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CMB2004 > L5-6 > Flashcards

L5-6 Flashcards

(119 cards)

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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
phosphorylation of mdm2
phosphorylated w p53 at ser15 by ATM/ATR kinases, disrupting interaction
25
mdm2 feedback loop
p53 activates mdm2 gene expression, limiting self therefore inactivation of p53 when mdm2 is overexpressed
26
ARF
tumour suppressor expression induced by oncogenes disrupts p53 and mdm2 interaction binds mdm2 decreasing ub ligase activity
27
cancer mutations in p53
in DNA binding domains
28
Li-Fraumeni syndrome
hereditary mutation in TP53 (genetic blueprint for p53)
29
HIF/P53 similarities
rapid activation due to constitutive production and activation proteolysis regulation both p53/NFkB activated by similar stimuli
30
differences within NFkB/HIF/p53
NFkB involves inhibitor degradation HIF/p53 degraded continuously
31
cross-talk regulation
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
32
what happens to naive T cells after leaving the thymus?
they recirculate via secondary lymphoid tissue blood/ lymphatics Ag/ APC contact > clonal proliferation and differentiation
33
CD8+ T cells
cytotoxic kill infected cell expressing peptide/ MHC I complexes
34
CD4+ T cells
helper secrete cytokines recognize peptide/ MHC II complexes
35
HEV
high endothelial venules
36
naive T cell circulation
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
37
CAM
cell adhesion molecules expressed on T surface (chemokine receptors) and bind ligands (chemokines) expressed by other cells mediate cell/cell interactions of sets
38
TCR recognition of APC peptides/ MHC complexes
TCR complex signal ^CAM affinity T division differentiation to effector cells and exit LN for T cell-mediated response
39
LFA-1
Leukocyte Function-Associated Antigen (integrin) initial binding of T
40
ICAM-1
Intercellular adhesion molecule initial binding of T cell
41
lymphoid tissue components
lymph nodes spleen where T recognize Ag/ MHC on APC APC's
42
naive T cell
a T cell that must encounter an Ag for survival
43
interaction allowing initial APC-T cell binding
low-affinity LFA-1/CAM-1 interactions
44
no. signals required by naive T cell for activation
3
45
signal 1 for naive T cell activation
signal from TCR contacting MHC/ peptide on APC involves CD3 zeta chain
46
signal 2 for naive T cell activation
professional APC's express co-stimulatory molecules: B7.1/2 binding CD28 expressed by naive T cells
47
signal 3 for naive T cell activation
APC release cytokines binding cytokine receptors upregulated on naive T cells
48
naive T cell activation overview
1. activation > TCR 2. survival> co-stimulation 3. differentiation> cytokines
49
requirements for effector T cells to bring about effect
no/ reduced signal 2
50
negative feedback co-stimulation
activated T cells proliferate and express ICOS/ CTLA-4
51
ICOS
Binds ICOSL on APC induces cytokine secretion (CD28 related)
52
CTLA-4
CD28 antagonist stronger binding to B7.1/2 than CD28 delivers negative signal to T cell (CD28 related)
53
CTLA-4 mutations
autoimmune diseases
54
CTLA-4 use in clinical settings
anti-CLA-4 treatment of Cancer to increase immune response to tumour e.g. melanoma/ renal carcinoma
55
variation in co-stimulatory expression
constitutive in mature dendritic cells inducible on macrophages/ B cells
56
danger signal
APC activation after binding pathogen-associated molecules to receptors expressed for PRR > APC upregulation of MHC and co-stimulatory molecules
57
danger signal function
ensures signal 2 to activate T cell mediated response only occurs during infection
58
cytokine action
dictate activated CD4 T cell differentiation into effector cell subsets
59
Th1 cytokines
IL-12 IFN-gamma (differentiates into T-bet cell which produces IL-2/ IFN-gamma)
60
Th2 cytokines
IL-4 (differentiates into GATA3 producing IL-4/IL-5)
61
dendritic cells function
present Ag constitutive activate naive T
62
MHC expression in dendritic cells
decrease in immature dendritic high in lymphoid tissue dendritic cells
63
dendritic cell location
throughout body
64
antigen uptake of dendritic cells
macropinocytosis phagocytosis in tissue dendritic
65
2 types of dendritic cells
myeloid plasmacytoid
66
myeloid DC
DC2,3 potent APC Naive T activation
67
plasmacytoid DC
in viral infection pDC/ DC6 secerete T1 alpha/ beta interferons express TLR 7/9
68
where are myeloid dendritic cells derived
bone marrow
69
immature myeloid dendritic cell location
epithelia
70
co-stimulatory molecules expressed by myeloid dendritic cells
B7 Only when matured/ activated
71
