innate immunity - fac.ksu.edu.sa · innate / inborn non-specific ... • anatomical barriers -...
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Innate Immunity
By
Dr. Gouse Mohiddin Shaik
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Types of immunity
Immunity
Acquired / adaptive
Specific
3rd line of defense
Passive
Natural
(Placental transfer)
Artificial
(IgG injection)
Active
Natural
(infections)
Artificial
(Vaccination)
Innate / inborn
Non-specific
Phagocytosis (PAMP – PRR)
Antimicrobial proteins
Defisins
2nd Line of defense
Physical barriers
Skin, Saliva, Mucous, Stomach acid, Tears
1st line of defense
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Innate immunity
• Innate immunity is non-specific arm of the immune system
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Innate immunity
• Anatomical barriers
• Mechanical factors
• Chemical factors
• Biological factors
• Cellular Components
• Neutrophils, NK cells, Macrophages...
• Humoral Components
• Complement – major one
• Platelets, Cytokines..
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Anatomical barriers
• Anatomical barriers - Mechanical
System/Organ Cell type Mechanism
Skin Squamous epithelium Physical barrier
Desquamation
Mucous membranes Non-ciliated epithelium
(e.g. GI tract)
Ciliated epithelium (e.g.
respiratory tract)
Epithelium (e.g.
nasopharynx)
Peristalsis
Mucociliary elevator
Flushing action of tears,
saliva, mucus, urine
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Anatomical barriers
• Anatomical barriers - Chemical
System/Organ Component Mechanism
Skin Sweat Antimicrobial fatty acids
Mucous membranes HCl (parietal cells), tears
& saliva
Defensins (respiratory &
GI tract)
Surfactants (lung)
Low pH
Lysozyme
phospholipase A
Antimicrobial
Opsonin
Opsonin enhances phagocytosis
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Anatomical barriers
• Anatomical barriers - Biological
System/Organ Component Mechanism
Skin and mucous
membranes
Normal flora Antimicrobial substances
Competition for nutrients
and colonization
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Humoral Components
Component Mechanism
Complement Lysis of bateria and some viruses
Opsonin
Increase in vascular permeability
Recruitment and activation of phagocytic cells
Coagulation system Increase vascular permeability
Recruitment of phagocytic cells
Beta-lysin from platelets – a cationic detergent
Lactoferrin and
transferrin
Compete with bacteria for iron
Lysozyme Breaks down bacterial cells walls
Cytokines Various effects
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Cellular Components
Cell Mechanism
Neutrophils Phagocytosis and intracellular killing
Inflammation and tissue damage
Macrophages Phagocytosis and intracellular killing
Extracellular killing of infected or altered self targets
Tissue repair
Antigen presentation for specific immune response
NK and LAK cells Killing of virus-infected and altered self targets
Eosinophils Killing of certain parasites
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Phagocytosis
Phagocytosis and intracellular killing
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Phagocytosis
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Neutrophils
• Azurophilic granules
• Granules – primary and secondary
• CD66 marker
• O2 dependent killing
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Macrophages
• Kidney shaped nucleus
• Rich in lysosomes
• CD14 marker
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Phagocytic response
• The SOS signals – N-formyl methionine-
containing peptides
– Clotting system peptides
– Complement products
– Cytokines released by tissue macrophages
• Phagocyte response – Vascular adherence
– Diapedesis
– Chemotaxis
– Activation
– Phagocytosis and killing
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Neutrophil extravasation
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Neutrophil extravasation
Video
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Initiation of Phagocytosis
• Attachment via
receptors
– FcR, complement R,
scavenger R, Toll-like
R
• Pseudopod
extension
• Phagosome
formation
• Granule fusion and
Phagolysosome
formation
A
B
C
D
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Fc receptors
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Toll-like receptors
Major group of PRR
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Toll-like receptors
• TLRs are transmembrane proteins
• “Toll” identified as essential molecule for embryonic
patterning in Drosphila
• Evolutionary conserved among insects & humans
• 10 TLRs reported (1-10)
• Expressed differentially on immune cells (low level)
• Also expressed on other cell types (e.g., endothelial
cells)
• Respond to different stimuli
• Expression modulated in response to stimuli – i.e.,
inducible
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Respiratory Burst
OXIDATIVE (RESPIRATORY) BURST
Prodution of reactive oxygen compounds by the enzyme NADPH-oxidase
Localized in the phagosome membrane and catalyses the reactions:
(surface) O2 → O2- (superoxide anion-radical)
_________________________________________
(cytoplasm) NADPH → NADP+ + H+
Superoxide reacts further to produce toxic compounds (“singlet oxygen“, H2O2,
ClO-)
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O2 independent killing
Effector molecule Function
Cationic proteins (cathepsin) Damage to microbial membranes
Lysozyme Hydrolyses mucopeptides in the cell
wall
lactoferrin Deprives pathogens of iron
Hydrolytic enzymes (proteases) Digests killed organisms
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NO dependent killing
Macrophage
IFN-gamma TNF
O2 + L-arginine NO + citrulline
NO synthetase
• Happens in macrophages
• Bacteria binds to macrophage
• Production of TNF-alpha
• Upregulates iNOS
• Release of NO
• NO is toxic to infected cells in the vicinity of macrophage
INF-gamma is product of adaptive immune system
Extracellular killing
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NK cells
• Natural killer cells
• Kills virus-infected or cancer cells
• Has granules also
• CD56 and CD16 and no CD3
• Activated by IL2 and INF-gamma and becomes LAK (limphokine activated killer cells)
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NK cell killing
NK cell
Infected/transformed cell
No MHC
Inhibitory R NK R
• Infected or altered
self (transformed) cell
downregulated MHC
• NK does not receive
inhibitory signal
• Signals kill infected
cell
Killer inhibitory receptor (KIR)
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How immune system is alerted ?
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Hypothesis
• Stranger hypothesis (janeway 1989)
• PRRs on immune cells detect strange patterns on microbes
• TLR-5 recognizes flagellin
• Danger hypothesis (P. Metzenger 1994)
• Alerted against tissue damage associated with microbial infection
• Uric acid crystals activate Dendritic cells
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Determinants involved in Innate
immune system
• PAMPs- pathogen associated molecular
patterns (Flagelling, LPS, pep.glycan,
unmethylated CpG)
• PRRs- pattern recognition receptors
• DAMPs – Death or Damage or Danger
associated molecular patterns (Heat shock
proteins, chromatin complex, ATP, uric
acid ….
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Stranger model
Merits
• Explains the concept of
tolerance to self
• Inline with induction of
tolerance experiments
• Why xeno transplants are
rejected
• Why tumors are not
rejected
Problems
• Doesn’t explain why we are tolerant to commensal bacteria, fetus, hormones
• Why no immune response to inert foreign antigens and food we eat
• Why allo-transplants have high response then xeno
• Why autoimmunity
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Stranger vs Danger model
Problems with Stranger
• Doesn’t explain why we are tolerant to commensal bacteria, fetus, hormones
• Why no immune response to inert foreign antigens and food we eat
• Why allo-transplants have high response then xeno
• Why autoimmunity
Explanation of Danger
• No cell death in all these events
• If you add adjuvant, YES….
• DAMPs of allo-transplants are more reactive then xeno
• DAMPs activate APC
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Stranger vs Danger
Stranger vs Danger model of
alerting immune system
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Determinants recognized by
Innate immune system