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MIIM30003 > Lectures 1-3 > Flashcards

Lectures 1-3 Flashcards

1
Q

What are autoinflammatory diseases caused by? Give two examples.

A

dysregulation of the innate immune system

e.g. loss of function or gain of function mutation

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2
Q

Where do mutations occur in relation to the innate immune response?

A

within a single gene encoding a component of this response

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3
Q

How does the adaptive immune system behave in the case of autoinflammatory disease?

A

behaves normally, although prolonged strong stimulation from the innate immune system may lead to abnormalities such as autoantibody production

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4
Q

What does excessive signalling from innate immune components stimulate?

A

stimulates to innate and adaptive effectors to cause the pathology of the disease

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5
Q

What are inflammasopathies the result of?

A

overproduction of IL-1β and IL-18 due to unnecessary inflammasome activation

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6
Q

What is the commonality of all inflammasomes? Why?

A

produce IL-1β and IL-18

this is because the pathways of all inflammasomes converge to activate caspase 1 which cleaves pro-IL-1β and pro-IL-18

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7
Q

Why do activating mutations in the different inflammasomes cause different diseases?

A

different inflammasomes may be dominant in different types of innate immune cells + variable amounts of pro-IL-1β and pro-IL-18

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8
Q

What domains are found in pyrin, NLRP3, NLRC4, NLRP1 and ASC respectively?

A 
pyrin: PYD-(coil-coil)-(B-boxes)
NLRP3: PYD-NACHT-LRR
NLRC4: CARD-NACHT-LRR
NLRP1: PYD-NACHT-LRR-FIIND-CARD
ASC: CARD-PYD
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9
Q

What is the NLRP3 inflammasome activated by?

A

mitochondrial DNA, T3SS system components, bacterial toxins, ROS, disruption of lysosomes

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10
Q

What type of mutation is a PAAND mutation?

A

dominant mutation in the gene for pyrin

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11
Q

What did the PAAND mutation teach us about pyrin?

A

pyrin detects pathogens as bacterial toxins inactivate RhoGTPases such as RhoA -> decreased phosphorylation of S242R on pyrin -> decreased binding of 14-3-3 to pyrin results in activation -> activated pyrin stimulates the inflammasome

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12
Q

Why does the PAAND mutation cause pathology?

A

this mutation leads to a loss of 14-3-3 binding meaning that an individual does not even need to have an infection in order for there to be inflammation without any benefits of getting rid of the pathogen

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13
Q

What is gout caused by?

A

an immune response to monosodium urate crystals deposited in the joints

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14
Q

How does gout cause inflammation?

A

MSU crystals activate the NLRP3 inflammasome

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15
Q

What condition are cholesterol crystals associated with?

A

atherosclerosis

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16
Q

What is the indirect signal which encompasses many triggers of the NLRP3 inflammasome?

A

K+ efflux

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17
Q

What was NLRP3 originally called?

A

cryopyrin

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18
Q

What can loss of function mutations in the pyrin domain of NLRP1 lead to?

A

the development of cancer

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19
Q

How do mutations in NLRP1 lead to cancer?

A

the NLRP1 P1214R mutation prevents DPP9 binding -> DPP9 can no longer carry out its function of binding both sides of the FIIND domain (ZU5/UPA) -> C-terminus is able to become active (unbound) -> CARD domain is released and the inflammasome is formed

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20
Q

What is functional degradation of NLRP1?

A

cleavage of the N-terminus by pathogen effectors which leads to activation of NLRP1 (dominant destabilising mutations in the pyrin domain increase this form of degradation)

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21
Q

What is the role of the CARD domain?

A

activates the inflammasome

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22
Q

What do mutations in NLRC4 cause?

A

enterocolitis and high serum ferritin levels

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23
Q

How is the NLRC4 inflammasome activated by pathogens?

A

NLRC4 detects bacteria with T3SS through NAIP (which recognises the needle of the T3SS)

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24
Q

How do mutations in NLRC4 cause high serum ferritin levels?

A

overactivation of the inflammasome results in chronically activated macrophages, cells which phagocytose healthy cells and red blood cells resulting in the release of ferritin

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25
Q

How do mutations in NLRC4 cause high serum ferritin levels?

A

overactivation of the inflammasome results in chronically activated macrophages, cells which phagocytose healthy cells and red blood cells resulting in the release of ferritin

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26
Q

How are NLRC4 mutations treated?

A

by blocking IL-18

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27
Q

What is NLRP3?

