPECIFICITY

Limited diversity Greater diversity

RECEPTORS

NONCLONAL DISTRIBUTION CLONAL DISTRIBUTION

Toll-like Receptors (TLRs)

Figure 2-1 Cellular locations of pattern recognition molecules of the

innate immune system. Some pattern recognition molecules of the TLR
family (see Fig. 2-7), such as TLRs 2, 4, and 5, are expressed on the cell
surface, where they may bind extracellular pathogen-associated molecular
patterns. Other TLRs are expressed on endosomal membranes, such as
TLRs 3, 7, 8, and 9, all of which can recognize nucleic acids of microbes that
have been phagocytosed by cells. Cells also contain cytoplasmic sensors of
microbial infection (discussed later in the chapter), including the NLR family
of proteins, which recognize bacterial peptidoglycans, and a subset of CARD
family of proteins, which bind viral RNA
TOLL-LIKE RECEPTOR
STRUCTURE AND
SIGNALING PATHWAYS
Figure 2-2 Mammalian TLRs: specificities,
basic signaling mechanisms, and cellular
responses.
Ligands for TLRs are shown together with
dimers of the TLRs that specially bind them.
Note that some TLRs are expressed in
endosomes and some on the cell surface (see
Fig. 2-7). The basic steps in TLR signaling,
illustrated only for TLR3 and TLR4, are
applicable to all TLRs. Further details about
the signaling pathways are described in Box 2-
1.
Components of the Innate Immune System

Figure 2-3 Epithelial

barriers.
Epithelia at the portals of
entry of microbes
provide physical barriers,
produce antimicrobial
substances, and harbor
intraepithelial
lymphocytes that are
believed to kill microbes
and infected cells.
Figure 2-4 Morphology of neutrophils. The light micrograph of a
blood neutrophil shows the multilobed nucleus, because of which
these cells are also called polymorphonuclear leukocytes, and the
faint cytoplasmic granules
Figure 2-5 Maturation of mononuclear phagocytes. Mononuclear
phagocytes develop in the bone marrow, circulate in the blood as
monocytes, and are resident in all tissues of the body as
macrophages. They may differentiate into specialized forms in
particular tissues. CNS, central nervous system
 blood monocytes blood monocytes Tissue macrophage

Figure 2-6 Morphology of mononuclear phagocytes. A. Light micrograph of a monocyte in a peripheral blood
smear. B. Electron micrograph of a peripheral blood monocyte. (Courtesy of Dr. Noel Weidner, Department of
Pathology, University of California, San Diego.) C. Electron micrograph of an activated tissue macrophage
showing numerous phagocytic vacuoles and cytoplasmic organelles. (From Fawcett DW. Bloom & Fawcett's
Textbook of Histology, 12th ed. Chapman & Hall, 1994. With kind permission of Springer Science and Business
Media.)
 RECRUITMENT OF LYMPHOCYTES

Figure 2-7 Recruitment of leukocytes. At sites of infection, macrophages that have encountered microbes
produce cytokines (such as TNF and IL-1) that activate the endothelial cells of nearby venules to produce
selectins, ligands for integrins, and chemokines. Selectins mediate weak tethering and rolling of blood
leukocytes, such as neutrophils on the endothelium; integrins mediate firm adhesion of neutrophils; and
chemokines increase the affinity of neutrophil integrins and stimulate the migration of the cells through the
endothelium to the site of infection. Blood neutrophils, monocytes, and activated T lymphocytes use essentially
the same mechanisms to migrate to sites of infection
 Phagocytosis of Microbes

