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Biomed Season Finale > Cell Signalling in Health and Disease > Flashcards

Cell Signalling in Health and Disease Flashcards

Toll-Like Receptor Signalling

1
Q

what is needed for a foreign protein to induce an immune response

A

an adjuvant

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2
Q

what is the immune system dogma

A

only responds to foreign molecules

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3
Q

what is toll-like receptor 4 activated by

A

lipopolysaccharides

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4
Q

function and description of LPS-binding protein (LBP)

A

is an acute-phase protein released by the liver
binds to LPS

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5
Q

what is the function of the LPS-LBP

A

transfers LPS onto CD14 on the surface of phagocytes

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6
Q

what occurs once LPS is bound to CD14 on phagocytes

A

CD14 interacts with TLR4
leads to activation of NFkappaB in the nucleus

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7
Q

what binds to the LPS bound TLR4

A

the adapter protein - Myd88
binds to the TIR domain of TLR4

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8
Q

what does TIR bound Myd88 accomplish

A

activates IRAK
IRAK phosphorylates TRAF6

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9
Q

what is the function of phosphorylated TRAF6

A

activates MAPKKK and TAK1 which become a complex

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10
Q

function of activated MAPKKK-TAK1

A

degrades IkB
leads to NFkB entry into nucleus

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11
Q

what are the 2 TLR4 signalling pathways

A

Myd88 dependent
Myd88 independent, TRIF dependent

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12
Q

what does TLR4 siganlling via the TRIF dependent pathway lead to

A

IFN-beta response

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13
Q

what are the general features of TLR Myd88 - dependent pathway

A

activated by most TLR’s
leads to activation of MAP kinases and NFkB
expression of inflammatory cytokines
up-regulation of co-stimulatory molecules and MHC on cell surface

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14
Q

what are the general features of the TLR Myd88-independent pathway

A

activated by TLR4/3
leads to activation of IRF-3 and production of type I interferon
increased co-stimulation and MHC on cell surface
expression of inflammatory cytokines
maturation of dendritic cells

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15
Q

what is NFkB

A

it is an inducible transcription factor expressed in all mammalian cells

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16
Q

why is NFkB usually inactive

A

because inhibitory transcription factors are usually bound

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17
Q

how is NFkB liberated and activated

A

phosphorylation of IkB leads to its ubiquitination
leads to release of active NFkB

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18
Q

what is the NFkB family composed of

A

5 related transcription factors:
p50
p52
RelA
c-Rel
RelB

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19
Q

what is required for NFkB mediated transcription

A

formation of heterodimers with activation domains

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20
Q

macrophages have stimulant-dependent responses, what is the difference in response to a LPS and glucan-beta

A

LPS - leads to tolerant macrophage
- desensitized/immune tolerance
-decrease in IL6/TNFalpha
glucan-beta - leads to trained macrophage
- sensitized/trained immunity
- increase in IL6/TNFalpha

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21
Q

how does the dose of LPS affect the macrophage response

A

high dose of LPS - results in tolerant macrophage
low dose - doesn’t result in tolerant macrophage

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22
Q

how does an LPS stimulus affect chromatin formation

A

leads to acetylation - subsequent loosening of chromatin for gene transcription

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23
Q

how does a second LPS stimulus affect chromatin formation

A

leads to deacetylation - no transcription
the cell has become tolerant

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24
Q

how can nucleic acids be a PAMP, when our own cells contain them in RNA/DNA

A

toll-like receptors bind to features of nucleic acid specific to microbes absent in mammalian cells

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25
Q

what is TLR9 specific for and why

A

an unmethylated CpG DNA
bacterial CpGs are unmethylated whereas mammalian CpGs are usually methylated

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26
Q

what does TLR3 recognise

A

long double stranded RNA - common in microbes, rare in mammals

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27
Q

what is the NOD protein structure composed of

A

CARD - Caspase activating and recruitment domain
NBD - nucleotide binding domain
LRR’s - leucine rich repeats

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28
Q

what is the difference between NOD - 1/2

A

NOD-1 - one CARD domain
NOD-2 - two CARD domains

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29
Q

what are the ligands of the NOD receptors and where are they found

A

peptidoglycans
found in gram+ bacteria in cell wall
also found in thin layer of periplasmic space in gram - bacteria

