INNATE IMMUNITY
Dewi K Paramita
dkparamita@ugm.ac.id
Basic Immunology
Postgraduate Program in Biomedical Science
Faculty of Medicine, Universitas Gadjah Mada
Immune responses
Innate Adaptive
Immune response Immune response
Time
Specificity
Memory
Three phases of responses to an initial infection
Innate immunity
1. Fixed defenses of the body :
a. Epithelia à lining the internal & external surfaces of the body
b. Phagocytes lie beneath the epithelial surface
inflammatory responses
2. Pattern recognition system
3. Complement system
Microorganism cause diseases
• Viruses
• DNA viruses
• RNA viruses
• Bacteria
• Fungi
• Parasites
• Protozoa
• Worms (Helminth)
Pathogen can be found in different compartment of the
body, where they must be combated by different host
defense mechanism
Pathogen infect the body through a variety of routes
Most of pathogen infect through mucosal epithelia
Epithelial surfaces make up first line defense against
infection • Epithelial à lining the external and internal surface
of the body
• Surface epithelia provide mechanical, chemical and
microbiological barriers to infection.
• Infection occur when pathogen colonize and cross
epithelia
Pathogen damage tissues
Direct Indirect
Neutrophils release many proteins and small
molecule inflammatory mediator à for
controlling infection and cause tissue damage
Direct
mechanisms
Exotoxin à act at
surface of the host
cell
Endotoxin à triger
phagocyte to
release cytokines
à produce local or
sistemic symptoms
Cytopathic
patogen à directly
damage the cells
they infect
Indirect
mechanisms
Involving the adaptive
immune response
Antigen-antibody
complexes à activates
neutrophils and
macrophages
Antibody and host
tissue cross reaction.
Killing of infected cells
by T cells
Stage of infection and the immune response to it
After entering the tissues, many pathogens are
recognized, ingested and killed by phagocytes
Macrophage derived from
circulating monocytes.
Macrophages express receptor
for many bacterial component,
including bacterial carbohydrate
(manose and glucan receptors),
lipids (LPS receptors) and other
derived components (Toll-like
receptors/ TLR).
Signaling through some receptors,
such as TLR à secretion of “pro-
inflammatory cytokines” (IL-1β,
IL-6, TNF-α)
• During phagocytosis macrophage and neutrophil produce bactericidal
agent
• Some substances (toxic) can interact with large antibody-coated
parasitic worms or host tissues à can cause extensive tissue damage
Pathogen recognition and tissue damage initiate an
inflammatory responses.
Inflammation at the site of infection is
initiated by macrophages
Three essential roles of inflammation in combating
infection:
1. Deliver additional effector molecules and cells to site of
infection à to augment the killing of invading
microorganisms.
2. Induce local blood clotting à provides physical barrier to
the spread of infection in bloodstream.
3. Promote the repair of injured tissue
Infection stimulates macrophages to release cytokines and
chemokines that initiate an inflammatory response, eg. TNF-α
Inflammatory mediators released by macrophages are
prostaglandings, leukotrienes, platelet-activating factors/PAF
Characteristics of inflammatory responses are pain, redness, heat and
swelling at the site of infection.
Important cytokines secreted by macrophages in
response to bacterial product
Cytokines IL-1β, TNF-α and IL-6 have a wide spectrum of biological
activities that help to coordinates the body’s responses
Acute-phase response molecules bind pathogen, but not the
host cells
The release of TNF-α by
macrophages induces local
protective, but TNF-α can
be damaging when release
systematically
The first leukocytes attracted to the site of inflammation
is neutrophils and followed by monocytes, which
differentiate into tissue macrophages.