A

an example of a protein that is able to activate the inflammasome under certain conditions

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28
Q

How are NLRP3 mutations such as cryopyrin associated periodic syndromes (CAPS) treated?

A

by blocking IL-1b

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29
Q

What is the potential unifying hypothesis of NLRP3 activation?

A

disruption of the trans-Golgi-network -> exposure of negatively charged lipids which are attracted to positively charged lysines within NLRP3 -> formation of the speck

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30
Q

Why is potassium efflux important before formation of the inflammasome?

A

otherwise NLRP3 proteins would not bind to the negatively charged lipids on the destabilised trans-Golgi-network

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31
Q

Why is FMF common in the Mediterranean?

A

these mutations provide protection against Yersinia pestis infections (the plague) as they promote activation of the inflammasome (positively selected)

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32
Q

Why does Yersinia and C. difficile inactivate RhoA?

A

in order to take over the cell’s machinery to use for their own purposes of proliferation

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33
Q

How is PAAND and FMF treated?

A

by blocking IL-1b

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34
Q

How does Yersinia interact with pyrin?

A

YoE or YopT modulate RhoA to stop phagocytosis by host cells -> pyrin can sense loss of RhoA and defend against pathogen -> YopM turns on PKN1/2 to inhibit pyrin -> pyrin FMF mutants can’t be inhibited by PKN1/2

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35
Q

What is the mechanism of FMF mutations?

A

pyrin is rendered insensitive to PKN1/2 (recruited by YopM to phosphorylate pryin) and, therefore, becomes activated much more easily

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36
Q

What is the main role of DPP9?

A

prevents separation of the NLRP1 N-terminus from the C-terminus in the steady state (so that cleavage of NLRP1 only occurs in the presence of pathogen effectors)

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37
Q

How are NLRP1 mutations such as NAIAD treated?

A

by blocking IL-1b

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38
Q

What is the primary inflammatory defect that triggers disease in patients with DPP9 loss of function mutations?

A

NLRP1 activation

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39
Q

What are symptoms of DPP9 loss of function mutations?

A

immune-associated defects, poor growth, pancytopenia and skin pigmentation abnormalities

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40
Q

What are interferonopathies caused by?

A

the overactivation of pathways that lead to the expression of interferons

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41
Q

How is type I interferon production induced?

A

different stimuli are detected by various cells sensors which activate members of the IRF transcription factor family

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42
Q

How are cell sensors involved in interferonopathies?

A

mutations in these sensors can cause disease due to excess production and activity of interferons and/or by loss of immune function

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43
Q

Interferonopathies can be caused by mutations in…

A

STING, RNASEH2A, β1i of the immunoproteasome and RIG-I

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44
Q

How is STING involved in the detection of RNA in the cytoplasm?

A

cGAS detects DNA in the cytoplasm and produces cGAMP which activates STING -> STING activation leads to the activation of IRF3

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45
Q

What are the consequences of mutations in Samdh1 and Trex1?

A

no longer able to degrade and clear host DNA -> activation of cGAS and STING

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46
Q

How come cGAS is not activated by nuclear DNA when cells divide?

A

cGAS bound to chromatin with histones is inactive

47
Q

What happens when there are mutations in histone pre-mRNA processing genes?

A

cGAS dependent interferonopathy AGS

48
Q

What is the role of mitochondrial antiviral signalling protein (MAVS)?

A

acts as a signalling platform

49
Q

What does RIG-I and MDA5 bind to respectively?

A

RIG-I: 5’ ppp dsRNA

MDA5: long dsRNA

50
Q

What is the role of ADAR1?

A

edits adenosine to inosine preventing self-recognition of Alu duplex RNA (MDA5 is no longer able to recognise and bind to ADAR1)

51
Q

What happens when there are loss of function mutations in ADAR1?

A

results in the detection of self RNA by RNA sensors in the cytoplasm

52
Q

What are proteasome-associated autoinflammatory syndromes (PRAAS) caused by?

A

mutations in the subunits of the proteasome and the inducible immunoproteasome which leads to a decrease in proteasome activity

53
Q

Why are PRAAS considered interferonopathies?

A

decreased proteasome activity leads to accumulation of IL-24 in the cytoplasm -> triggers PKR -> stimulates production of type I interferons

54
Q

What does NOD1 and NOD2 recognise?

A

different products of the bacterial cell wall structural component peptidoglycan

55
Q

How are NOD proteins able to detect different species of bacteria?

