Innate Immunity

Lectured by :
Riandini Aisyah
 Topics

1. The front line of host defense

2. Pattern recognition in innate immune system
3. The complement system and innate immunity
4. Induced innate response to infection
Found in: all multicellullar organisms Vertebrates only

Substances A limited number of Virtually any component of

that trigger: pathogen-associated pathogens
molecular patterns (PAMPs)

A limited number of Pattern

Receptors: Recognition Receptors Highly variable receptors of
(PRRs) expressed on many 2 types: antibody made by B
cells types cells and TCR made by T
cells
 Innate v.s. Adaptive immune defense

Innate Adaptive
•directly available •must be induced
•no long-lasting protection •long-lasting protection
•limited specificity: •highly specific:
general recognition criteria recognition by individual
lymphocytes
•removal by killing and/or •removal by killing
phagocytosis and/or
•macrophages, phagocytosis
granulocytes, NK cells •T- and B lymphocytes
 Mechanisms of innate immunity

- phylogenetically older

- exist before or react immediately after contact with pathogen

- are not enhanced upon repetead contact with pathogen (no memory)

- react predominantly to infectious agents

- first line of defense

- stimulate and shape adaptive imunity

The arms of Immune System
1. Innate Immunity : first line of defense
 Components of innate immunity

- epithelial barriers (skin and mucosal membranes)

- cells (phagocytes, NK cells...)

- humoral components (complement, cytokines etc.)

The function of Immune System
 It Isn’t Easy Being a Pathogen
Multiple flagella
allow H. pylori to

What a pathogen must do penetrate the

coating of the
stomach
in order to cause disease: epithelium.

1. Gain access to the body.

2. - Attach to, and/or enter cells of its

host.
H. pylori
from a
- Receptors on pathogen must fit, gastric
lock-and-key, with receptor sites biopsy

on host cell.

3. Reproduce while avoiding host’s

immune system system long enough to
produce harmful changes.

Images: Helicobacter pylori, Yutaka Tsutsumi, M.D; Deep gastric

ulcer, Samir; Histopathology of H.pylori from a gastric biopsy, KGH From the Virtual Microbiology Classroom on ScienceProfOnline.com
 Pathogen

Innate defense mechanisme

Adaptive immune response

Pathogen can enter the body via many routes
Epithelial form barrier to infection
Physical & Biochemical barriers
 Skin – _________ Components of Defense
Two major layers:

1. _____________
 Outer layer composed of multiple layers of
tightly packed cells

First Line of Defense

 Few pathogens can penetrate these layers
 Shedding of dead skin cells removes attached
microorganisms

 Epidermal dendritic cells phagocytize

pathogens.
 These cells extend out among other cells of the
epidermis, forming a network to intercept
invaders.

2. _____________
 Contains protein fibers called collagen
 Give skin strength and pliability to resist abrasions
that could introduce microorganisms

Image: “Skin” tattoo, Source unknown;

Skin diagram, Daniel de Souza Telles From the Virtual Microbiology Classroom on ScienceProfOnline.com
• Infectious disease microorganisms succeed
to establish a local site of infection and
replicates to allows its further transmission
• Pathogen spread is countered by an inflammatory
response
 Cells of innate immunity

Cell type Pricipal function(s)

Monocytes/Macrophages Phagocytosis, inflammation,

T-cell activation, tissue repair

Neutrophils Phagocytosis, inflammation

NK cells Killing of infected or tumor cells

Dendritic cells Phagocytosis, activation of naive T-cells

Mast cells Inflammation

Eosinophils Defense against parasites

Macrophage activation
induces endocytosis and
degradation of the pathogen
 Phagocytosis and
killing of
microbes

Killing of
microbe

http://highered.mcgraw-
hill.com/sites/0072556781/student_view0/chapte
r31/animation_quiz_3.html
 Role of phagocytes in innate immunity

Order of events in infection

1. Entry of pathogen

2. Recognition of pathogen

3. Phagocytosis and killing of a pathogen

4. Inflammation induction

5. Attraction of cells to infection site

6. Pathogen elimination and/or adaptive immunity activation

7. Tissue repair and remodeling (macrophages)

- enzymes and cytokines (growth factors, metaloproteinases...)

