Immunology Refresher: Innate Immunity
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The existence of successful infections means that host defences do not constitute an
impenetrable barrier
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Infections are relatively common with >400 distinct microorganisms know to infect humans
alone
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Average person will experience at least 150 infections during their lifetime
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But, likely encounter with millions of microbes each day.
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Disease is very rare? Immunity is very efficient?
Innate immune system:
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Two major branches of immune system: Innate and Adaptive.
Innate IS is ‘first line’ of defense against infection
If innate immunity fails adaptive IS is required
These two systems are not separate and highly interactive and cooperative
4 major component
o (1) Anatomical
o (2) Physiological
o (3) Phagocytic barriers
o (4) Inflammation
Anatomical:
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Consists of dermis and epidermis = skin
It is an efficient physical barrier, proven by how easy it is to get an infection from cut or
scrap.
Epidermis
o Several layers of tightly packed epithelial cells
o Outer layers are dead and keratinised
o Provides physical barrier to infection
Dermis
o Connective tissue
o Blood vessels
o Hair follicles
o Sweat and sebaceous glands
 Sebum: contains lactic and fatty acids. From Sebaceous glands
 Maintains skin at pH 3-5 which inhibits microbial growth
Mucosal Membranes:
o Strong anti infection roles including
muso-ciliary elevator and stomach acids
o Conjunctivae: tears
o Alimentary canal: saliva
o Respiratory tracts: mucus and cilia
o Urogenital tracts: mucus, spermine
o Secretions and cilia wash away potential
invader
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Secretions also contain anti-bacterial and anti-viral substances
Mucus can trap microorganisms (MOs) and cilia can move mucus+MOs from
infected area
Normal flora: natural, non-invasive, symbiotic MOs that colonise host.
Normal flora can outcompete pathogens for attachment sites and nutrients
 It is a key anti-microbial agent as young babies with underdeveloped
immune system = flora helps prevent infection.
Physiological Barriers:
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Temperature, pH and various soluble factors can prevent MOs from growing
o e.g. gastric juices: very few MOs can survive passage through the stomach at such
low pH
One of the reason newborns more susceptible to gastrointestinal diseases because stomach
contents are less acidic
Example of soluble factors:
o Lysozyme: hydrolytic enzyme in mucus and tears.
 cleaves peptidoglycan in bacterial cell walls
o Interferons: group of proteins produced by virus-infected host cells
 Signal to neighbouring un-infected cells to induce an anti-viral state
o Soluble factors also include the complement proteins:
 Complement: serum proteins that circulate in an inactive state that is
activated by specific and non-specific mechanisms
 Four functions in immune response
 Lysis of cells, bacteria and viruses
o Can lyse enveloped viruses
o Through MAC
 Opsonisation, which promotes phagocytosis – key
o = coating of bacteria (e.g.) to allow
identification by phagocytes which have
complement receptors (to detect
opsonized C3b) and FC receptors to
detect the Fc domain of bound
antibodies.
o Phagocytes exhibit weak binding to
pathogens without opsinisation.
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Trigger activation of other IS factors
Immune clearance: clumps complexes together to aid clearance
from body
Cell of the immune system:
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Innate immune cells = from myeloid progenitors (except NK cell)
Phagocytic Barriers:
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Binding of opsins to receptors rearranged the cytoskeleton = allows pseudopod to extend
around pathogen to form phagosome.
Phagocytosis:
o Uptake of material from environment (can include whole MOs)
o Once engulfed the vesicle containing the material can fuse to lysozyme containing
vesicle
o This degrades material
o Insoluble material removed from cell by exocytosis
o Subversion:
 Some pathogens survive in phagocytic cells
 E.g. Salmonella directs uptake and resides intracellularly in Salmonellacontaining vesicle used a type 3 secretion system
 Prevents phago-lysosomal fusion
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Provides protected niche within the macrophage, allow it systemic
movement.
Inflammation:
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Is the non-specific initial response to tissue injury and pathogen detection.
5 major effects:
o Redness
o Heat
 To prevent microbe replication as most microbes have a very small range of
temperatures at which replication can occur.
o Swelling
 Causes by recruit of fluid containing signalling molecules and immune cells.
o Pain
 Consequence of swelling, will prevent further injury through use.
o Loss of use
Histamine is released by damaged tissues. Histamine increases blood flow to the area and
causes the capillaries to become leaky, allowing phagocytes and blood clotting factors to the
area of damage.