A

able to differentiate between which type of peptidoglycan (murein) is produced by each species

56
Q

What does activation of NOD proteins result in?

A

the production of proinflammatory cytokines such as TNF

57
Q

Is any ubiquitinated protein degraded by the proteasome?

A

no

58
Q

What is the role of OTULIN and A20?

A

act as deubiquitinases

59
Q

What happens if there is a loss of function mutation in OTULIN?

A

this will indirectly increase the level of ubiquitinated proteins in the cell as ubiquitin is not removed from proteins normally deubiquitinated by OTULIN

60
Q

What do activating mutations in STING cause?

A

autoinflammatory disease such as STING associated vasculopathy with onset in infancy (SAVI) -> increased IFN

61
Q

What is the role of JAK inhibitors such as ruxolitinib? What are they used to treat?

A

prevents IFN signalling by inhibiting IFNAR1/2

JAK inhibitors are used to treat SAVI

62
Q

Which mutations cause familial chilblain lupus and Aicardi-Goutieres Syndrome?

A

mutations that prevent DNA clearance

63
Q

What is Trex1?

A

a DNA exonuclease

64
Q

What is Samdh1?

A

a phosphohydrolase which degrades dNTPs

65
Q

What diseases are caused by mutations in MDA-5 or RIG-I?

A

Aicardi-Goutieres Syndrome and Singleton-Merten Syndrome

66
Q

What symptoms are PRAAS characterised by?

A

recurrent fever, skin eruptions, arthritis, elevated ESR/CRP, lipodystrophy, basal ganglia calcification

67
Q

Which ligands are detected by NOD1 and NOD2 respectively?

A

NOD1: iE-DAP (all gram -ve, some gram +ve)
NOD2: MDP (most bacteria)

68
Q

Why do NOD2 loss of function mutations result in Crohn’s disease?

A

there is a normal baseline activation of NOD2 in the gut which promotes tonic inflammation that recruits the right balance of immune cells in the GIT which can act against the teeming mass of bacteria in this location

69
Q

What does activation of NOD1/NOD2 lead to?

A

the production of proinflammatory cytokines and antimicrobial peptides

70
Q

What do activating mutations in NOD2 cause?

A

Blau syndrome

71
Q

What type of ubiquitination does A20 and OTULIN target?

A

linear ubiquitination only

72
Q

What is TNF signalling involved in and what is a major aspect of this signalling?

A

TNF signalling triggers the production of NF-kB and a major aspect of this signalling is linear ubiquitination

73
Q

Which type of ubiquitination is involved in the degradation of proteins?

A

Lys63-Ub ubiquitination

74
Q

What is the role of HOIP, HOIL-1 and SHARPIN?

A

involved in the addition of linear ubiquitins to the TNF signalling machinery

75
Q

What happens if there are defects in linear ubiquitination of the TNF signalling pathway (loss of HOIL, HOIP or RIPK1)?

A

immunodeficiency + increased cell death and inflammasome activation resulting in autoinflammation

76
Q

What happens if there is excess ubiquitination of TNF signalling components (due to loss of A20 or OTULIN)?

A

results in autoinflammatory disease

77
Q

How are infected cells able to spread danger signals?

A

package RNA and DNA into exosomes which go out into the circulation and are sampled by bystander cells -> stimulation of RIG-I + the cGAS/STING pathway
inflammasome specks are able to induce inflammasome activation in bystander cells even after the original infected cell has died

78
Q

What are the two main compartments of cells?

A
  1. the nucleo-cytosolic space

2. the luminal space of the ER, Golgi, secretory vesicles and the endosomal-lysosomal system (the “vesicular” system)

79
Q

How are proteins tagged for degradation?

A

the C-terminal glycine of a ubiquitin molecule is linked to a lysine in the target protein and further ubiquitin molecules are linked via their glycine residue to lys48 of the preceding ubiquitin molecule

80
Q

When is the immunoproteasome formed?

A

when the catalytic beta subunits of the constitutive proteasome are substituted for inducible beta subunits

81
Q

Why is TAP embedded in the ER membrane?

A

so that peptides for antigen presentation can be transported to the newly synthesised MHC I molecules

82
Q

Which peptides does TAP pump?

A

peptides of 8-40 amino acids in length, although the preferred size is 9-12

83
Q

Does human TAP have C-terminal residue preference?

A

no

84
Q

Which proteasomes does TAP transport peptides from?