 Inflammation induction

Proinflammatory cytokines
TNF ― Tumor Necrosis Factor
IL-1 ― Interleukin-1
Chemokines ― Chemotactic cytokines
 Leukocytes arrive at the site of infection (extravasation)
http://www.youtube.com/watch?v=WEGGMaRX8f0

http://www.youtube.com/watch?NR=1&v=DMvixApKzKs
Various adhesive
Selectins Integrins molecules

WeakInbinding
some inflammatory diseases therapy is directed against
and rolling Activation and
proinflammatory firm
cytokines or adhesive molecules
binding Transmigration
(eg: TNF in rheumatoid arthritis or VLA-4 in multiple sclerosis)

Endothelium

TNF & IL-1

Arrival to the site of infection
Macrophages Chemokines
Bactericidal agents released/produced by macrophages
 Main Combating Infection Process in Innate
Immunity

Inflammation in site of infection induced by

macrophage
• Inflammation plays 3 essential roles in combating
infection:
1. Deliver additional effector to site of infection
2. Provide physical barrier microvascular
coagulation
3. Promote repair of injured tissue
Characteristic of inflammatory responses are: pain,
redness, heat, and swelling
Inflammatory Mediators in Innate
Immunity
 Cytokines secreted by phagocytes in response to infection
include:
 IL-1
 activates vascular endothelium and lymphocytes
 Increases adhesiveness of leukocytes
 IL-6
 Induces B-cell terminal maturation into Ig-producing plasma cells
 IL-8
 Induces expression of b2 integrin adhesion molecules on neutrophils, leading
to neutrophil migration to infection site
 IL-12
 Activates NK cells and induces Th1-cell differentiation
 IL-18
 TNF-a
 Activates vascular endothelium and increases vascular permeability, leading to
accumulation of Ig and complement in infected tissues
Other Mediators and Molecules
 Phagocytes
 Toxic oxygen radicals
 Peroxides
 Nitric oxide (NO)
 Lipid mediators of inflammation
 Prostaglandins
 LTB4
 Platelet activating factor
 Complement component C5a
 Stimulates mast cells to release histamine, serotonin and LTB4
 IL-1, IL-6 and TNF-a
 Induce acute-phase response in liver
 Induce fever
 IL-1 and IL-18 signaling pathways activate NF-kB, important in innate
immunity
Role of NK cells in innate immunity

NK – Natural killer

Killing of cells infected by

intracellular pathogens
(eg. viruses) and
tumor cells

Activation of
macrophages (by IFN-γ)
 NK cell killer function

Depends on balanse of signals by activating and inhibitory receptors

 NK cell killer function

Depends on balanse of signals by activating and inhibitory receptors

NK cell is inhibited

NO KILLING
 NK cell killer function

Depends on balanse of signals by activating and inhibitory receptors

NK cell is activated
KILLING
Mechanism of NK cell recognition
 NK cell killer function

Apoptosis induction in infected and tumor cells

Killing mechanisms same as in cytotoxic T-cells

- Perforin and granzymes

- FasL and Fas

perforin
NK cell

granzymes
Infected or
tumor cell
apoptosis
FasL Fas
Humoral mechanism of innate immunity

- complement proteins (8th week seminar)

- cytokines

- other plasma proteins (CRP, MBL etc.)

 Cytokines in innate immunity

Macrophage and NK cell Inflammation induction

Activation (IL-12 and IFN-γ) (TNF, IL-1, chemokines...)

Antiviral effects (IFN type I, IFN-α and IFN-β)

(eg. INF-α in HCV therapy)

Differentiation of T-cell subpopulation (eg. IL-12)

 2.Pattern recognition in
innate immune system

Pattern recognition molecule (PRM) of antigen recognized by

:
pattern recognition receptor (PRR) of macrophage
Innate Immune Recognition

 All multi-cellular organisms are able to recognize and

eliminate pathogens
 Despite their extreme heterogeneity, pathogens share
highly conserved molecules, called “pathogen-associated
molecular patterns” (PAMPs)
 Host cells do not share PAMPs with pathogens
 PAMPs are recognized by innate immune recognition
receptors called pattern-recognition molecules/receptors
(PRMs/PRRs)
Typical PAMPs
 Lipopolysaccharides
 Peptidoglycans
 Certain nucleotide sequences unique to bacteria
 Other bacterial components
Endogenous Signals Induced by PAMPs

