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Innate Immunity-Barriers and Danger Lecture 8, Residence macrophages.,…
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Residence macrophages.
Heterogeneous population of long lived tissue resident mononuclear cells. Phagocytose
- ("to eat) from their environment.
- waste disposal
- look for infection.
Name is dependent on location
- skin; Langerhans cell
- liver; Kupffer
- Nervous system; microglia
- Derived from blood monocytes
- effector mechanism phagocytosis and intracellular killing
Macrophages and infection
Phagocytes.
- Antigen presenting cells.
Found under the skin and mucosal layers and in the lungs.
- Act to protect against invaders that penetrate barriers.
Exist in 3 states.
- resting
- Activated (primed)
- Hyperactivated.
Phagocytosis Chemotaxis
- chemical signals attract phagocytes to the micro organism.
Adherence;
- Attachment of a phagocyte to the surface of the micro-organism.
Ingestion:
Opsonization:
- micro-organism is coated with a serum protein, making ingestion easier.
Formation of phagosome,
- fusion of phagosome with the lysosome to form phagolysosomes.
Digestion
- of ingested microbes by enzymes.
the formation of residual body containing indigestible material.
Exocytosis
- the disposal of waste material as soluble debris.
Danger
A sentinel cells
- resides in the tissue waiting for an infection to occur.
- The toll- like receptor binds to a pathogen.
- The binding process activates the cell by transmitting signals to the nucleus.
- The activated cell kills he pathogen and alerts the rest of the body of infection.
Swelling
- Increases temperature.
- Leaky vessels. Promotes the migration of leukocytes into inflamed tissue.
- Flooding the tissue with complement and antibodies.
Fever
- When activated cells of the immune system receive signals (cytokines)
- Activates other immune cells
cause other immune response.
- Inflammatory cytokines such as TNF- alpha and IL-1 are released by macrophages and other leukocytes these can contribute to fever.
- IL-1 and TNF-alpha stimulate prostaglandin production by the anterior hypothalamus, leading to an increase in body temperature
Benefits of a fever
- Optimal growth temperature of many micro-organisms is very narrow.
- increasing the body temperature this can slow the pathogen growth.
- body temperature increases, in response heat shock proteins (HSP) are produced.
- HSPs can act as DAMP which activates T cells increasing local level of pro-inflammatory cytokines.
- Certain enzymatic reactions increase with temperature increasing metabolism.
- Increasing the rate of immune reactions:
- Production and activity of phagocytes
- multiplication of lymphocytes
- rate of antibody and cytokine production.
ate of leukocytes release from bone marrow
tissue repair.
- high temperature can also denature enzymes.
Immune system components
Neutrophils
most common white blood cell. Your bone marrow produces 1011 daily
Travel the blood looking for pathogens.
effector mechanism: phagocytosis and intracellular killing. Intracellular killing Degranulation
- reactive oxygen species (ROS)
- Nitric oxide species (NOS)
Neutrophil extracellular traps (NETS)
Eosinophil
- Dangerous killers of extracellular pathogens.
Blood borne
- key cells in innate defences against parasites( allergies/asthma)
Effector mechanism:
- release highly basic and cationic proteins
not very phagocytic.
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Mast cells
- Tissue residents ( basophils is blood equivalent)
most inflammatory cell in the body > major target for anti-inflammatories.
Effector mechanism
- Degranulation and inflammatory mediator release.
Natura killer cells
Blood borne
- Important in anti-viral and anti-tumour defences.
Innate lymphocyte
Effector mechanism:
- bind to body cells and release cytotoxic granules. apoptosis
Mediators
Innate responses
- pro- inflammatory cytokines/chemokines
- Complement proteins
- acute phase proteins
- Type 1 interferons.
Mediators cytokines.
- Immune effects eg Interleukins (IL-2...)
- Chemotactic eg chemokines (~50)
- Pro-inflammatory eg TNF-α, IFN-, IL-1β
- Anti-inflammatory eg IL-10, TGFβ
- Anti-viral effects eg interferons (α and β)
- Haematological effects eg colony stimulating
factors (GM-CSF)
- Cell biological effects eg growth factors
(TGFβ)
- Make immune cells
- active them
- Help them move around the body.
- Switch them off.
- Maintain balance (repair tissue, destroy activated cells at the end of a response etc)
Cytokines
- can turn immune response on:
- activation: improve the ability to recognise and destroy.
- NFα is ‘pro-inflammatory’ and will activate a wide range of immune cells, induce fever etc...
IL-2 will activate T lymphocytes
Innate reorganisation
- Detect the molecules unique to the micro-organism
- Receptors are coded by germ-line DNA and are
- Evolved over millennia
- Biased to recognise the enemy.
Innate receptors recognise:
- Repeating molecular structures in microbial cell walls .
- Unique forms of RNA/DNA not found in mammalian eg ds RNA , CpG -DNA- repeats.
Enemy parasites
Trypanosomiasis - T.cruzi in a blood smear.
Shistosomiasis - S.Mansoni eggs in
intestine wall
Pathogen-associated molecular
patterns (PAMP)
- Innate responses are directed against common microbial structures found on pathogens.
- These molecular patterns serve as ' antigens' to pattern recognition molecule of the innate defences.
Examples are as follows;
Terminal mannose residues.
Repeating -CHO found on many micro-organisms
Lipopolysaccharides- found on gram negative bacteria. Glossary term 'pattern recognition molecules'
Pattern recognition Molecules.
Macrophage mannose receptor.
- Phagocytosis.
Collectins e.g. Mannose binding lectin (MBL)
and surfactant Protein D SP-D) and SP-A
- Complement activation &/ or phagocytosis.
CD14 and toll receptors.
- phagocytosis and macrophage activation
Danger signals
Exogenous. (External)
- Lipopolysaccharides (LSP)
- Peptidoglycan
- RNA (ss/ds)
CpG DNA
Endogenous.(Internal)
- Extracellular ATP.
- Hypotonic stress.
- Uric acid crystals.
- Heat shock proteins.
Innate immunity response to Danger.
- Pathogen associated molecular patterns (PAMP)
many types.
- non self
- Danger- Response.
mammalian cell walls and DNA
- self
- no danger
- No response.
PAMP - PRR - Signal.
The current paradigm states innate immune
responses are biased toward pathogens.
At the molecular level, Pattern Recognition
Receptors (PPR) exploit unique differences
between mammalian cells and pathogens and
target pathogen associated molecular patterns (PAMP)
Signals from PRR are integrated by a highly
conserved family of Toll receptors
Toll like receptors (TLR 1-10)
- Each TLR is a type 1 membrane protein.
- Ligand recognition via an extracellular
leucine-rich domain.
- Complex (TLR may recognise PRR and/ or
PAMPs)
- Signaling via an intracellular tail which
activates nuclear transcription factors and
leads to the transcription of new genes
Dendritic Cells.
- innate immune cell Derived from same blood monocyte precursor as
macrophage
Tissue resident phagocyte (sampling antigens in
environment.
Recognises pathogens using pattern recognition
receptors (sense ‘danger’)
Mature in response to ‘danger’, migrate out of tissue
to lymph nodes carrying pathogen antigens