Figure 2-8 Phagocytosis and intracellular destruction of microbes. Microbes may be ingested by different membrane receptors of phagocytes;
some directly bind microbes, and others bind opsonized microbes. (Note that the Mac-1 integrin binds microbes opsonized with complement proteins,
not shown.) The microbes are internalized into phagosomes, which fuse with lysosomes to form phagolysosomes, where the microbes are killed by
reactive oxygen and nitrogen intermediates and proteolytic enzymes. NO, nitric oxide; ROS, reactive oxygen species
 Other Functions of
Activated Macrophages
Figure 2-9 Effector functions of
macrophages. Macrophages are activated
by microbial products such as LPS and by
NK cell-derived IFN-γ (described later in
the chapter). The process of macrophage
activation leads to the activation of
transcription factors, the transcription of
various genes, and the synthesis of
proteins that mediate the functions of these
cells. In adaptive cell-mediated immunity,
macrophages are activated by stimuli from
T lymphocytes (CD40 ligand and IFN-γ)
and respond in essentially the same way
(see Chapter 13, Fig. 13-14).
Figure 2-10 Activating and inhibitory receptors of
NK cells.

A. Activating receptors of NK cells recognize ligands

on target cells and activate protein tyrosine kinase
(PTK), whose activity is inhibited by inhibitory
receptors that recognize class I MHC molecules and
activate protein tyrosine phosphatase (PTP). NK cells
do not efficiently kill class I MHC-expressing healthy
cells. B. If a virus infection or other stress inhibits
class I MHC expression on infected cells, and
induces expression of additional activating ligands,
the NK cell inhibitory receptor is not engaged and the
activating receptor functions unopposed to trigger
responses of NK cells, such as killing of target cells
and cytokine secretion.
 COMPONENTS OF INNATE IMMUNITY

BARRIERS
Epithelial layers Prevent microbial entry
Defensins/cathelicidin Microbial killing
Intraepithelial lymphocytes Microbial Killing

CIRCULATING EFFECTOR CELLS.

Neutrophils Early phagocytosisand killing of microbes.
Macrophages Efficient phagocytosis and killing of microbes,
secretion of cytokines that stimulate inflamation.
NK cells Lysis of infected cells, activation of macrophage
 COMPONENTS OF INNATE IMMUNITY

CIRCULATING EFFECTOR PROTEINS

Complement Killing of microbes, opsonization of microbes,
activation of leukocytes
Mannose-binding Opsonization of microbes, activation of complement
Lectin (collectin) (lectin pathway)
C-reactive protein Opsonization of microbes, activation of complement
(pentraxin)

CYTOKINES
TNF,IL-1, chemokines inflammation
INF-α,-β Resitance to viral infection
INF-γ Marophage activation
IL-12 INFγ production by NK cells and T cells
IL-15 Proliferation of NK cells.
IL-10, TGFβ Control of inlammation.
INHIBITORY AND ACTIVATING
RECEPTORS OF NK CELLS
Figure 2-11 Functions of NK
cells.
A. NK cells recognize ligands on
infected cells or cells undergoing
other types of stress, and kill the
host cells. In this way, NK cells
eliminate reservoirs of infection
as well as dysfunctional cells. B.
NK cells respond to IL-12
produced by macrophages and
secrete IFN-γ, which activates
the macrophages to kill
phagocytosed microbes.
 The Complement System

Figure 2-12 Pathways of complement activation. The activation of the complement system may be initiated by three
distinct pathways, all of which lead to the production of C3b (the early steps). C3b initiates the late steps of
complement activation, culminating in the production of peptides that stimulate inflammation (C5a) and polymerized
C9, which forms the membrane attack complex, so called because it creates holes in plasma membranes. The
principal functions of major proteins produced at different steps are shown. The activation, functions, and regulation of
the complement system are discussed in much more detail in Chapter 14.
Role of Innate Immunity in Stimulating
Adaptive Immune Responses
Figure 2-13 Stimulation of adaptive immunity by
innate immune responses.