Pathogens are recognised, ingested and kill by phagocytes
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G-protein-coupled receptors on phagocytes link microbe recognition with increased
efficiency of intracellular killing
o NADPH Oxidase produces oxygen free radicals which attack nucleic acids
NETosis can occur. = programmed death of neutrophils in response to activation. Released
DNA and other molecules forms fibrillar net that traps micro-organisms.
o The DNA net is covered in anti-microbial factors.
Microbial recognition and tissue damage initiates an inflammatory response, releasing
cytokines, soluble signally molecules.
o Chemokines are a subset of cytokines and recruit immune cells down a gradient.
o Immune cells are activated when they leak capillaries.
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Systemic effects occur with local infection. Cytokines get into the peripheral blood stream,
and change the surface or circulating immune cells and the endothelial wall in a gradient like
fashion = this increases the interaction of leukocytes (WBCs) with the endothelium, slowing
them in the blood until they stop at the highest concentration = where infection is. This
triggered extravasion and activation, delivering the WBCs to the site of infection, down a
gradient.
Normal vs too much cytokine activation:
o Think about what pathogen causes vs hosts effect.
o Systemic infection: macrophage may be activated in
the liver – secreting TNFa into the blood directly =
making the blood vessels too leaky.
o =systemic oedma, decreasing blood volume &
collapsing vessels = increase in immune cells. Intra
vescular coagulation and organ failure.
o Protective response vs pathogenic response.
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Cytokines made by macrophages and dendritic cells induce a systemic reaction known as the
acute-phase response
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Interferons induced by viral infection make several contributions to host defense
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Intracellular receptors recognise viral DNA/RNA in host and induce anti-viral states
in surrounding cells.
 This may include stopping the formation of activated ribosome, sacrificing
cells around the infected one but stopping the spread.
Innate Lymphoid Cells amplify signals of innate immunity and have killing features similar to that of
cytotoxic T cells, but do not express antigen-specific receptors. = NK Cells
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NK cells are activated by type I interferon and macrophage-derived cytokines
They bridge the gap between innate and adaptive immune system.
NK cells has inhibitors from MHC1 on healthy cells and activator receptors = stress induced
cell antigens on infected cells.
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Other viruses may cause an increase in cell stress antigen.
3 major events in inflammation:
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Vasodilation:
o causes redness and temp increase know as: erythema
o increase in diameter of blood vessels
o engorgement of capillary networks as vessels are constricted
Increase in capillary permeability
o Causes increase in influx of fluid (exudate) into tissue
Causes swelling: known as edema
Influx of phagocytes from capillaries due to increase permeability
o Diapedesis or Extravasation
Inflammation Cascade:
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Initiation and mediators of inflammation poorly understood
MOs cause start cascade
Damaged host cells start cascade
Plasma proteins and products of immune cells can start cascade
Factors that can initiate inflammation:
o HISTAMINE: principle mediator
 Chemical released by damaged host cells
 Binds receptor on nearby capillaries and venules
 This causes vasodilation and increased permeability
 Anti-histamines used in allergy treatment
o ACUTE-PHASE PROTEINS
 Found in serum and their concentration in tissue is dramatically increased
during inflammation
 e.g. C-reactive protein: major acute-phase protein produced by the liver.
 Binds C-polysaccharide found in bacterial and some fungal cell walls
 Binding activates the complement system
o Kinins:
 Small peptides usually inactive in plasma
 Tissue injury activates them
 Can cause vasodilation and increased permeability
 e.g. Bradykinin: this also stimulates pain receptors in infected area
 This has protective role preventing further contact with inflamed area
o Platelets and fibrin
 Vasodilation and increased permeability allows clotting factors such as
platelets to enter infected area
 Insoluble fibers of Fibrin are deposited
 This walls off inflamed area protecting rest of body from potential infection
 May be subverted – some microbes may benefit from being walled
off from adaptive immune system.
As infection is being cleared:
o MOs are phagocytosed and killed by Innate and Adaptive IS
o Accumulation of dead cells, digested material and fluid make up PUS
As inflammation subsides:
o Debris cleared by phagocytic cells
o Tissue is repaired
o Capillaries grow into fibrin clot
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Clot dissolves
New connective tissue laid down & Scar tissue forms