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Topic 3:Innate Immunity
Dr. Teoh Chun Ming
(tcm3@[Link])
Official (Closed) - Non Sensitive
Basic Consideration
Innate immunity
Innate defense
Can be produced prior to exposure by a specific pathogen
No changes – DNA/genes
All organisms have
Adaptive immunity
Only found in vertebrates
Fish, mammals, reptiles, birds, amphibians
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Immunology!
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Inflammation
Fever
Sign of immune up-regulation
Higher body temperature – better survival rate & optimum enzyme
functionality
Induction – treat cancer
Goes hand in hand with inflammatory response
Local response
Calls in phagocytic cells – site of infection/injury
Any injury – triggers local inflammatory response
Swelling (tissue leaks), redness (blood flow increased), heating up and pain
Symptoms by vascular changes: capillaries – more permeable, plasma (edema)
and cells (extravasation) - enter infected tissue
Leukocyte extravasation – changes in surface CAM molecules (adhesion
molecules)
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Immunology!
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Inflammation - Injury
- Some injuries that breaks blood vessels
- The white blood cells/other sensors in the damaged
tissues will release chemokines, a type of cytokine that
attracts cells (neutrophils) to the side of infection
- Damage signals recruited neutrophils – the first
responders
- Neutrophils pack up and leave the circulatory system
in response to cytokines that are produced as a result
of the injury
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Immunology!
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Inflammation
Signals and Receptors:
White blood cells/damaged tissues release chemokines (a type of cytokine) – upregulate
inflammation, attracting immune cells – site of infection
Activation of cells – pattern receptors – activates inflammatory signals
Neutrophils
o Leave the blood stream
o Respond by changing conformation – integrins (adhesion molecules)
o Stick to the blood vessels
• Rolling – neutrophils stick briefly and release – causes them to bounce/roll –
endothelial surface. Mechanical stress – internal changes leads to activation
• Activation
• Arrest
• Transendothelial migration – neutrophils enter the tissue – participate – inflammatory
response. They will respond to local signals, increase their ability to phagocytize,
digest material - phagolysosome
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Immunology!
Inflammation – Neutrophil
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extravasation
- Changes on the surface of
this cell that involve
changes in the
carbohydrates and in other
cell adhesion molecules:
selectins, intergrins etc
- Macrophages are also
involved in the
extravasation response
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Immunology!
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Innate Targeting of Pathogens
PAMPs (Pathogen Associated Molecular Patterns) Recognised by PRRs (Pattern Recognition
Receptors)
Proteins
o Flagellin - bacteria
o Profilin – surface protein of protozoan (taxoplasmosis), secreted to the surface,
helps parasite move towards & enter the host cell
Carbohydrates and glycopeptides
o Zymosan – component – fungal cell walls, no PAMP for chitin as yet
o Peptidoglycan – cell wall component – gram positive and gram negative bacteria –
gram positive much thicker
o Lipids – attach to signature carbohydrates/peptides
o Nucleic acids
• DNA with specific methylation patterns
• Wrong strandedness – single stranded DNA, double stranded RNA
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Immunology!
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Innate Targeting of Pathogens
Categories of PRRs (specific receptor bind to characteristic pathogen molecules)
Extracellular
o Lysozyme (mucus & tears) – against peptidoglycan
o Psoriacin (skin) – against [Link] - can be induced – sunlight (UVB) via Vitamin D
o AMPS – defensive peptides – kill by disrupting bacterial membranes
o Mannose-binding lectin (plasma) – activates complement
o C-reactive protein (CRP) (plasma) – recognize microbes, damage self-cells
o Lipopolysaccharide binding protein (LBP) – recognize gram negative bacteria
Cytoplasmic
o NOD proteins (Nucleotide-binding oligomerization domains)
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Immunology!
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Innate Targeting of Pathogens
Categories of PRRs (specific receptor bind to characteristic pathogen molecules)
Membrane bound
o Toll-like receptors (TLRs)
• Work singly or in pairs – single: extend onto the endoplasmic reticulum lumen;
pairs: from the plasma membrane
• Binding – pathogen on the outside triggers signals on the inside
• Internal signal activates NK-kB (transcription factor) – major internal
inflammation regulator
• NF-kB – production of cytokines – alerting other immune cells
• Categorise the pathogen and set of inflammatory & adaptive response
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Immunology!