 Mediate inflammatory cytokines

 Antigen-presenting cells recognize PAMPs
 Same APC processes pathogens into specific pathogen-derived
antigens and presents them with MHC encoded receptors to T-
cells
 T-cell responds only when presented with both signals
 Different Effector Cytokines in Response to Different
Pathogens (Th1 vs. Th2)
Antimicrobial Peptides/Defensins
 Four hundred peptides described to date
 Defensins (3- 5-kD, four families in eukaryotes)
 a-defensins (neutrophils and intestinal Paneth cells)
 b-defensins (epithelial cells)
 Insect defensins
 Plant defensins
 Defensins appear to act by binding to outer
membrane of bacteria, resulting in increased
membrane permeability.
 May also play a role in inflammation and wound repair
 Recognition of pathogens

The cells of innate immune system recognize features common

to many pathogens (pattern-recognition molecules) such as:
• certain carbohydrate structures
• certain sugar molecules (mannose)

The receptors on innate immune cells involved in recognition

are called pattern-recognition receptors (PRRs):
• scavenger receptor
• mannose receptor
• Toll-like receptor
• CD14 / LPS receptor
Toll-Like Receptor (TLR)
Macrophage
activation by LPS

Toll-like receptors
(TLRs) form a family of
receptors that signal the
presence of pathogen,
e.g. TLR4 signals the
presence of LPS.
LPS binding triggers
the formation of
cytokines a.o. of TNF-a
and might, thus, induce
septic shock.
Toll pathway leads to the
expression of co-
stimulatory molecules
essentials for adaptive
immune response
induction : B7.1 (CD80) &
B7.2 (CD86)
3. The complement system and
innate immunity
Complement System
 Three pathways now known
 Classical
 Alternative
 Lectin or MBL pathway (binding to mannose-containing
carbohydrates)
 Host cells have complement regulatory proteins on their
surface that protect them from spontaneous activation of
C3 molecules
Complement: activation routes and effector functions
Immune defense functions of complement
Cellular distribution and function of complement receptors
Small complement
components can
induce local
inflammatory
responses by:
-Chemoattractive
and
-Anaphylactive
activities

Features of
inflammation:
Pain, redness, heat
and swelling at the
site of
inflammation
4. Induced innate response to
infection

Cytokine  signalling pathway 

cell-cell communication
 Different types of cytokines

• Haemopoietic cytokines (growth and differentiation factors):

IL-3: interleukin-3
GM-CSF: granulocyte/macrophage colony stimulating factor
G-CSF: granulocyte colony stimulating factor

• Inflammatory cytokines:
IL-1: interleukin-1
IL-6: interleukin-6
TNF-a: tumor necrosis factor a
IL-8: interleukin-8
ECF: eosinophil chemotaxtic factor

• Regulatory cytokines:
IL-2: interleukin-2 IL-4: interleukin-4
INF-g : interferon-g IL-5: interleukin-5
IL-12: interleukin-12 IL-10: interleukin-10
 Chemokines (Chemoattractive cytokine)
Chemokines: small polypeptides that are synthesized by many
cell types,
e.g. dendritic cells, macrophages, granulocytes,
lymphocytes, endothelial cells, stromal cells

Based on N-terminal amino acid sequence chemokines

can be divided into CXC, CC, C and CXXC types.
Receptors for these types are present on many cell types.

Main functions of chemokines:

1. cell recruitment and migration
2. cell activation and degranulation

Cytokines are mostly involved in

lymphocyte development, maturation and regulation
 Chemokines play a prominent role in
cell migration

Chemokines regulate normal lymphocytes migration and homing

Chemokines attract inflammatory cells to the site of infection

Chemokines may activate cells to release inflammatory factors

Chemokines may have an additional regulatory function

 Molecules involved in cell migration

Adhesion molecules play a role in cell-cell contacts

Adhesion molecules involved in leukocyte interactions
 Leukocyte interaction with inflamed endothelium

Chemokines upregulate adhesion molecules on endothelial cells

Local and
systemic effects
of TNF-a
Cytokine released by phagocytosis activate the acute phase
response
Dendritic cells bridging innate and adaptive
immune system
 Summary
 Innate system of host defense:
 Barriers by epithelial
 Cells and molecules destroy pathogen which can breach the
epithelial, e.g: macrophages
 Recognition by innate immunity elimination of
pathogen through various effector mechanisms
References
 Charles A. Janeway, Paul Travers, Mark Walport, Mark Shlomchik.
Immunobiology: The Immune System in Health and Disease. Sixth
Edition.

Ellen Robey, Robert Beatty, Laurent Coscoy. Molecular Immunology

Dennis E. Leopatin. Immunology.