Innate immunity - innate leukocytes, PRR, MAMP + DAMPs Flashcards
Name the innate leukocytes, where are they derived from?
HSCs : Myeloid + lymphoid stem cells
- Polymorphonuclear leukocytes (PMN)
- neutrophil, eosinophil, basophil, mast cells
- Macrophage, monocyte, dendritic cells
- NK cells
- all derived from HSCs myeloid lineage except NK cells
Describe the Polymorphonuclear granulocytes (polymorphs or granulocytes) and how they were disovered
- Basophil,
- found with basic blue dye (→ baso-phil)
- Eosinophil,
- red dye called eosin (eosino-phil)
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Neutrophil
- neutra-phil
Describe Neutrophils
Abundance, where they are released and found, how long they live, main functions, interactions, special features
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Make up most (60-70%) leukocytes in blood
- millions made every day and released from bone marrow
- Released in large numbers from bone marrow
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Live for < 24hr in blood
- short lived in blood
- Life extended on entering tissues in response to chemoattractants
- chemoattractants like C5a
- longer lived in tissue
- Receptors for C3b, IgG, IgA
- opsonisation
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Main function is phagocytosis, but also “NETosis”
- NETosis = when neutrophils are dying they throw out fibers (DNA and histones) to form a “net” which can catch bacteria (contain antimicrobials and e.g. defensins)
- so even when dying they try kill bacteria
- neutrophil extracellular trap
Describe Eosinophils
Abundance, where they are found, main function, interactions, special features
- Few in blood (normally), but also beneath mucous surfaces
- Receptors for C3b, IgG, IgA, (IgE)
- opsonisation phagocytosis (not very good at phagocytosis)
- Release toxic proteins, free radicals
- upon recognition pathogen → release toxic proteins from granules and free radicals (e.g ROS which can bind to components to pathogens to cause damage)
- Defence against multicellular parasites
- through releasing these toxic proteins and free radicals onto parasite
- Role in allergy (especially asthma)
- if eosinophils activated inappropriately → can cause damage in the lungs
Describe Basophils
- Very few in blood. ~1% of white blood cells
- Receptors for C3a, C5a, IgE
- chemoattractants response, and IgE
- Release heparin and histamine
- upon stimulation by pathogen
- don’t really phagocytose
- release heparin (increase blood flow) and histamine (inflammatory mediator)
- Defence against parasites, role in allergy
- induce inflammation, increase blood flow
- increase in Basophils in allergy suffering people.
Describe mast cells
- Restricted to tissues - protect mucosal surfaces.
- just under the skin
- similar properties to basophils
- Receptors for C3a, C5a, IgE
- Release histamine etc.
- from their granules
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“Sentinel” cells, defence against parasites, role in allergy
- sentinel as in alert the body
What are monocytes? whats the difference between monocytes and macrophages
- In blood → Monocytes
- Macrophages found in tissues
- Upon infectoin → monocytes can/may migrate to site of infection and differentiate into macrophages
- However! macrophages seed into the tissue very early into development (feotus development) and self renew in the tissues
- macrophages more
Describe macrophages
Macrophages can be derived from monocytes during infection
- Different tissues have different resident macrophages
- e.g. alveolar macrophages (lung), microglia (brain)
- Long-lived
- Act as “sentinel” cells – often the first to detect infections
- “Big eaters” – can phagocytose 100 bacteria/cell
- Receptors for C3b, IgG, IgA
- opsonins
- IgG and IgA help recognition
- Produce pro-inflammatory mediators
- e.g. cytokines
- Can present antigen to T lymphocytes
- important
- antigen-presenting leukocyte → can initiate adaptive immune response
Describe Dendritic cells
- Found in skin and lymphoid tissues
- Take up foreign material by phagocytosis/micropinocytosis
- “cell drinking” can drink fluid around cells?