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Innate Targeting of Pathogens
Categories of PRRs (specific receptor bind to characteristic pathogen molecules)
TLR – differential function
o Internal TLRs – TLRs 3, 7, 8 and 9 – extend to RER (rough endoplasmic
reticulum/phagolysosomal membrane with recognition region in the lumen: respond
to bacterial/viral DNA & RNA
o External TLRs – TLRs 1, 2, 4, 5, and 6 extend from plasma membrane to exterior of
the cell – respond to characteristic pathogenic cell surface components
o Paired TLRs – usually external: may work as homodimers/heterodimers
o Same TLR has different recognition properties, depending on its partner (when
paired)
o Negative regulation – must be able to turn the inflammation off otherwise excess
inflammation/autoimmune disease
o Interact with MD2 at surface when binding LPS and other viral and cancer proteins;
interact with MyD88 to initiate signal sequence
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Immunology!
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Innate Targeting of Pathogens - TLRs
- TLRs are eventually going to signal an
inflammatory response that will activate NF-kB
- NF-kB – transcription factor that wil turn on a
whole bunch of genes to help you fight various
infections
- Some are found in the plasma membrane – facing
with their receptor parts outwards so they can
sample pathogens in the environment
- Some are found in the endomembrane – arrange
with their receptors facing inward
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Immunology!
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Cell Types and Function
Phagocytosis
Macrophages & Neutrophils
Capture pathogen in phagosome – promoted by PAMP, complement/antibody on the
surface of pathogen
Activates membrane pump – triggers respiratory burst (O2 uptake) by NADPH
phagosome oxidase (phox enzymes) complex
Not mitochondrial respiration
Is a direct uptake of oxygen by enzymes to create toxic reactive oxygen species (ROS)
which include: phagosome lysosome
o Superoxide radicals (O2-)
o Hydrogen peroxide (H2O2)
o HOCl (hypochlorous acid/bleach)
o Reactive nitrogen species (RNS) – nitric oxide
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Immunology!
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Cell Types and Function –ROS/RNS
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Immunology!
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Cell Types and Function
Phagocytosis
Superoxide radicals – generate RNS including NO – toxic
Oxidation – coupled to K+ transport – interior becomes hypertonic.
K+ enters to compensate – negative charges – leads to a rise in pH (8.5)
Once pH 8.5, neutralization is done by transporting H +
Change in K+ and tonicity dispersed protein granules, relase
o Hydrolytic enzymes - eg nucleases
o Peptides that poke holes – bacterial plasma membrane, eg BPI or defensin
o Microfilaments package the exterior of the vacuole
• preventing swelling that occurs after influx of K+ and increasing osmotic pressure
• Maintaining the concentration of toxic compounds inside
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Immunology!
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Cell Types and Function – Phox Complex
K+ Oxygen radical
Oxidative process
Happening in the membrane complex,
membrane of the phagolysosome
K+
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Immunology!
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Cell Types and Function
Cells
Neutrophils
o first on-site defenders along with macrophages – most important phagocytes
Macrophages
o Phagocytosis causes them – secrete IL-1, IL-6 and TNFa (all are inflammation
activators)
o Always on the lookout for pathogens
o After phagocytizing, they relay info about the pathogen – T H cells (neutrophils will
not relay info)
Dendritic cells
o Most important initial trigger – adaptive response
o Phagocytise mainly to sample pathogens & activate inflammation
o Specifically designed to activate TH cells
o Phagocytes that secrete a lot of cytokines
o Coordinate with TH cells
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Immunology!
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Cell Types and Function
Cells
Natural Killer Cells (NK cells)
o Function by pattern recognition
o Mainly attack rogue-self by inducing apoptosis
o Innate but lymphoid cells
o Recognises self-cells
o Help activate macrophages which go on to activate T H cells
Take note: only macrophages and dendritic cells can present antigens – particularly
effective in alerting naïve T cells/activate T H cells
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Immunology!
Innate and Adaptive Immunity
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Compared
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Immunology!