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CMB2004 > L5-6 > Flashcards

L5-6 Flashcards

1
Q

E3 ubiquitin ligase

A

protein facilitating ubiquitin chain attachment to a target protein

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2
Q

UPP (ubiquitin proteasome pathway)

A
  1. 5 ub molecule chain to protein substrate for 26s proteasome recog
  2. ub removed and protein linearized/ injected into core of proteasome for degradation to peptides
  3. peptidases degrade to amino acids
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3
Q

hypoxia

A

lowering of O2 concentration compared to sea level +/- 20.9%

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4
Q

cellular responses to hypoxia

A

O2 homeostasis restoration
cell survival
cell death

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5
Q

HIF

A

Hypoxia Inducible Factor
heterodimeric txn factor (alpha and beta)

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6
Q

HIF family members

A

1alpha
2alpha
3alpha
1beta

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7
Q

bHLH

A

helix-loop-helix
located on 1a2a3a and 1b of HIF

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8
Q

PAS

A

per/ARNT/sim
on all HIF family members

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9
Q

ODD

A

oxygen dependent degradation domain
on 1a2a3a

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10
Q

NLS

A

nuclear localization signal
on 1a/2a on HIF

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11
Q

HIF 1alpha

A

ubiquitous expression in all tissues
not regulated by O2
HLH/PAS/ODD/NLS/CTAD

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11
Q

HIF2alpha

A

expressed in certain tissues
same as 1alpha

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12
Q

HIF3alpha

A

certain tissues
no CTAD
dominant neg inhibitor of 1alpha/2alpha
activates different set of genes in hypoxia

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13
Q

proline hydroxylases

A

regulate HIF
require O2

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14
Q

HIF 1alpha regulation

A

constitutive RNA pol II transcription of Ch14 gene and translated to protein
res hydroxylation regulates sub-units PTR

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15
Q

HIF 1 alpha in normoxic conditions

A

protein hydroxylase hydroxylates HIF, E3 ubiquitin ligase (Von Lindau Protein) binds
HIF degraded

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16
Q

HIF1 alpha in hypoxic conditions

A

PH doesn’t hydroxylate HIF, therefore Von Lindau protein doesn’t bind
HIF stays

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17
Q

FIH

A

factor inhibiting HIF
does asparagine phosphorylation
requires oxygen

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18
Q

What happens when HIF1alpha is active in hypoxic condition?

A

dimerizes with HIF1beta
activates target gene txn
CTAD can interact with co-activators (p300/CBP)

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19
Q

HIF targets

A

oxygen supply regulation
transcription
cell death
HIF control
cell growth

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20
Q

modular domains of p53

A

Transactivation domain
proline rich
dna binding
nuclear localization sequence
tetramerisation
C-terminal

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21
Q

p53 outcomes

A

apoptosis
tumour suppression
development
stem cell modulation
fertility

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22
Q

mdm2

A

inhibitor of p53
phosphorylated in case of DNA damage/ cell cycle abnormalities/ hypoxia
type of E3-ub ligase

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23
Q

mdm2 function

A

promotes ubiquitination of p53 and proteasome degradation

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24
Q

phosphorylation of mdm2

A

phosphorylated w p53 at ser15 by ATM/ATR kinases, disrupting interaction

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25
Q

mdm2 feedback loop

A

p53 activates mdm2 gene expression, limiting self
therefore inactivation of p53 when mdm2 is overexpressed

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26
Q

ARF

A

tumour suppressor
expression induced by oncogenes

disrupts p53 and mdm2 interaction
binds mdm2 decreasing ub ligase activity

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27
Q

cancer mutations in p53

A

in DNA binding domains

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28
Q

Li-Fraumeni syndrome

A

hereditary
mutation in TP53 (genetic blueprint for p53)

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29
Q

HIF/P53 similarities

A

rapid activation due to constitutive production and activation
proteolysis regulation
both p53/NFkB activated by similar stimuli

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30
Q

differences within NFkB/HIF/p53

A

NFkB involves inhibitor degradation
HIF/p53 degraded continuously

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31
Q

cross-talk regulation

A

RelA can suppress p53 and vice versa
activation of p53 decreases p300 association w RelA so less txn occurs
NFkB can also induce mdm2 expression

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32
Q

what happens to naive T cells after leaving the thymus?