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30
Q

what do NOD1/2 receptors bind to

A

NOD1 - Meso-DAP domain of peptidoglycan
NOD2 - MDP domain of a peptidoglycan

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31
Q

how does NOD1/2 activation leads to activation of NFkB

A

NOD1/2 signal via serine/threonine RIP2 kinase (RICK)
RICK mediates ubiquitination of NEMO/IKKgamma
leads to activation of NFkB

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32
Q

besides NFkB what else does NOD signalling activate

A

activation of MAPK

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33
Q

what does LPS-TL4 signalling increased expression of NFkB lead to the increased expression of what

A

leads to the increased expression of NLR3P and IL-1b

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34
Q

what does the increased expression of NLR3P/IL-1b lead to

A

forms a complex with ASC - preventing the ubiquitination of ASC

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35
Q

what does ASC/NLR3P/IL-1b form

A

forms an inflammasome
NLR3P forms a star shape around stacks of ASC

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36
Q

what does an inflammasome form

A

the caspase activity

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37
Q

how do phagocytes sabotage TLR signalling

A

1 - camouflaging or changing the molecules that interact TLR
2 - interference with downstream TLR signalling
3 - hijacking lymphocytes to hide

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38
Q

function of the glycoprotein hemagglutinin (HA)

A

it is a lectin that mediates binding of the virus to target cells and entry of the viral genome

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39
Q

function of the glycoprotein neuraminidase (NA)

A

involved in the release of progeny virus from infected cells

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40
Q

how does neuraminidase achieve its function

A

cleaves the sugars that bind the mature viral particle

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41
Q

what is the RNA that is largely responsible for a viruses’ virulence

A

NS1

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42
Q

what do virus infected cells release to halt viral infection

A

IFN-alpha
IFN-beta

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43
Q

what is the function of IFN-alpha/beta

A

induces resistance to viral replication in all cells
increases MHC class I and increases antigen presentation
activate dendritic/macrophages
activate NK-cells to kill infected cells

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44
Q

what must be done to the CARD domain of RIG-1 for IFN induction

A

it must be ubiquitinated

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45
Q

what is responsible for ubiquitinating RIG-1

A

TRIM25

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46
Q

what is the difference between normal cells and cells infected with influenza in terms of RIG-1

A

in influenza infected cells the CARD domain of RIG-1 is not ubiquitinated
prevents IFN response

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47
Q

function of TRIM19

A

inhibits replication of many DNA/RNA viruses

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48
Q

function of TRIM5alpha

A

blocks replication of HIV

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49
Q

what is the function of TRIM21

A

key in initiating antibody response to influenza

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50
Q

outline the difference between autocrine/endocrine/paracrine function

A

autocrine - cell signals are expressed that effect the cell that released them
paracrine - cell signals released affect nearby cells
endocrine - cell signals released into bloodstream to effect distant cells

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51
Q

what does the release of IL-4 from T helper cells effect

A

B-cells - activation/proliferation/differentiation
thymocyte - proliferation
mast cells - proliferation

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52
Q

how do activated T helper cells effect macrophages

A

via release of IFN-gamma

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53
Q

what interleukins induce proliferation in B cells and what are the released from

A

IL-2
IL-4
IL-5
T helper cells

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54
Q

what does the release of IL-4 and IL-5 from Th cells to B cells cause

A

causes a class switch to IgE antibodies

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55
Q

how does IFN-gamma released from Th cells affect B-cells

A

inhibits class switch to IgE

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56
Q

how are Th cells activated

A

IL-12 released by macrophages

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57
Q

why do cytokines only effect cells in close proximity

A

most cytokines have a very short half-life

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58
Q

what is needed for cytokines to induce an effect on cells

A

high concentration of cytokines
may require cell-cell interaction

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59
Q

what are the cytokine receptor families

A

1 - immunoglobulin (IL-1)
2 - Class I cytokine (haematopoietin)
3 - Class II cytokine (interferons)
4 - chemokine family
5 - tumour necrosis family

60
Q

what are the 3 domains of cytokine receptor families

A

extracellular domain
transmembrane domain
cytoplasmic domain

61
Q

what is the GM-CSF receptor subfamily and how does it effect cytokine affinity

A

it is a common beta-subunit of the receptor
when absent it leads to low affinity
when present alongside the alpha-subunit it leads to high affinity

