INNATE or NATIVE IMMUNITY

MUH. ILYAS YUSUF, APT

 INNATE IMMUNITY
• Early lines of defense against
microbes
• Cellular and biochemical defence
mechanisms and are poised to
respond rapidly to infections
• These mechanisms react to
microbes and to the products of
injured cells, and they respond in
essentially the same way to
repeated infections
The principal components
* Physical & chemical barriers :
epithelia, antimicrobial peptides
* Phagocytic cells, DCs, NK cells
* Blood proteins : complements
* Protein called cytokines that
regulate and coordinate many of
the activities of the cell of innate
immunity
 INNATE
IMMUNE SYSTEM ADAPTIVE
Immunity Immunity
Microbe
Epithelial B lymphocytes
barriers
Proliferation
Differentiation

DC
Phagocytes
T lymphocytes Effector
Tcells
Complement
NK
cells Activation

T cells
Yoes Prijatna Dachlan 2010
B1 B cells
 Innate immunity Adaptive immunity

Inflammatory Antigen specific

immune response immune response
Magnitude of responses

Granulocytes, Macrophages

DC
NK
TLR cytokines Antigen presenting Antigen specific
NK killing 1. Ab (IgG,IgA,IgE)
interferons 2. Cellular imm resp
IgM CTL,Th, T-reg

Minutes Hours Days Months Years

(Ishii; Akira, 2008)

 Prevents, controls, eliminates
infection
PAMPs

Recognition of
microbes
DAMPs
INNATE
FUNCTION
TO Stimulates adaptive immune responses;
MICROBES Influence the nature of the adaptive responses to
make them optimally effective against different
types of microbes

Inflammation

Type of responses

Antiviral defense

(ABBAS, 7th ed., 2012)

(Ivan Roitt, 2011)
(Ivan Roitt, 2011)
PAMPs PRRs
• microbial components that stimulate • The host molecules (receptors) that
innate immunity recognize PAMP
• simple molecules and regular patterns of
molecular structure

(Abbas, et al.,2007; Murphy, 1.Membrane signaling receptors (TLR)

et al., 2008; Paul WE, 2008) 2.Phagocytic PRR

3.Secreted PRR
 1. PRR pemberi sinyal adanya infeksi
Merupakan keluarga TLR (Toll like receptor)

Aktivasi signaling pathway

pro-inflammatory

Menginduksi sejumlah gen

Produk gen

Protein & peptida Cytokine & Chemokine MHC & molekul

Sebagai efektor accessory
anti mikroba Pathogen guna mengInduksi
Signaling PRR adaptive
Intracellular PRR Immune response

dsRNA

Immune response genes

(Paul WE, 2008)
cytokine apoptosis
2. PRR fagositik (Phagocytic PRR)
 Reseptor terekspresi di: M, netrofil, sel dendrit
 PRR + PAMPS

Sel fagosit
Scavenger receptor
Mannose receptor
fagolisosom  glucan receptor

Mekanisme efektor
Eliminasi mikroba

Pathogen
Phagocytic PRR
Phagocytosis

(Paul WE, 2008)

 3. Secreted PRR
- Peran fisiologisnya berbeda
- Fungsi utama: (a) Aktivasi komplemen
(b) Opsonisasi  fagositosis
- Diproduksi & disekresi terutama oleh hepatosit
-  PRR selama Acute-phase response
- Seringkali disebut juga Acute-phase protein

Pathogen - Collectin
- C-reactive protein
Soluble PRR - PGRP (Peptidoglycan-
recognition protein)
Complement Pathogen
Soluble PRR

Classical and
Lectin pathway Receptor for soluble PRR
Phagocytosis

(Paul WE, 2008)

C-reactive protein binds phosphorylcholine
on bacterial surfaces
BASIC SIGNALING MECHANISMS

Plasma
membrane

Recruitments of adapter proteins

Recruitments and activation of protein kinases

Activation of transcription factors

Gene transcription
 TOLL-LIKE RECEPTORS (TLRs)
An evolutionarily conserved family of PRRs expressed on many cell
types, which play essential roles in innate immune responses to
microbes
TLRs contain a TIR (Toll/IL-1 receptor homology domain in their
cytoplasmic region), which is essential for signaling

