Innate Immunity-Barriers and Danger Lecture 8, Residence macrophages.,…
Heterogeneous population of long lived tissue resident mononuclear cells. Phagocytose
Name is dependent on location
- ("to eat) from their environment.
- waste disposal
- look for infection.
- skin; Langerhans cell
- liver; Kupffer
- Nervous system; microglia
- Derived from blood monocytes
- effector mechanism phagocytosis and intracellular killing
Macrophages and infection
Exist in 3 states.
- Antigen presenting cells.
Found under the skin and mucosal layers and in the lungs.
- Act to protect against invaders that penetrate barriers.
- Activated (primed)
- chemical signals attract phagocytes to the micro organism.
- Attachment of a phagocyte to the surface of the micro-organism.
Formation of phagosome,
- micro-organism is coated with a serum protein, making ingestion easier.
- fusion of phagosome with the lysosome to form phagolysosomes.
- of ingested microbes by enzymes.
the formation of residual body containing indigestible material.
- the disposal of waste material as soluble debris.
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.
- Increases temperature.
- Leaky vessels. Promotes the migration of leukocytes into inflamed tissue.
- Flooding the tissue with complement and antibodies.
- 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
- high temperature can also denature enzymes.
Immune system components
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)
- Dangerous killers of extracellular pathogens.
- key cells in innate defences against parasites( allergies/asthma)
- release highly basic and cationic proteins
not very phagocytic.
- Tissue residents ( basophils is blood equivalent)
most inflammatory cell in the body > major target for anti-inflammatories.
- Degranulation and inflammatory mediator release.
Natura killer cells
- Important in anti-viral and anti-tumour defences.
- bind to body cells and release cytotoxic granules. apoptosis
- pro- inflammatory cytokines/chemokines
- Complement proteins
- acute phase proteins
- Type 1 interferons.
- 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
- Cell biological effects eg growth factors
- 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)
- 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 receptors recognise:
- 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.
- Repeating molecular structures in microbial cell walls .
- Unique forms of RNA/DNA not found in mammalian eg ds RNA , CpG -DNA- repeats.
Trypanosomiasis - T.cruzi in a blood smear.
Shistosomiasis - S.Mansoni eggs in
Examples are as follows;
- 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.
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.
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
- Lipopolysaccharides (LSP)
- RNA (ss/ds)
- Extracellular ATP.
- Hypotonic stress.
- Uric acid crystals.
- Heat shock proteins.
Innate immunity response to Danger.
mammalian cell walls and DNA
- Pathogen associated molecular patterns (PAMP)
- non self
- Danger- Response.
- 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
- Complex (TLR may recognise PRR and/ or
- Signaling via an intracellular tail which
activates nuclear transcription factors and
leads to the transcription of new genes
- innate immune cell Derived from same blood monocyte precursor as
Tissue resident phagocyte (sampling antigens in
Recognises pathogens using pattern recognition
receptors (sense ‘danger’)
Mature in response to ‘danger’, migrate out of tissue
to lymph nodes carrying pathogen antigens