Antigen recognition by lymphocytes provides signal

1 for the activation of the lymphocytes, and
molecules induced on host cells during innate
immune responses to microbes provide signal 2.
In this illustration, the lymphocytes are B cells, but
the same principles apply to T lymphocytes. The
nature of second signals differs for B and T cells
and is described in later chapters.
 RINGKASAN
• Imunitas innate garis pertahanan pertama
terhadap mikroba. Exist sebelum mikroba
datang.
• Komponen imunitas innate adalah
pertahanan epitel, leukosit (neutr, makrofag
dan sel NK), protein efektor dalam sirkulasi
(komplemen, kollektin, pentraksin) dan
sitokin (TNF, IL-1, kemokin, IL-2, INF tipe 1
dan INFγ
 RINGKASAN
• Menggunakan reseptor untuk mengenal PAMPs
(pathogen associated molecular pattern)
pada mikroba, dimiliki bersama oleh mikroba
dan tak ada dalam sel mamalia.
• PAMP sangat penting untuk kehidupan mikroba
sehingga sukar untuk mutasi (menghentikan
ekspressinya agar selamat dari respon Imun
innate).
• TLRs adl reseptor terpenting karena dapat
mengenal variasi yang luas dari ligand( asam
nukleak mikroba, KH, glikolipid dan protein)
 RINGKASAN
• Makrofag mengenal dan berespon terhadap
mikroba melalui banyak reseptor (TLRs, C-
type lectins, scavenger receptors danN-formyl
Met-Leu-Pe receptors).
• Netrofil dan makrofag membunuh mikroba yg
difagositosis dengan ROS, Nitric Oxide dan
lisozim dalam fagolisosom.
• Makrofag menghasilkan sitokin untuk inflamasi
(proinflamasi) dan tissue remodeling pada
daerah infeksi.
 RINGKASAN
• Neutropil dan monosit (prekursor makrofag
jaringan) berpindah dari sirkulasi ke daerah
inflamasi selama respon imun innate.
• Sitokin yang dihasilkan didaerah infeksi (IL-1
dan TNF) akibat stimulasi produk mikroba akan
memicu ekspressi molekul adesi pada endotel
vena yang akan memediasi perlekatan leukosit
pada endotel untuk selanjutnya migrasi ke
daerah infeksi.
 RINGKASAN
• Tahapan migrasi mulai dari perlekatan
lemah dengan molekul adesi (endothelial
selectin …..leucocyte-selectin ligands )
disusul perlekatan kuat (leucocyte
integrin, chemokines) kemudian
diapedesis (keluar dari sirkulasi)
• Kemokin mengantar leukosit sejak keluar
dari sirkulai menuju ke daerah infeksi.
 RINGKASAN
• Sel NK adalah limposit yg bekerja untuk kuman
intraseluler dengan membunuh sel yang
mengandung mikroba dan menghasilkan INFγ
yang memicu aktipasi makrofag.
• Pengenalan sel terinfeksi oleh Sel NK diatur
melalui kombinasi reseptor aktipasi dan
inhibisi. Reseptor inhibisi mengenal molekul
MHC I agar tidak membunuh sel normal tetapi
membunuh sel terinfeksi karena molekul MHC I
berkurang.
 RINGKASAN
• Sistem komplemen diaktifkan oleh mikroba dan
produk dari aktipasi komplemen akan
meningkatkan fagositosis dan pembunuhan
mikroba oleh makrofag dan stimulasi inflamasi.
• Effektor molekul dalam plasma seperti
pentraksins (CRP), kollektin dan fikolin mengikat
ligan mikroba dan mempercepat pemersihan
mikroba melalui mekanisme yg tergantung
komplemen atau tidak.
 RINGKASAN
• Sitokin pada imun innate bekerja untuk
rekrut dan aktipasi leukosit (TNF,IL-1,
kemokin), meningkatkan eliminasi mikroba
oleh fagosit (INFγ), stimulasi respon sel NK
dan limposit T (IL-2)
• Pada infeksi berat, produksi berlebihan
sitokin membahayakan penderita bisa
menyebabkan kematian.
 RINGKASAN

• Molekul yang dihasilkan oleh imun innate

memicu imun adaptif dan mempengaruhi
responnya.
• Makrofag yg diaktifasi oleh mikroba dan
INFγ mengeluarkan molekul assessori
yang meningkatkan aktipasi sel T