PAM + TLR

ADAPTER MyD88 Mal/TIRAP Trif TRAM

Myd88 adapter- TIR domain- Trif-related adapter
like; containing molecule
TIR domain- adapter
containing protein inducing
interferon-β
 (Yoes Prijatna Dachlan 2011)

(Abbas,AK.,et al,
2007)
 TLRs (1)
*The innate immune system is responsible for initiating a
cytokine response designed to tailor the adaptive
immune system
*The signal transduction pathways leading to this
cytokine release are highly coordinated
*This coordination begins through the initial recognition
of pathogens by TLRs
*TLRs recognize PAMPs, the components of pathogens
 TLRs (2)
*The TLR family members are expressed in Mo, MØ
and DC → activation of transcription factors →
induce the expression of hundreds of cellular
genes. This gene induction is cell-type specific and
determines the adaptive immune response.
*E.g. Mo and MØ → proinflammatory cytokines (IL-
1, TNFα, IFN) → acute inflammatory response
*DC → expression of co-stimulatory molecules that
facilitate DC maturation and Ag presentation
ability
 Peptidoglycan (G+)
Lipoprotein
Lipoarabinomannan LPS (G-)
(Mycobacteria) Lipoteichoic
GPI (T. cruzi) acid Unmethylated
Zymosan (Yeast) (G+) ds RNA Flagellin CpG DNA

TLR6 TLR2 TLR1 TLR4 TLR3 TLR5 TLR9

MP4
CD14

TLR4 : M, sel dendrit, netrofil, sel mast, sel B

TLR9 (di manusia): sel B, sel dendrit (plasmacytoid dendritic cell)
TLR5 : sel epitel, M, sel dendrit
TLR3 : sel epitel, sel dendrit (plasmacytoid dendritic cell)
TLR2 : M, sel dendrit, sel B
TLR1 & TLR6 : dimana-mana

Plasmacytoid DC = CD4+ CD11c – (Pre DC 2)

(= IFN producer cell)
IFN APC
producer cells
TLR, NOD and INNATE IMMUNITY

(Stephens DS; Shafer WM, 2008)

 B-1 B Cells
*Number : about 5% (minor population)
* Marker : CD5+
* Appear during fetal life
* Responds : poorly to protein Ag, much better to
Cbh
* Members : IgM-bearing cells
* Less somatic hypermutation and class switching
* To note, γδ T cells seem to defend the body
surfaces, whereas B-1 cells defend the body cavity
B1 cells respond to polysaccharide Ag

(Murphy, et al., 2008)

NEUTROPHIL

Fever

(Abbas, et al.,2007)
 Inflammatory Mediator in Dengue Virus Infection
In Children: The Role of IL-8 in Plasma Leakage
(Widodo ADW, Dachlan YP, 2009)
Endothel
Plasma Leakage

Tissue Damage

Elastase

Virus Dengue
IL-8
Lactoferin
Degranulasi

Endothel
Plasma Leakage

Ref: Huang, 2000; Juffrie, 2000; Bosch, 2002; Talavera, 2004.

 NK cells must have some mechanism for distinguishing infected from
uninfected cells
PROTECTION SENSITIVITY

Uninfected Infected cell Altered/

cell Absent
MHC class I MHC class I
Inhibitory ligands
Inhibitory ligands
Activating ligands
Activating
ligands

Inhibitory
Inhibitory
Activating receptors Activating
receptors
receptors receptors
NK cell NK cell

SELF TOLERANCE ACTIVATION

(Vivier, E., Colonna, M., 2006)
 bacteria
Pathogens adherence to epithelium

Local infection, penetration of

epithelium
MØ DC • antimicrobial peptides
• phagocytes and complement
destroy invading pathogens
bacteria • activation of Tγδ cells
• cytokines
• activation of NK cells
TLR

DCs migrate to lymphnodes to initiate adaptive immunity

APC Adaptive immunity

• specific Ab
• activated MØ
• Th & Tc
 (Tsuda, et al., 2011)
(The Immune Response to Infection, 2011; Kaufmann)
 TLR

TLR-mediated protective TLR-mediated pathological

immune responses immune responses
(2008)