- Digest foreign material and display fragments on their cell surface
- Specialised for presenting antigen to T cells
- efficient at presenting because →
- Constitutively express high levels of Major Histocompatibility Type II (MHCII) proteins
Describe the importance and process of phagocytosis
- Phagocytosis
- “professional phagocytes” (neutrophils, monocytes, macrophages, dendritic cells)
- these carry out phagocytosis very effciently
- many other normal cell types can do phagocytosis like e.g. epithelial cells but not efficiently
- mainly important in bacterial and fungal infections
- “professional phagocytes” (neutrophils, monocytes, macrophages, dendritic cells)
- Bacterium binds to the phagocyte (recognition)
- Phagocyte pseudopods extend and engulf organism
- Invagination of phagocyte membrane traps the organism within a phagosome
- Phagosome vesicle fused with specialised lysosomes present in the phagocyte
- lyosome (primarily contain free radicals)
- phagolysosome
What stops phagocytes from phagocytosing self cells
NOTE: Healthy “self” cells express a protein (CD47) which is recognised by phagocytes and prevents phagocytosis.
What in phagocytes phagosome/phagolysosome kills the pathogen? i.e. the phagocyte bactericidal agents
- Short-lived, contained in phagosome, produced following “oxidative burst”
- Acidic pH in phagolysosome, usually bacteriostatic but sometimes bactericidal
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Free radicals (very reactive, bind to bacterial proteins and DNA and denature it)
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Toxic oxygen-derived products
- Hydrogen peroxide H2O2, superoxide O2- etc.
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Toxic nitrogen oxides
- e.g. nitric oxide NO
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Toxic oxygen-derived products
- Antimicrobial peptides
- e.g. defensins
- enzymes
- e.g.lysozyme and acid hydrolases (
- Competitors
- stop bacteria dividing, bacteria need Fe and B12
- Lactoferring (competitor) binds iron → stop bacterial growth
Describe oxygen-dependent killing and “oxidative burst”
- these are contained in lysosome so not dangerous to our other cells
- Oxygen-dependent killing
- “Oxidative burst” - transient increase in oxygen consumption following phagocytosis due to activation of a membrane-bound NADPH oxidase.
- rapid increase (transient increase) in oxygen consumption (caused by activation of membrane-bound NADPH oxidase (enzyme normally inactive → activated upon phagocytosis) → oxygen dependent killing → converts oxygen to superoxide ion O2- (very reactive) → superoxide dismutase converts superoxide to hydrogen peroxide (bleach)
- in neutrophils myloperoxidase converts hydrogen peroixed to chlorite ions (bleach that you pour into toilet)
- very reactive free radicals → can bind to bacterial DNA and proteins and denature them
- NADPH + 2O2 → NADP+ + H+ +2●O2- → H2O2 + Cl- → OH- + HOCl
- increase in oxygen activated nitric oxide synthetase → causes production of nitric oxide form arginine and oxygen (very reactive)
- Inducible nitric oxide synthetase in the phagosome membrane can also lead to the production of nitric oxide and other toxic reactive nitrogen species
- arginine + 2O2 → citrulline + NO
Describe NK cells
- not phagocytic
- Derived from lymphoid progenitor
- big nucleus and granules
- Kill infected host cells
- Important in viral infections and bacteria that survive inside host cells
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Recognise “altered self”
- recognise changes in expression of self Major Histocompatibility Type I (MHCI) proteins
- all nucleated cells express MHC I proteins
- self labels
- virus often interferes with levels of expression of MHC I
- NK cells can detect the MHC1 expression decrease
- Important in viral and some intracellular bacterial infections, especially until adaptive immunity is triggered
- Receptors for IgG
- allows killing of antibody coated infected host cells
- Also active against some cancer cells
- cancer cells often down regulate MHC I expression to evade immune system
- NK cells can also detect and kill these
How do NK cells kill infected host cells?
- Activated NK cells produce a pore-forming protein, perforin(similar in structure to MAC), which inserts into the membrane of the infected host cell, forming a pore. → contents of granules can enter target cell → granule contents (granzymes) released into the target cell → activate apoptosis pathway → infected host cell die
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Recently discovered that a granzyme can enter intracellular bacteria, killing them directly.
- some granzymes can kill intracellular bacteria
- Polarisation of NK cell granules at the interface between the NK cell and target cell
- Granule contents (“granzymes”) are released into the target cell, activate apoptosis pathway.
- Target cells undergo apoptosis.
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Recently discovered that a granzyme can enter intracellular bacteria, killing them directly.
- some granzymes can kill intracellular bacteria