A

both the constitutive proteasome and the immunoproteasome

85
Q

Why does TAP use ATP?

A

because it is an active transport process but obviously denaturation of the peptides is not required

86
Q

Why are most peptides transported by TAP not incorporated into MHC class I molecules?

A

because they are cleared from the ER by the ERAD (ER associated degradation) system

87
Q

What happens to MHC class I molecules?

A

they are ubiquitinated and transported to the cytosol for proteasomal degradation via the generic ERAD pathways

88
Q

Why are ERAD pathways sometimes co-opted by viuses?

A

to block MHC class I assembly and to evade CD8 T cell recognition

89
Q

Which acid proteases are contained within endosomes and lysosomes?

A

multiple cathepsins as well as an enzyme which breaks (reduces) disulphide bonds called GILT

90
Q

How can cytosolic proteins end up in lysosomes?

A

via autophagy

91
Q

Why don’t MHC class II molecules have a cytosolic signalling domain which targets them to endosomes?

A

because if this was the case, MHC class II molecules would be unable to leave the endosome

92
Q

Does HLA-DM have a similar role to tapasin?

A

yes

93
Q

What is MARCH-1?

A

an E3 ligase on the cell membrane or membrane of endosomal compartments

94
Q

What is the role of MARCH-1?

A

ubiquitinates the cytoplasmic tail of MHC class II molecules

95
Q

What is the goal of MHC I presentation?

A

to display in real-time on the plasma membrane a sample of all the proteins synthesised by the cell

96
Q

What is the MHC I presentation machinery a combination of?

A

“multifunctional” proteins co-opted for an antigen presentation role, and “dedicated” proteins whose primary function is to assist in antigen presentation

97
Q

What is the proteasome used for?

A

to dispose of proteins that are no longer necessary, allowing “recycling” of their component amino acid residues

98
Q

Why can’t the proteasome be made “to suit” the antigen presentation machinery?

A

because it has to cope with other functions and instead the antigen presentation machinery has to be adapted to make the most of the proteasome products

99
Q

What is the proteasome an example of?

A

a “multifunctional” protein co-opted for antigen presentation

100
Q

What stimulates expression of immunoproteasomes?

A

y-IFN / viral infections induce the formation of immunoproteasomes (addition of the PA28 ring)

101
Q

Why is the immunoproteasome formed?

A

more efficient at generating antigenic peptides (not proved)

102
Q

What are peptides generated by proteasomes/immunoproteasomes further degraded by?

A

cytosolic aminopeptidases (proteases that remove residues from the N-terminal end of peptides)

103
Q

Which residue of MHC I ligands is “fixed” by the proteasome and which residue is more “flexible”?

A

the C-terminal residue is “fixed” and the N-terminal residue is more “flexible”

104
Q

What is the peptide loading complex composed of? What are these components involved in?

A

several ER chaperones, TAP and other accessory molecules which are involved in MHC I folding, and assembly of MHC I-peptide complexes

105
Q

What is the half-life of each MHC I-peptide complex directly proportional to?

A

the affinity of the interaction between the MHC I peptide-binding site and the peptide

106
Q

What does protein loading complex editing ensure?

A

that only complexes carrying peptides that confer a minimum stability leave the ER

107
Q

What are the characteristics of a high-quality peptide?

A

fits well into the peptide binding groove, contains the right anchor residues and lacks residues that hamper binding

108
Q

What does cross-presentation allow dendritic cells to do?

A

to present antigens to T cells even when they have not been infected themselves

109
Q

How do dendritic cells carry out cross-presentation?

A

by phagocytosing infected cells and transporting viral antigens into the cytosol so they can be presented via the MHC class I presentation pathway

110
Q

What is the cytosolic pathway of cross-presentation?

A

endocytosed antigens are transferred to the cytosol, thereby accessing the “canonical” MHC I presentation machinery

111
Q

What is the issue with the cytosolic pathway of cross-presentation?

A

the mechanism of antigen transfer from endosomes to the cytosol remains poorly characterised

112
Q

What is the endosomal pathway of cross-presentation?

A

antigens are processed in endosomes, and peptides are loaded to MHC I molecules also in endosomes (which are recycled from the PM)

113
Q

What is the issue with the endosomal pathway of cross-presentation?

A

unclear whether “good quality” MHC-I peptide complexes can be generated in endosomes, which lack the PLC
unclear whether the endosomal proteases can generate the same antigenic peptides that are generated by the proteasome

MIIM30003 (2 decks)

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