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Immunology > L4: PRR Signalling > Flashcards

L4: PRR Signalling Flashcards

1
Q

what does PRR mean?

A

Pattern Recognition Receptors

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2
Q

who is the grandfather of immunology?

A

Charles Janeway

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3
Q

what do PRRs recognise?

A

non self signals
structures essential and common to pathogen but absent completely from host
PAMPs

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4
Q

what cells have PRRs?

A

innate immune cells

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4
Q

what are PAMPs?

A

pathogen associated molecular patterns

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5
Q

what are PRRs homologous too?

A

resistance proteins in plants

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6
Q

what domains within various families of PRRs have high similarity?

A

ligand binding and effector domains

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7
Q

what 3 cellular levels do PRRs act at?

A

surface, endosomal, cytoplasmic

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8
Q

what are vitaPAMPs?

A

patterns that appear when active infection involving DNA/RNA REPLICATION is occuring

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9
Q

what are DAMPs?

A

danger associated molecular patterns
associate with same PRRs as MAMPs and PAMPs but are often self-origin not foreign

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10
Q

what are MAMPs?

A

microbe associated molecular patterns

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11
Q

what are examples of DAMPs?

A

metabolites in unusual locations
modified metabolites - oxLDL
alarmins - IL-1alpha, HMGB1

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12
Q

why do DAMPs engage PRRs if they are not foreign?

A

they have similar structure to PAMPs/MAMPs

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13
Q

what disadvantage do PRRs have due to their non-specific binding characteristic?

A

unresolvable inflammation can occur

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14
Q

what is molecular mimicry?

A

mistaken identity due to similar structure

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15
Q

give an example of molecular mimicry in the body

A

auto immune disease
broken tolerance in T-cells, they begin to react to self antigens

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16
Q

when are DAMPs released?

A

naturally in response to tissue damage from infection

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17
Q

what is a receptor called when it has no effector function?

A

a signal inducer (the signal it induces may activate an effector function)

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18
Q

what do signal inducing receptors do?

A

they can enhance phagocytosis, gene expression and metabolism

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19
Q

name 2 types of phagocytic receptors:

A

C-type lectin receptors (CTLR)
Scavenger receptors
Dectin-1 (signalling not phagocytic)

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20
Q

what are CTLR Phagocytic receptors involved in?

A

sugar binding (glycoproteins on pathogen cell walls)
triggering of internalisation and phagocytosis
intracellular ITAM domain interacts with kinases
signalling function - cytokine production
cytokine production leads to change in gene expression

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21
Q

what are phagocytic scavenger receptors involved in?

A

transport and internalisation of self-lipoproteins and sugars (signs of cell death)
can also recognise pathogen cell walls

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22
Q

what is the theory surrounding scavenger receptors?

A

they were thr first PRR
others originated from this one by gene duplication and expansion events

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23
Q

what are toll-like receptors (TLR)?

A

prototype PRR involved in signalling

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24
what mutation caused susceptibility to fungal infection in drosophila?
mutation in TL4 receptor they had the ability to bind LPS but the NF-kB pathway was not being activated
25
Nick Gay demonstrated that drosophila TLR is homologous to...
human IL-1R (both bind cytokine), similar intracellular and extracellular domains
26
Charles Janeway and Medzhitov identified the first human TLR was involved in...
activation of NF-kB and instruction of inflammation
27
what AA caused a mutation in the TLR-4 of mice, causing developmental defects and susceptibility to fungal infections?
proline changed to histidine
28
what is the intracellular domain of the TLR-4 called?
TIR domain
29
what is characteristic about TLR extracellular domains?
they are leucine rich
30
what protein structure do TLRs have?
horse shoe
31
do TLR homo or heterodimerise?
heterodimerise
32
what two pathways can be activated following ligand binding to leucine rich TLR-4 heterodimerisation?
Mal and TRAM
33
what adaptor proteins associated with TLR4 promote the Mal pathway?
myD88
34
what adaptor proteins associated with TLR-4 promote the TRAM pathway?
TRIF
35
what downstream signalling does the TRAM pathway activate?
NFkB (cytokine signalling) and IRF3 (interferon regulatory factors effect gene expression)
36
what downstream signalling does the Mal pathway activate?
NFkB and AP-1 production of proinflammatory cytokines
37
what accessory protein on TLR-4 helps it to bind LPS?
MD2
38
what is the real activating ligand of TLR-4 that causes heterodimerisation?
MD2-LPS complex
39
what does TLR-1/2 recognise?
triacylated lipopeptides
40
what does TLR 2/6 sense?
deacylated lipopeptides
41
what signal does TLR-2 activate?
Mal-MyD88/ NFkB - cytokine signalling
42
what does TLR-3 sense?
dsRNA of viruses
43
does TLR-2 hetero or homodimerise?
heterodimerise
44
does TLR-3 hetero or homodimerise?
homodimerise
45
what signalling pathways does TLR-3 activate?
recruitment of TRIF protein then recruitment of TRAF3 protein production of IRF3 IRF3 induces gene expression changes
46
what signalling is TLR-9 involved in?
IFNs via IRF7 and NFkB via MyD88
47
what does TLR-5 sense?
flagellin
48
what signalling is TLR-5 involved in?
NFkB
49
what does TLR-7/8 sense?
ssRNA
50
why is it difficult to know functions of TLR-8 and TLR-10
they are not functional in mice
51
what TLR is not functional in humans?
TLR-11 binds profilin protein
52
list 5 TLR effector functions:
1) MyD88/NFkB signalling pathways - proinflammatory cytokine TFs 2) Enhanced expression of antimicrobial genes - Cox2/Ptgs2, iNOS, AMPs, complement proteins 3) TRIF/IRF signalling 4) Activation of MAP-kinases - AP-1 5) Alteration of phagocytic capacity 6) Phagocytosis can deliver receptors to intracellular compartments
53
what do nod-like receptors sense? (NLR)
breakdown products of peptidoglycan
54
what does NOD1 recognise?
ie-DAP
55
What does NOD2 recognise?
MDP
56
Describe the structure of NLR...
modular, lucine rich repeats, noch-binding domain (NBD), CARD domain
57
what is the significance of CARD-CARD interaction in NLR?
it interacts with adaptor protein RIP2 which activates NFkB and MAP-K pathways (similar to TLR)
58
How does Pro-IL-1beta mature to IL-1beta?
proteolytic cleavage by caspase-1
59
what results from mutations in NLR-3?
Cryopyrin associated periodic syndromes (CAPs) spontaneous inflammation
60
what do NLRs instruct within the cell?
formation of the inflammasome complex
61
what does the inflammasome complex consist of?
pro-caspase-1, ASC adaptor protein and NLR sensor protein
62
what does NLRP1 respond to?
B. Anthracis and lethal toxin
63
what does NLRC4 respond to?
flagellin
64
how is caspase 1 activated?
caspase-11 binding to cytosolic LPS
65
what does NLRP3 respond to?
pore forming toxins, DAMPs (extracellular ATP)
66
How do DNA sensors such as ALRs drive the construction of inflammasome?
they respond to intracellular DNA via HIN domains and DNA binding domains
67
what is cGAS?
a cytosolic enzyme that acts as a nucleic acid sensor it drives pro-inflammatory NFkB and interferon activation by sensing presence of dsDNA
68
how does cGAS function?
1) senses dsDNA in cytosol - unusual 2) cGAMP secondary messenger is produced 3) it binds to adaptor proteins on STING complex located on ER 4) IRF3 and NFkB pathways activated

Immunology (5 decks)

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