62
Q

describe the majority of cytokine receptor chains

A

alpha chain - specific cytokine binding site
beta/gamma chain - required for high binding affinity

63
Q

what is the IL-2 receptor subfamily

A

a common gamma subunit required for high cytokine binding affinity

64
Q

what is X-linked severe combined immunodeficiency

A

an due to a defect in the gamma-chain on the X chromosome (aka - bubble boy)
highly compromised immune system
lack of T cells/NK cells and functional B cells

65
Q

what is the Class I/II receptors transduction similar to

A

JAK/STAT pathway

66
Q

what does the TNF receptor family activation lead to

A

caspase and NFkB activation

67
Q

what type of receptor is the chemokine receptor family

A

G-protein associated receptors

68
Q

outline the JAK section of the JAK/STAT transduction mechanism

A

JAK - is a Janus kinase bound to the tyrosine kinase receptor
once a cytokine binds to the TK, JAK is activated and phosphorylates the TK and phosphorylates STAT

69
Q

outline the STAT section of the JAK/STAT transduction mechanism

A

STAT - signal transducers and activators of transcription
once STAT is activated (phosphorylated) by JAK it dimerises
once dimerised they enter the nucleus and initiate transcription

70
Q

what happens when IFNy binds to a IFNy receptor (IFN type II signalling)

A

activation of STAT1 via phosphorylation to form a homodimer (opposite of dimerise)

71
Q

what is the function of a STAT1 homodimer and what does it lead to

A

recognises GAS elements in the promoter region of target genes
release of inflammatories
release of macrophage activators
release of chemokines

72
Q

what happens when IFNa binds to a IFNa receptor (IFN type I signalling)

A

a heterodimer of STAT1-STAT2 is formed via phosphorylation
the STAT1-STAT2 heterodimer along with IFN-9 binds to the IFN-stimulated response element (ISRE)

73
Q

what does IFN type 1 signaling cause

A

release of antivirals
release of antiproliferative factors
release of chemokines

74
Q

what is the effect of IL-6 binding to its receptor

A

homodimer of STAT3 is formed via phosphorylation
also binds to GAS on promotor regions of target genes

75
Q

what is STAT-3 activated by

A

cytokines that bind to their corresponding receptor which contains a gp130 chain

76
Q

how are STATS affected directly after ligand binding

A

activated rapidly
recruited to the intracellular domain of the receptor via binding of SH2 and phosphotyrosine residues

77
Q

what does STAT-1/3 promote

A

STAT-1 - promotes apoptosis and anti-proliferatives
STAT-3 - promotes anti-apoptotic effect and cellular proliferation
they are antagonistic

78
Q

what are the similarities between IL-12/23

A

share a p40 subunit and their receptors both possess a IL-12Rbeta1 subunit

79
Q

what STAT’s are involved in IL-12/23

A

IL-12 - STAT-4
IL-23 - STAT-1/3/5

80
Q

what are Th1 cells involved in

A

cell-mediated immunity
intracellular pathogens:
- viruses and certain bacterias

81
Q

what are Th2 cells involved in

A

antibody-mediated immunity
needed to control extracellular pathogens including yeast and worms

82
Q

what are Th1 cells activated by and what do they release

A

activated by IL-12
release IFNy, IL-2, TNF-b

83
Q

what are Th2 cells activated by and what do they release

A

activated by IL-4
release IL-4/5/10/13
release of IL-4 leads to a positive feedback loop

84
Q

how can some viruses and bacteria trick NK/dendritic cells

A

can induce IL-12 secretion to induce IFN-y production
naiive CD4+ T cells activated via IFN-y and IL-12 are committed to become Th1 cells

85
Q

how can some pathogens such as some worms trick NK cells

A

induce IL-4 secretion
naiive CD4+ T cells activated by IL-4 are committed to become Th2 cells

86
Q

what is the predominant activity of dendritic cells in the absence of infections

A

high production of TGF-b
low production of IL-6

87
Q

what are CD4+ T cells in the absence of infection induced to express

A

express Foxp3
present with a regulatory phenotype

88
Q

what do dendritic cells produce during the early stages of infection and why

A

high production of IL-6
CD4+ activated by IL-6 express RORyt and become Th17 cells