myeloid dendritic cell induction
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
naive T cell activation by dendritic cells
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
PAMP
pathogen associated molecular pattern
74
cross-presentation
DC1 processing exogenous Ag and present via MHCI DC activate CD8 T CD8 can then kill infected w/o co-stim
75
macrophage MHC expression
induced by bacteria and cytokines inducible co-stimulation delivery
76
macrophage location
lymphoid tissue connective tissue body cavities
77
78
macrophage function
pathogen scavengers/ killers (phagocytotic) APCs
79
what do macrophages express?
MHC II and B7
80
macrophage activation
activated by T cells produce inflammatory cytokines
81
B cell Ag uptake
Ag-specific receptor
82
B cell MHC expression/ co-stim delivery
constitutive MHC expression inducible co-stim delivery
83
B cell location
lymphoid tissue peripheral blood
84
B cell characteristics
poor phagocytosis
85
B cell function
internalize soluble Ag for processing/ presentation by BCR BCR Ag binding up-regulates B7> can provide signal 2
86
B cells as Ag-specific APC
1. Ag-specific B cell binds Ag 2. Ag internalized by receptor mediated endocytosis 3. presentation of specific antigen fragments
87
interleukin 2
cytokine for T cell survival *naive T has low affin for IL2R until activated and then secretes IL2
88
IL2 binding to IL2R on activated T
> much T proliferation
89
IL-2 function
rapid T division expands Ag-specific activated T population *target of immunosuppressant drugs!!!
90
effector T
no co-stim required upon TCR engagement change adhesion molecule expression enter tissues not lymph nodes via activated endothelia
91
CD8 T stimulation
require high levels of co-stim activity direct activation by infected/ cross-presented APC
92
clonal deletion of immature lymphocytes
results in cell death/ receptor editing/ BCR downregulation
93
non-self Ag B cell activation
survival and plasma cell differentiation producing same antibody of BCR B cells move into blood/ lymphatics after selection
94
B cell activation upon binding to antigens
move into circulatory system to lymphoid organs for activation
95
what do activated B cells produce?
plasma/ memory cells in bone marrow/ lymphoid tissue
96
humoral response
antibody secretion by plasma cells
97
3 effects of humoral response
1. neutralization (bacterial adherence prevention) 2. opsonization (phagocytosis promotion) 3. complement activation (c ^ opsonization and lyzes bacteria)
98
B-cell activation
naive B cell secretes Ig/ BCR (IgM + IgD) and encounter non-self Ag in secondary lymphoid tissue
99
B cell signal 1
Ag binding to BCR BCR cross-linkage ^ intracellular kinases
100
ITAM
Immunoreceptor Tyrosine-based Activator Motif
101
what is an ITAM
conserved region in cyto domain of signalling chains in cyto tails of Igalpha/beta
102
B cell signal 1 enhancement
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
2 types of B cell signal 2
thymus independent thymus dependent (depend on Ag)
104
thymus independent B signal 2 cause and result
Ag / extensive cross-linking of BCR > IgM production with no T cells required
105
TI-1 Ag (B signal 2)
bind to BCR/ other receptors act as polyclonal activators of high volume BCR+TLR= B activation, prolif + Ig secretion
106
TI-2 Ag
repeated epitopes cross-link many BCR on same B cell e.g. polysaccharide
107
difference between TI-1 and TI-2
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
what do antibodies to TD Ag require?
CD4+ T cells (absent in thymus absence)
109
TI vs TD Ag Ig response
TD Ag Ig response> TI Ag Ig response
110
Thymus dependent Ag development
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
product of Thymus dependent Ag
all Ig classes produced
112
use of TI Ag> TD Ag conversion
increases efficiency of vaccine against pathogens of T1 antigens
113
epitopes recognized by Ig/ T linkage
from parts of the same molecule/ different molecules of same complex
114
conjugate vaccine
T1 Ag capsular polysaccharide coupled to a protein so is TD Ag > therefore child can be immunized
115
why can children only be immunized by the conjugate vaccine?
Ig responses typically develop over 5 years old
116
B/T Cell conjugates | when do these occur?
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 ## Footnote then expresses CD40 ligand and secrets cytokines
117
AID | what induces activation induced deaminase? what's it required for?
induced by CD40 | required for class-switching/ SHM
118
where do B cells receive signal 2
in B cell follicle/ subcapsular sinus of dendritic cell

CMB2004 (4 decks)

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