Greg - Pattern Recognition Receptors Flashcards
What specificity does the innate immune system have?
It knows what is a fungus, a bacteria, a parasite etc
How does the innate immune system have some specificity?
The innate system can recognise structural components that don’t change over long periods of time e.g. LPS
What four things must an APC do in order to initiate an immune response?
(4)
Leave the tissue by downregulating adhesion molecules so it can release from tissue and move into fluid
Upregulate MHC
Upregulate costimulatory molecules
Secrete cytokines
What is the “Danger Model” of the immune system?
The innate immune system has evolved to recognise signals that indicate that infection or tissue damage is happening
Who came up with the “Danger Model”?
Polly Matzinger
What does PRR stand for?
Pattern Recognition Receptors
What are the two classifications of PRRs?
PAMPs
DAMPS
What are PAMPs?
Pathogen associated molecular patterns
What are DAMPs?
Damade/danger associated molecular patterns
Where are the three places PRRs can be located?
Anchored in the cell membrane
Inside cells located in endosomes/lysosomes or in the cytosol
Secreted from the cell
Give an example of a receptor anchored in the cell membrane
Toll-like receptors
Give an example of a receptor anchored in the cell membrane
Toll-like receptors
Give two examples of receptors found in the cell
Nod-like receptors
Rig-I-receptors
Give two examples of receptors secreted from cells
C-reactive protein
Mannose binding lectin
What are DAMPs?
(2)
Molecules often derived from tissue damage that cause host cells to undergo necrotic death
Harmful Molecules and or contents of the cell that spill out of the cell when they die via necrosis
What is cell necrosis?
Unorganised death of a cell
Give some examples of DAMP
(7)
gDNA fragments
Chromatin components
Mitochondrial DNA
Uric acid crystals
Heat shock proteins
Products of complement activation
What does the deposition of uric acid crystals lead to?
Goitre
How many TLRs do humans have?
Humans have 11 but the 11th is not active
Describe the basic structure of a TLR
(5)
Extracellular pattern recognition zone
Intracellular TIR domain
Single pass through membrane
Horseshoe shaped
18-25 motifs made of 20-29 amino acids rich in leucine
What is the TIR domain?
(4)
Cytoplasmic signalling domain
Toll-Interleukin-1 Receptor
Present in TLRs and IL-1B receptors
Contains 3 highly conserved amino acid sequences called boxes, 1, 2 and 3
What two types of receptors are TIR domains found on?
TLRs
IL-1B receptors
What happens when TLRs bind their ligand?
(2)
They are induced to dimerize
Most are homodiners of a single polypeptide
Give a TLR that forms heterodimers
TLR2
Give two heterodimer options for TLR2
TLR1 with 2
TLR6 with 2
What does TLR 7 detect?
Viral single stranded RNA
What does TLR 10 detect?
We don’t really know, could be vestigial
What does TLR 9 detect?
CpG -> cysteine followed by guanine (not really found in humans but a lot id found in pathogens)
Describe the relationship between TLRs, their location and their function
TLRs on the outside of the cell tend to detect bacterial and fungal PAMPs
TLRs that detect viral PAMPs are found inside the cell in endosomes and lysosomes
What is unique about TLR4?
It can move between the inside and outside of a cell
What TLR detect LPS?
TLR4-TLR4 homodimer
Describe the movement of TLR4
TLR4 can move from the plasma membrane to endosomes/lysosomes after ligand binding
How is LPS detected?
(4)
LPS binds to CD14 which associates to the MD2 of TLR4
LPS binding protein (LBS) delivers LPS to CD14
Complex formed from MD2, TLR4, CD14, LPS
Cytolines may then be released, MHC expression might be increased
Describe the TLR signalling pathway of detection
(4)
Complex of TLR 4, MD2, CD14 and LPS is assembled on macrophage surface
MyD88 binds TLR4 and activates IRAK4 to phosphorylation TRAF6 which leads to phosphorylation and activation of IKK
IKK phosphorylates Ik(kappa)B which leads to the degradation and release of NFkappaB which enters the nucleus
NFkappaB activates transcription of genes for inflammatory cytokines, which are synthesised in the cytoplasm and secreted via the ER
List the molecules in the receptor signalling pathway
Complex of TLR 4, MD2, CD14 and LPS
MyD88
IRAK4
TRAF6
IKK
Ik(kappa)B
NFkappaB
NFkappaB
Cytokines
What are protein kinases?
Enzymes that can add phosphate groups to certain amino acids in proteins
What are the most common targets for kinases?
Serine/threonine or tyrosine
Explain what happens when there is extracellular recognition of LPS?
(6)
The TIR domain of TLR4 binds to a similar TIR domain of the adaptor protein MyD88 and forms a protein bridge to bring other molecules together
MyD88 has another ‘death’ domain where it recruits IRAK4 (a protein kinase)
IRAK4 has a death domain as well which is what binds to MyD88
IRAK4 is activated and it phosphorylates IRAK1
IRAK1 binds and phosphorylates TRAF6
This complex dissociates from receptor and leads to the activation of IkappaB kinase
What activates IRAK4?
The death domain of IRAK4 binds to the death domain of MyD88
What does activated IRAK4 do?
It phosphorylates IRAK1
What does IRAK1 do?
IRAK1 binds and phosphorylates TRAF6
What does TRAF6 do?
IRAK1 TRAF6 complex dissociates from receptor and leads to the activation of IkappaB kinase
How does IRAK1/TRSF6 complex lead to the activation of IkappaB
(4)
The complex dissociates from the receptor which phosphorylates and activates IKK via kinase cascade
IKK phosphorylates IkB
IkB dissociates from NFkB
NFkB moves into nucleus where it directs the activation of genes for cytokines, adhesion molecules and other proteins that expand and intensify the APC effector functions
List the results of TLR-induced changes in gene expression
(4)
Surface expression of co-stimulatory molecules
Cytokine secretion
Chemokine secretion
Migration of dendritic cells
Give some examples of co-stimulatory molecules
B7
(CD80/CD86)
List five pro-inflammatory cytokines
IL-6
TNF-a
IL-1B
CXCL8
IL-12
What does IL-6 do?
(2)
Causes fever
Induces acute-phase protein production by hepatocytes
What does TNF-a do?
(4)
Activates vascular endothelium and increases vascular permeability -> increased entry of complement and cells to tissues -> increased fluid drainage to lymph nodes
Causes fever
Causes mobilization of metabolites
Shock
What does IL-1B do?
(6)
Activates vascular endothelium
Activates lymphocytes
Causes local tissue destruction
Increases access of effector cells
Causes fever
Causes production of IL-6
What does CXCL8 do?
Chemotactic factor that recruits neutrophils and basophils to site of infection
What does IL-12 do?
Activates NK cells
What cytokines cause fever?
IL-6
TNF-a
IL-1B
What cytokine induces acute phase protein production?
IL-6
What cytokine mobilises cells and fluid in inflammation?
TNF-a
What cytokine produces IL-6
IL-1B
What cytokine activates natural killer cells?
IL-12
What cytokine acts as a chemotactic factor for neutrophils and basophils?
CXCL8