89
Q

what is IL-4 employed in the defence against

A

parasitic worms
allergy
asthma

90
Q

what is IL-12 employed in the defence against

A

extracellular bacteria
cancer
autoimmunity

91
Q

what is IFN-y employed in the defence against

A

intracellular pathogens

92
Q

what is TGF-b involved in

A

immunosuppression

93
Q

what is macrophage polarisation driven by and what does it induce

A

driven by cues in the tissue microenvironment
induces cytokines, growth factors and microorganism associated molecular patterns

94
Q

what cytokines are involved in the Th1 response within a tumour microenvironment

A

IFN-y
TNF-a

95
Q

what cytokines are involved in the Th2 response within a tumour microenvironment

A

IL-10
IL-4
TNF-b

96
Q

how is regulation of cytokine signaling performed

A

receptor internalisation
protein tyrosine phosphatases
dephosphorylation of activated STAT’s
recycling of STAT monomers to cytoplasm

97
Q

how are JAKS inhibited

A

SOCS protein

98
Q

how are STATS inhibited

A

PIAS binds to STAT dimers
prevent DNA recognition

99
Q

what is a cytokine inhibitor

A

IL-1RA
binds to IL-1 receptor but does not initiate a response

100
Q

what is the function of the TCR

A

allows T-cells to identify infected or malignant cells

101
Q

how do TCR’s recognise infected/malignant cells

A

interactions with major histocompatibility molecules on the surface of APC’s

102
Q

what is the structure of the TCR

A

a heterodimer
each chains consists of a variable and constant domain

103
Q

what are the APC’s that express both MHC I/II

A

macrophages
dendritic cells
B-cells

104
Q

function of CD4 and CD8

A

they are co-receptors found on T-cells that also bind to MHC to boost TCR signalling

105
Q

what do CD4/8 each target

A

CD4 - MHC class II
CD8 - MHC class I

106
Q

what is the structure of the immunological synapse

A

dSMAC - beneath layer of bulky molecules
pSMAC - middle layer of cell adhesion molecules
cSMAC - uppermost layer of TCR, accessory and siganlling molecules

107
Q

give a summary of how a immunological synapse is formed

A

first pSMAC adhesions molecules bind loosely to the cell, allowing TCR to inspect
if TCR recognises a pMHC clusters of signalling molecules are formed
the T cells polarises and the mTOC moves underneath the synapse

108
Q

what are the pros and cons of using imaging cell-cell interactions to study the synapse

A

pros - optimum image quality
multiple antibodies can be studied at once
cons - cells need to be fixed, so only one time point

109
Q

what are the pros and cons of using GFP tagging to study the synapse

A

pros - multiple time points
cons - large GFP molecules can change the activity of the subject of study

110
Q

what is are the features of the zeta chain of the TCR

A

intracellular chain
has the most binding sites for signalling molecules

111
Q

what are the major SRC kinases in T cells

A

Fyn and Lck

112
Q

what are the first 3 steps of in the synapse formation

A

1 - synapse forms as T cell approached the APC
2 - the TCR recognises the peptide in the MHC and binds
3 - initial signals are sent by phosphorylation

113
Q

outline step 4 in the formation of the synapse

A

CD45 (in dSMAC) is a phosphatase that can remove inhibitory phosphates from kinases - first is Fyn
Structure of SMAC is important for bridging these molecules together - clustering

114
Q

outline step 5 in the formation of the synapse

A

the co-receptors (CD4/8) have another kinase - Lck - on their tail
this is also brought in when the co-receptor binds MHC

115
Q

what are the benefits of using phosphorylation in signalling cascades

A

extremely rapid
no protein synthesis/degradation required
creates binding sites on proteins
rapidly reversed using phosphatase - quick responses

116
Q

what is the function of Fyn/Lck and what does it lead to

A

phosphorylate the ITAMs in the zeta chain
allows ZAP70 to bind
ZAP70 is then phosphorylated
leads to downstream substrate activation

117
Q

what are steps 6/7/8 of synapse formation

A

6 - these kinases (Fyn/Lck) phosphorylate ITAMs on the zeta chain
7 - the pITAMs are bound by ZAP70
8 - ZAP70 is then phosphorylated and activated