A

they recirculate via secondary lymphoid tissue blood/ lymphatics
Ag/ APC contact > clonal proliferation and differentiation

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33
Q

CD8+ T cells

A

cytotoxic
kill infected cell expressing peptide/ MHC I complexes

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34
Q

CD4+ T cells

A

helper
secrete cytokines
recognize peptide/ MHC II complexes

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35
Q

HEV

A

high endothelial venules

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36
Q

naive T cell circulation

A
  1. enter lymph node via HEV from blood
  2. move into T cell area
  3. inactivated T leave via cortical sinuses to lymphatics and re-enter circulation
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37
Q

CAM

A

cell adhesion molecules
expressed on T surface (chemokine receptors) and bind ligands (chemokines) expressed by other cells
mediate cell/cell interactions of sets

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38
Q

TCR recognition of APC peptides/ MHC complexes

A

TCR complex signal
^CAM affinity
T division
differentiation to effector cells and exit LN for T cell-mediated response

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39
Q

LFA-1

A

Leukocyte Function-Associated Antigen (integrin)
initial binding of T

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40
Q

ICAM-1

A

Intercellular adhesion molecule
initial binding of T cell

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41
Q

lymphoid tissue components

A

lymph nodes
spleen
where T recognize Ag/ MHC on APC
APC’s

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42
Q

naive T cell

A

a T cell that must encounter an Ag for survival

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43
Q

interaction allowing initial APC-T cell binding

A

low-affinity LFA-1/CAM-1 interactions

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44
Q

no. signals required by naive T cell for activation

A

3

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45
Q

signal 1 for naive T cell activation

A

signal from TCR contacting MHC/ peptide on APC
involves CD3 zeta chain

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46
Q

signal 2 for naive T cell activation

A

professional APC’s express co-stimulatory molecules: B7.1/2 binding CD28 expressed by naive T cells

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47
Q

signal 3 for naive T cell activation

A

APC release cytokines binding cytokine receptors upregulated on naive T cells

48
Q

naive T cell activation overview

A
  1. activation > TCR
  2. survival> co-stimulation
  3. differentiation> cytokines
49
Q

requirements for effector T cells to bring about effect

A

no/ reduced signal 2

50
Q

negative feedback co-stimulation

A

activated T cells proliferate and express ICOS/ CTLA-4

51
Q

ICOS

A

Binds ICOSL on APC
induces cytokine secretion
(CD28 related)

52
Q

CTLA-4

A

CD28 antagonist
stronger binding to B7.1/2 than CD28
delivers negative signal to T cell
(CD28 related)

53
Q

CTLA-4 mutations

A

autoimmune diseases

54
Q

CTLA-4 use in clinical settings

A

anti-CLA-4 treatment of Cancer to increase immune response to tumour
e.g. melanoma/ renal carcinoma

55
Q

variation in co-stimulatory expression

A

constitutive in mature dendritic cells
inducible on macrophages/ B cells

56
Q

danger signal

A

APC activation after binding pathogen-associated molecules to receptors expressed for PRR
> APC upregulation of MHC and co-stimulatory molecules

57
Q

danger signal function

A

ensures signal 2 to activate T cell mediated response only occurs during infection

58
Q

cytokine action

A

dictate activated CD4 T cell differentiation into effector cell subsets

59
Q

Th1 cytokines

A

IL-12
IFN-gamma
(differentiates into T-bet cell which produces IL-2/ IFN-gamma)

60
Q

Th2 cytokines

A

IL-4
(differentiates into GATA3 producing IL-4/IL-5)

61
Q

dendritic cells function

A

present Ag
constitutive
activate naive T

62
Q

MHC expression in dendritic cells

A

decrease in immature dendritic
high in lymphoid tissue dendritic cells

63
Q

dendritic cell location

A

throughout body

64
Q

antigen uptake of dendritic cells

A

macropinocytosis
phagocytosis
in tissue dendritic

65
Q

2 types of dendritic cells

A

myeloid
plasmacytoid

66
Q

myeloid DC

A

DC2,3
potent APC
Naive T activation

67
Q

plasmacytoid DC

A

in viral infection
pDC/ DC6
secerete T1 alpha/ beta interferons
express TLR 7/9

68
Q

where are myeloid dendritic cells derived

A

bone marrow

69
Q

immature myeloid dendritic cell location

70
Q

co-stimulatory molecules expressed by myeloid dendritic cells

A

B7
Only when matured/ activated

71
Q

myeloid dendritic cell induction

A

danger signal induces to mature/ migrate to lymph node (T cell areas of lymphoid tissues)
DC MHC I/II loaded w peptides from pathogens in peripheral tissues ^ co-stim/ CAM

72
Q

naive T cell activation by dendritic cells

A
  1. immature DC in peripheral tissues encounter pathogens/ PAMP activated
  2. TLR signalling ^CCR7 and ^processing of pathogen-derived Ag
  3. CCR7 directs migration into lymphoid tissues/ ^co-stim/ MHC molecule expression
  4. mature DC in T zone primes naive T
73
Q

PAMP

A

pathogen associated molecular pattern

74
Q

cross-presentation

A

DC1 processing exogenous Ag and present via MHCI
DC activate CD8 T
CD8 can then kill infected w/o co-stim

75
Q

macrophage MHC expression

A

induced by bacteria and cytokines
inducible co-stimulation delivery

76
Q

macrophage location

A

lymphoid tissue
connective tissue
body cavities

78
Q

macrophage function

A

pathogen scavengers/ killers (phagocytotic)
APCs

79
Q

what do macrophages express?

