Lecture 3- innate immunity and inflammation Flashcards
what are the stages of phagocytosis?
Some PRRs are phagocytosis receptors
Phagocytosis:
i. Internalisation
ii. Acidification
iii. Lysosome fusion
iv. Toxic contents (NO, O2-, H2O2, defensins,
proteases)
v. Pathogen Death
what is cytokine production?
Some PRRs are Toll-like receptors (TLR).
TLR and PAMP –> cell activation and cytokine production
what are toll-like receptors
Toll-like receptors share common intracellular and extracellular domains
10 different TLRs have been found in humans
-TLR-2/-6 recognizes peptidoglycan
-TLR-4 recognizes LPS (best characterized interaction)
-TLR-5 recognizes flagellin
-TLR-9 recognizes bacterial DNA
how are cytokines produced?
Cytokines are small soluble proteins rapidly secreted by one cell that can alter the behavior or properties of the cell itself or another cell.”
Responding cells carry a specific receptor to recognise the cytokine
what is the role of cytokines in inflammation?
Different cells can send out different cytokines, which carry different messages.
Some cells send out many messages whilst others fewer.
Cells respond depending on whether they carry the correct receptor.
Their behaviour is altered, which may include sending messages of their own.
In this way sophisticated communication networks are alter the behaviour of cells in response to pathogens.
Enhanced killing Is just one behaviour. Other examples include enhanced migration, resistance to cell death, enhanced sensitivity to pathogens etc
what are chemokines?
Family of small cytokines that can promote chemotaxis
Chemotactic cytokines
Can be secreted by cells of the immune system but also stromal cells.
Responding cells carry a specific receptor that recognises the chemokine
what do chemokines do?
Chemokines are released at the site of injury or insult.
They form gradients
Cells expressing the corresponding receptor can respond to the chemokine by moving towards the signal.
The cells move from a low concentration towards the high concentration
CC chemokines promote migration of monocytes, CXC promote neutrophil migration
neutrophils are the first responders of the immune system, what are the stages of trans-endothelial migration?
this is a stepwise process : rolling ( lots inside )
- firm adhesion ( both outside and inside )
- transmigration ( LOTS outside and some inside )
how do cytokines activate immune cells?
TNFα binds to TNFR1 on neutrophils
Actions include:
enhanced migration
enhances killing capacity
resistance to cell death
enhanced sensitivity to pathogens
What is complete cascade?
-Comprises more than 30 plasma and cell surface proteins
- One protein activates the next, which activates the next
Protein activation often involves cleavage,
cutting the protein into two fragments, one big, one small
- Early proteins, Late proteins
- Massive amplification at C3
Numbers are not in order as order of discovery
Zymogens in blood circulation
b binds, a active fragment (smaller)
what happens when damage is a danger signal?
Histamine released and binds GPCRs to cause vasodilation which allows immune cells, proteins and fluid through capillary walls
Vasodilation both increases and slows blood flow (heat and redness)
histamine = vasodilation and increased vascular permeability
INFLAMMATION HAS THREE PURPOSES
DELIVER IMMUNE CELLS FROM THE BLOOD
INDUCE BLOOD CLOTTING TO LIMIT SPREAD
PROMOTE REPAIR
what happens when in inflammation, capillaries are leaky
1 - fluid leaks = complement proteins and coagulation proteins
2 - cells crawl out = neutrophils and monocytes
what are the 3 symptoms of inflammation
‘Rubor et calor, tumor et dulor’
Redness and heat, swelling and pain
what is the complement cascade?
- Vascular permeability and recruits more cells to the infection site (“chemotaxis”)
- Increases phagocytosis “opsonisation”
- Lyses bacteria
Anaphylotoxins cause lots of effects:
-vasodilation, histamine release from mast cells, and enhanced vascular permeability.They also mediate chemotaxis. Smooth muscle contraction.
Basically C5a has same role asTNFalphain vasodilation and adhesion
AS we’ve spoken a lot about chemotaxis, focus on opsonisation and lysis.
what is another consequence of increased vascular permeability?
proteins in the blood
- coagulation factors and complement
what starts the cascade?
2 ways complement proteins can be activated
CLASSICAL pathway - Antibody dependent, part of the adaptive immune response
ALTERNATIVE pathway -part of the innate immune response
for both systems, the key event is the generation of C3 convertase, which cleaves C3 into C3a and C3b
The CLASSICAL pathway and ALTERNATE pathways have different ways of cleaving C3 into C3a and C3b
What happened when the MΦ met the bacterium?
recognition =
Events can happen in parallel
Phagocytosis receptor causes restructure of the cell membrane which lead to formation of a phagosome and then this collides with a lysosome which can transfer contents into phagosome creating a “phagolysosome”
response =
Activation of the toll-like receptor leads to cytokine production
Require accessory proteins to bind eg MD4 and CD14, so partly direct and partly indirect
Then transcription factors are activated to induce expression, eg NFkB
These particular cytokines are associated with acute phase response of inflammation
Proinflammatory and responsible for vasodilation, expression of adhesion factors for transmigration and chemoattraction df immune cells, and activation of macrophages
TNF alpha activator of endothelial cells
what is The role of TNF-α? = leaky and sticky
- Increased vascular permeability (like histamine)
- Expression of adhesion molecules on epithelial cells
–> Monocytes & neutrophils - i) adhere ii) stop iii) exit
what is opsonisation?
Spontaneous protein cleavage by alternative pathway (cell wall binds C3 and makes cleavage unit with factor B, d and P)
Opsonisation is like a signal flag placed on the bacterial coat for the macrophage to come and find
Opsonins include antibodies and complement, activate actin polymerisation to internalise
what is the power of complement?
Proteins circulating in blood
C3 and C5 covertase
enzymes form on cell surface
- bind and cleave circulating serum proteins, e.g. C3
what is the Formation of the membrane attack
complex (MAC) pore?
-Uncontrolled influx of water and ions
-Cell lysis
what initiates the adaptive response
the activation of dendritic cell