118
Q

what is the final step - 9 - of the synapse formation

A

ZAP70 phosphorylates LAT
helps assemble signalling complexes

119
Q

what is LAT

A

a linker for T cell activation

120
Q

what does activation of LAT and SLP76 allow

A

allows the recruitment and activation of phopsholipase C gamma (PLCy) and guanine exchange factors

121
Q

what are the critical mediators of the next wave of signalling after phosphorylation

A

PLCy
guanine exchange factors

122
Q

how does activation of the PLCy pathway occur

A

PLCy has 2 SH2 domains which allow the recruitment to phosphotyrosine residues

123
Q

what is the function of PLCy

A

cleaves PIP2 into IP3 and diacylglycerol (DAG)

124
Q

function of IP3

A

opens Ca2+ channels - allows calcium entry from the ER and extracellular fluid
Ca2+ activates calmodulin

125
Q

what does calmodulin along with DAG activate

A

protein kinase C (PKC)

126
Q

what are the intracellular calcium levels compared to extracellular and how is maintained

A

100,000x lower than extracellular M
pumped out of the cell or into the ER

127
Q

what is the major use for Ca2+ ions in T cells

A

activation of the phospholipase C pathway

128
Q

what do we use to study calcium signalling

A

indo-1

129
Q

function of indo-1 to study calcium signalling

A

when indo-1 binds to calcium it emits a wavelength of 390nm (violet) and when unbound it emits a wavelength of 500nm (green)

130
Q

function of ionomycin

A

it is a calcium ionophore
increases calcium concentration in the cytoplasm

131
Q

what is a small G-protein signal that gets amplified - most important one

A

Ras

132
Q

what occurs to Ras and what is its function

A

recruited and held in place by adapter proteins
adapter proteins are assembled by phosphoLAT
Ras activates the MAP kinase siganlling pathway

133
Q

if an antigen triggering disease cannot be deleted as it is an important protein what can be done

A

we can try to disrupt its binding to the TRC by injecting altered peptide ligands

134
Q

what are altered peptide ligands

A

T-cell epitopes of the peptide with one or two amino acid variations that bind TCR but do not initiate T cell proliferations

135
Q

how do APL’s perform their function

A

once bound to TCR they recruit less src kinases leading to incomplete phosphorylation of ITAM’s
partial activation of ITAM’s leads to activation of only some pathways

136
Q

do APL work in patients

A

no
only really works in vitro

137
Q

what was used to prevent T cells targeting donor organs (immunosuppression)

A

inhibition of calcineurin
first prototype was cyclosporin

138
Q

what is calcineurin

A

Ca2+ dependent serine/threonine protein phosphatase that activates NFAT - key to T cell activation

139
Q

how do calcineurin inhibitors (CNI’s) perform their function

A

CNI’s bind to cytosolic proteins called immunophilins
CNI-immunophilin complex binds calcineurin to prevent its phosphatase activity
NFAT is not dephosphorylated - no T-cell activation - IL-2 release is inhibited

140
Q

do CNI’s work

A

yeah

141
Q

what is belatecept and how is it used to prevent T-cell co-stimulation

A

it is a CTLA4 antibody
extracellular domain of CLTA4 is fused to the Fc domain of an antibody
this Ig binds to B7 at higher affinity than endogenous C28
B7 is not available to interact T cells

142
Q

does belatecept work

A

yes
but cannot respond to actual threats to immune system

143
Q

what is one way in which tumour cells hide from the immune system

A

they upregulate PD1L/2 and CTLA4
meaning that when T-cells come to kill the tumour they recognise the CTLA4 and do not attack (exhausted)
the tumour uses negative co-stimulation

144
Q

what are some drugs that are used to try and prevent tumour cells from using negative co-stimulation to hide from the immune system

A

PDL-1inhibitors
PD-L1inhibitors
CTLA4 inhibitors

145
Q

do negative co-stimulatory inhibitors work

A

yes
but they do not work when the T cells cannot find the tumour - so inhibiting negative co-stimulation does not help - breast cancer

146
Q

what is a side-effect of negative co-stimulation inhibitors

A

autoimmune diseases
cytokine storm

147
Q
A

Biomed Season Finale (11 decks)

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