A

MHC II and B7

80
Q

macrophage activation

A

activated by T cells
produce inflammatory cytokines

81
Q

B cell Ag uptake

A

Ag-specific receptor

82
Q

B cell MHC expression/ co-stim delivery

A

constitutive MHC expression
inducible co-stim delivery

83
Q

B cell location

A

lymphoid tissue
peripheral blood

84
Q

B cell characteristics

A

poor phagocytosis

85
Q

B cell function

A

internalize soluble Ag for processing/ presentation by BCR
BCR Ag binding up-regulates B7> can provide signal 2

86
Q

B cells as Ag-specific APC

A
  1. Ag-specific B cell binds Ag
  2. Ag internalized by receptor mediated endocytosis
  3. presentation of specific antigen fragments
87
Q

interleukin 2

A

cytokine for T cell survival
*naive T has low affin for IL2R until activated and then secretes IL2

88
Q

IL2 binding to IL2R on activated T

A

> much T proliferation

89
Q

IL-2 function

A

rapid T division
expands Ag-specific activated T population
*target of immunosuppressant drugs!!!

90
Q

effector T

A

no co-stim required upon TCR engagement
change adhesion molecule expression
enter tissues not lymph nodes via activated endothelia

91
Q

CD8 T stimulation

A

require high levels of co-stim activity
direct activation by infected/ cross-presented APC

92
Q

clonal deletion of immature lymphocytes

A

results in cell death/ receptor editing/ BCR downregulation

93
Q

non-self Ag B cell activation

A

survival and plasma cell differentiation producing same antibody of BCR
B cells move into blood/ lymphatics after selection

94
Q

B cell activation upon binding to antigens

A

move into circulatory system to lymphoid organs for activation

95
Q

what do activated B cells produce?

A

plasma/ memory cells in bone marrow/ lymphoid tissue

96
Q

humoral response

A

antibody secretion by plasma cells

97
Q

3 effects of humoral response

A
  1. neutralization (bacterial adherence prevention)
  2. opsonization (phagocytosis promotion)
  3. complement activation (c ^ opsonization and lyzes bacteria)
98
Q

B-cell activation

A

naive B cell secretes Ig/ BCR (IgM + IgD) and encounter non-self Ag in secondary lymphoid tissue

99
Q

B cell signal 1

A

Ag binding to BCR
BCR cross-linkage ^ intracellular kinases

100
Q

ITAM

A

Immunoreceptor Tyrosine-based Activator Motif

101
Q

what is an ITAM

A

conserved region in cyto domain of signalling chains in cyto tails of Igalpha/beta

102
Q

B cell signal 1 enhancement

A

C cascade activated by Ag
BCR co-receptor complex
complement receptor and BCR
Ag covered in complex will engage complement receptor 2> augmenting signal

103
Q

2 types of B cell signal 2

A

thymus independent
thymus dependent
(depend on Ag)

104
Q

thymus independent B signal 2 cause and result

A

Ag / extensive cross-linking of BCR > IgM production with no T cells required

105
Q

TI-1 Ag (B signal 2)

A

bind to BCR/ other receptors
act as polyclonal activators of high volume
BCR+TLR= B activation, prolif + Ig secretion

106
Q

TI-2 Ag

A

repeated epitopes
cross-link many BCR on same B cell
e.g. polysaccharide

107
Q

difference between TI-1 and TI-2

A

TI-2 Ag require more Ag to induce B cell activation
both activate B cells producing IgM antibodies> will not induce class-switch Ig

108
Q

what do antibodies to TD Ag require?

A

CD4+ T cells
(absent in thymus absence)

109
Q

TI vs TD Ag Ig response

A

TD Ag Ig response> TI Ag Ig response

110
Q

Thymus dependent Ag development

A
  1. T activated by MHC/ APC peptide
  2. BCR binds Ag (signal 1)
  3. B internalizes, processes and presents to CD4 T CD40/CD40-L
  4. T secretes cytokines
111
Q

product of Thymus dependent Ag

A

all Ig classes produced

112
Q

use of TI Ag> TD Ag conversion

A

increases efficiency of vaccine against pathogens of T1 antigens

113
Q

epitopes recognized by Ig/ T linkage

A

from parts of the same molecule/ different molecules of same complex

114
Q

conjugate vaccine

A

T1 Ag capsular polysaccharide coupled to a protein so is TD Ag > therefore child can be immunized

115
Q

why can children only be immunized by the conjugate vaccine?

A

Ig responses typically develop over 5 years old

116
Q

B/T Cell conjugates

when do these occur?

A

when TD Ag is presented by B to CD4+ T cells at T/B boundary in lymph node

B binds Ag via BCR and presents peptide on MHC class II

then expresses CD40 ligand and secrets cytokines

117
Q

AID

what induces activation induced deaminase? what’s it required for?

A

induced by CD40

required for class-switching/ SHM

118
Q

where do B cells receive signal 2

A

in B cell follicle/ subcapsular sinus of dendritic cell

CMB2004 (4 decks)

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