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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
Q

what mutation caused susceptibility to fungal infection in drosophila?

A

mutation in TL4 receptor
they had the ability to bind LPS but the NF-kB pathway was not being activated

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25
Q

Nick Gay demonstrated that drosophila TLR is homologous to…

A

human IL-1R (both bind cytokine), similar intracellular and extracellular domains

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26
Q

Charles Janeway and Medzhitov identified the first human TLR was involved in…

A

activation of NF-kB and instruction of inflammation

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27
Q

what AA caused a mutation in the TLR-4 of mice, causing developmental defects and susceptibility to fungal infections?

A

proline changed to histidine

28
Q

what is the intracellular domain of the TLR-4 called?

A

TIR domain

29
Q

what is characteristic about TLR extracellular domains?

A

they are leucine rich

30
Q

what protein structure do TLRs have?

A

horse shoe

31
Q

do TLR homo or heterodimerise?

A

heterodimerise

32
Q

what two pathways can be activated following ligand binding to leucine rich TLR-4 heterodimerisation?

A

Mal and TRAM

33
Q

what adaptor proteins associated with TLR4 promote the Mal pathway?

A

myD88

34
Q

what adaptor proteins associated with TLR-4 promote the TRAM pathway?

A

TRIF

35
Q

what downstream signalling does the TRAM pathway activate?

A

NFkB (cytokine signalling) and IRF3 (interferon regulatory factors effect gene expression)

36
Q

what downstream signalling does the Mal pathway activate?

A

NFkB and AP-1
production of proinflammatory cytokines

37
Q

what accessory protein on TLR-4 helps it to bind LPS?

A

MD2

38
Q

what is the real activating ligand of TLR-4 that causes heterodimerisation?

A

MD2-LPS complex

39
Q

what does TLR-1/2 recognise?

A

triacylated lipopeptides

40
Q

what does TLR 2/6 sense?

A

deacylated lipopeptides

41
Q

what signal does TLR-2 activate?

A

Mal-MyD88/ NFkB - cytokine signalling

42
Q

what does TLR-3 sense?

A

dsRNA of viruses

43
Q

does TLR-2 hetero or homodimerise?

A

heterodimerise

44
Q

does TLR-3 hetero or homodimerise?

A

homodimerise

45
Q

what signalling pathways does TLR-3 activate?

A

recruitment of TRIF protein
then recruitment of TRAF3 protein
production of IRF3
IRF3 induces gene expression changes

46
Q

what signalling is TLR-9 involved in?

A

IFNs via IRF7 and NFkB via MyD88

47
Q

what does TLR-5 sense?

A

flagellin

48
Q

what signalling is TLR-5 involved in?

A

NFkB

49
Q

what does TLR-7/8 sense?

A

ssRNA

50
Q

why is it difficult to know functions of TLR-8 and TLR-10

A

they are not functional in mice

51
Q

what TLR is not functional in humans?

A

TLR-11
binds profilin protein

52
Q

list 5 TLR effector functions:

A

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
Q

what do nod-like receptors sense? (NLR)

A

breakdown products of peptidoglycan

54
Q

what does NOD1 recognise?

A

ie-DAP

55
Q

What does NOD2 recognise?

A

MDP

56
Q

Describe the structure of NLR…

A

modular, lucine rich repeats, noch-binding domain (NBD), CARD domain

57
Q

what is the significance of CARD-CARD interaction in NLR?

A

it interacts with adaptor protein RIP2 which activates NFkB and MAP-K pathways (similar to TLR)

58
Q

How does Pro-IL-1beta mature to IL-1beta?

A

proteolytic cleavage by caspase-1

59
Q

what results from mutations in NLR-3?

A

Cryopyrin associated periodic syndromes (CAPs)
spontaneous inflammation

60
Q

what do NLRs instruct within the cell?

A

formation of the inflammasome complex

61
Q

what does the inflammasome complex consist of?

A

pro-caspase-1, ASC adaptor protein and NLR sensor protein

62
Q

what does NLRP1 respond to?

A

B. Anthracis and lethal toxin

63
Q

what does NLRC4 respond to?

A

flagellin

64
Q

how is caspase 1 activated?

A

caspase-11 binding to cytosolic LPS

65
Q

what does NLRP3 respond to?

A

pore forming toxins, DAMPs (extracellular ATP)

66
Q

How do DNA sensors such as ALRs drive the construction of inflammasome?

A

they respond to intracellular DNA via HIN domains and DNA binding domains

67
Q

what is cGAS?

A

a cytosolic enzyme that acts as a nucleic acid sensor
it drives pro-inflammatory NFkB and interferon activation by sensing presence of dsDNA

68
Q

how does cGAS function?

A

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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