Cell adhesion molecule control the interaction between leukocytes and
endhotelial cells during inflammatory response
Phagocyte adhesion
vascular endhotelium is
mediated by integrins
Pattern recognition in innate immune
system
• Innate immune system à lack of specificity, but it can
distinguish self from non-self
• Regular patterns of molecular structure are present on
many microorganism but not on the host’s cells
• Pattern recognition system have different function:
• stimulate ingestion;
• as chemotactic receptors;
• induced production of effector molecules, induced responses
in innate immunity, induced protein that influence the initiation
of subsequent of adaptive immune responses
Comparison of the characteristic of recognition
molecules of the innate and adaptive immune system
Type of receptors in innate immunity
Type of receptor Recognition
Pattern recognition receptors (PRRs): Pathogen-associated molecular
manose-binding lectin (MBL) patterns (PAMPs)
Toll-like receptors (TLRs) Distinguish different type of pathogen
Nucleotide-binding oligomerization Intracellular sensor of bacterial
(NOD) infection
Other receptors that recognize Recognition
pathogen directly
Macrophage mannose receptors Bind certain sugar on surface of many
bacteria and virus
Scavenger receptors Recognize anionic polymers and
acetylated low density lipoprotein
Organization of cell walls of gram positive and
gram negative bacteria
Other example of pathogen associated molecular pattern
(PAMPs):
• Bacterial flagella à repeated protein subunits
• Bacterial DNA àunmethylated repeats of dinucleotide CpG
• Virus express dsRNA
Pattern recognition receptors (PRRs):
Manose Binding Lectin (MBL)
• Member of collectin family of proteins à contain
collagen-like & lectin (sugar) binding domain
• They bind to and coat the surface of pathogen (display a
particular spatial arrangement of mannose or fucose
residues) à more susceptible to phagocytosis by
macrophages.
• It can initiate lectin pathway of complement activation
Pattern recognition receptors (PRRs):
Manose Binding Lectin (MBL)
Toll-like receptor &
location in the
mammalian cell
Bacterial LPS signal through the
TLR-4 activate the transcription
factor NFκB
• TLR-4 needs CD14 and MD2 for
LPS reognition
• CD14 binds LPS à CD14-LPS
complex is ligand of TLR-4
• MD2 bind TLR-4 à TLR-4-MD2
complex interacts with LPS bound to
CD14 à signal activate NFκB
Nucleotide-binding
oligomerization (NOD)
• NOD present in the
cytosol
• It bind microbial product
• Activate NFκB à initiating
the same inflammatory
processes as TLRs
dsRNA induce the expression of interferons by activating
the interferon regulatory factors IRF3 and IRF7
Interferons are antiviral proteins produced by cells in
response to viral infection
Innate like
lymphocyte
Activation of TLRs and NOD proteins triggers the production
of pro-inflammatory cytokines and chemokines, and
expression of co-stimulatory molecules
Bacterial LPS induces changes in
langerhans cells, stimulating them
to migrate and to initiate adaptive
immunity by activating CD4 T cells
Complement System
• Complement system is made up of a large number of
different protein plasma proteins that interact with one
another to opsonize pathogen and to induce
inflammatory responses to fight the infection
• Several complement protein are proteases, that become
activated after cleavage by another proteases.
• The inactive form called pro-enzymes or zymogen
Three distinct pathway of complement activation
Overview of complement cascade and the main component
& effector action of complement
The classical pathway of
complement activation
The first protein in classical pathway
of complement activation is C1
The Lectin pathway of complement activation
• The lectin pathway is homologous to classical
pathway
• First enzyme activated are the mannose-binding lectin
associated serine proteases (MASP-1 and MASP2)
The lectin pathway is homologous to classical
pathway
The alternative pathway of complement
activation
• The pathway can be proceed on many
microbial surface in absence of specific
antibody
• Independent of
a pathogen
binding protein,
but it initiated by
spontaneous
hydrolisis of C3
Alternative pathway of complement activation can amplify
the classical and lectin pathway by forming alternative C3
convertase and depositing more C3b molecules on the
pathogen
Terminal complement proteins polymerize to form
pores in membrane that killed certain pathogen
First step in the formation of
membrane attack complex is the
cleavage of C5 by a C5 convertase
to release C5b
Assembly the membrane attack complex generates a
pore in the lipid bilayer membrane
Terminal complement components assemble to from
the membrane attack complex
Relationship between the factors of alternative, lectin
and classical pathway of complement activation
Distribution and function of cell surface receptors for
complement proteins
Anaphylatoxin C5a can enhance the phagocytosis of
opsonized microorganisms
Small fragments of some complement protein can
initiate a local inflammatory response
Proteins that regulate the activity of complement
Innate like lymphocyte
NK cells are activated by interferons and macrophage-
derived cytokines to serve as an early defense against
certain intracellular infection
NK cells killing depends on the balance between
activation and inhibitory receptors
Activating and inhibitory
receptors in NK cells; ligand
of activating receptors
B1 cells might be important in
the response to carbohydrate
antigens such as bacterial
polysacharides
Summary
• Innate immune defense:
• Barrier’s function à epithelia
• Cell for controlling the pathogen: mainly macrophages; innate like
lymphocyte
• Molecules for controlling the pathogen
• pattern recognition
• Complement system
• Inflammatory response
