immu2011 Flashcards
1
Q
What is the difference between dendritic cells in the periphery and dendritic cells in the lymph nodes
A
Dendritic cells in the periphery: PRR recognise PAMPs high phagocytic capacity process protein antigens onto MHCs migrate to T cell zones (in response to danger signals like TNF, they move to the lymph nodes) Dendritic cells in the lymph nodes: home to T cell zones, express the required surface molecules to naive T cells: MHC costimulatory molecules cytokines
2
Q
What are 4 main kinds of activatory signals to activate a naive T cell
A
MHC molecules
co-stimulatory molecules
adhesion molecules
cytokines
3
Q
Where does the CD4 co-receptor bind?
A
on the beta 2 chain on MHC class 2
4
Q
Where does the CD8 co-receptor bind?
A
on the conserved alpha 3 chain on MHC class 1
5
Q
What are the functions of CD co-receptors
A
stabilises low affinity binding of TCR to peptide MHC
ensures the appropriate T cell type is activated
6
Q
What is the function of CD3
A
provide an activation signal transduction via ITAM sequences
7
Q
LFA-1 receptor
A
ICAM1 is on the APC
LFA1 is on the TC
8
Q
B7/ CD28
A
B7 is expressed on the DC, and the expression is increased when APC encounters microbial antigen
B7 binds to CD28
Cd28 is found on t cells
9
Q
CTLA4
A
is structurally similar to CD28
It binds to B7
it is expressed on some T regs
10
Q
PD-1
A
also structurally related to CD28
found on T cells
binds to PD L1 and PD L2 on APC
They function to terminate responses of these cells
11
Q
Why are co-stimulators so important
A
Resting APCs, which have not been exposed to microbes or adjuvants, may present peptide antigens, but they do not express costimulators and are unable to activate naive T cells. •T cells that recognise antigen withoutcostimulation may become unresponsive (anergic or tolerant) to subsequent exposure to antigen. •Microbes + cytokines produced during innate immune responses to microbes, induce the expression of costimulators, (e.g. B7 molecules) -The B7 costimulators are recognised by the CD28 receptor on naive T cells, providing signal 2. -In conjunction with antigen recognition (signal 1), this recognition initiates T cell responses. •Activated APCs also produce cytokines that stimulate the differentiation of naive T cells into effector cells (more in our next lecture)
12
Q
following signalling, which genes are up regulated that are required for T cell proliferation and differentiation
A
The high affinity IL2 receptor (CD25 or IL2-alpha) and the IL2 itself
the naive T cells express a low moderate affinity interleukin called IL-2Rb
13
Q
What are some markers that identifies regulatory T cells
A
They are CD4+ and may express FoxP3
14
Q
How does T regs suppress immune responses
A
IL2 binding to CD25 on Tregs induces IL10 production. IL10 is an anti-inflammatory, immune modulating cytokine
They could out compete naive T cells for Dendritic cells and IL2 and suppress T cell proliferation
Function of FoxP3 is not completely clear, but it may cooperate with NFAT to activate CTLA4 transcription
Control inflammation and autoimmunity
and apparently could facilitate tumour escape from immune system
15
Q
how is Th1 activated
A
bacteria binds to an APC, and the APC would release IFN-gamma and IL12 to the naive T cell to upregulate T bet. This causes it to become Th1
16
Q
What do Th1 do?
A
They upregulate IFN gamma and upregulate macrophages +classical activation of macrophages and B cell recruitment and cause B cell to class switch to IgG.
17
Q
How are Th2 activated
A
a protein antigen or helminth binds to an APC. The APC would secrete IL4 which upregulates GATA3 which would upregulate Th2
18
Q
what do Th2 do
A
they secrete IL4 and IL13
IL4 and IL13 to macrophages would cause them to enhance tissue repair
IL4 to B cells would produce IgG4 in human and IgE. IgE drives mast cell degranulation
Th2 could also secrete IL4 and IL13 which causes intestinal mucosal secretion and peristalsis
IL5 causes eosinophil activation
19
Q
How are Th17 activated
A
Bacteria causes APC to release TGF beta, Il6 and Il23,
This causes upregulation of Ror-gamma T
20
Q
What do Th17 do?
A
They release IL17 and IL22 on tissue cells.
IL17 causes inflammation and neutrophil response, and the production of antimicrobial peptides. IL22 causes tissue cells to have increased barrier functions
21
Q
Th1 host defense against
A
intracellular microbes
22
Q
Th2 host defense against
A
helminthic parasites
23
Q
what kind of disease happens if Th1 is not appropriately controlled
A
autoimmune diseases; tissue damage associated with chronic infections
24
Q
What kind of disease happens if Th2 is not properly controlled
A
allergic diseases
25
What happens to activated CD8+ T cells
it leads to an upregulation of integrins, selectin ligands and chemokine receptors
the endothelial cells at the site of infection are induced by cytokines such as TNF and IL 1 to express selectins and ligands for integrins
26
what do granzymes do
They cleave caspases and induce apoptosis
27
what do perforin do
create holes in plasma membrane and facilitates entry of granzymes into target cell
28
Fas ligand
binds to fas or CD95 on infected cell
| binds to Fas which triggers caspase activation
29
what are the light chains made of?
1 constant domain and 1 variable domain
30
what are heavy chains made of
1 variable and 3 to 4 constant domains
31
what is the hinge region of the antibody
it basically allows variable regions to come closer together or further apart to bind epitopes close together or far apart on an antigen
32
Where are follicular B cells found
through the follicles of secondary lymphoid organs
They make up the bulk of T dependent, class-switched and high affinity antibody responses
33
Where are marginal B cell zones located?
In the peripheral region of the splenic white pulp
34
Where are B-1 cells found?
mucosal tissues and peritoneum
35
What are features of both B cells and B-1 cells
marginal zone B cells and B-1 cells express antigen receptors of limited diversity
They respond largely to polysaccharide and lipid antigens
They make predominantly T independent IgM responses
IgM antibodies produced spontaneously by B-1 cells, are sometimes called natural antibodies
they help clear apoptotic cells and may provide protection against some bacterial pathogens
36
How do naive Th cells make it to the t cell zones
Naive T cells express CCR7, and it allows them to home to CCL19 and CCl21 in the T cell zones.
Activated effector T cells lose CCR7 and upregulate other chemokine receptors that allow them to home to the periphery
37
what do naive B cells express to allow them to migrate to B cell follicles
They express CXCR5 which may allow them to migrate towards CXCL13 expressed in B cell follicles
38
How do newly activated B cells move to T cell zones
newly activated B cells lose CXCR5 and up regulate CCR7
the same chemokine expressed by naive T cells
this enables B cells to home to the T cell zones by migrating towards CCL19 and CCL21
39
How is the affinity often expressed?
Kd
The concentration of antigen required to occupy half the available antibody molecule in a solution.
The lower the Kd, the higher the affinity
40
outline the processes that make B cells mature (stages of humoral immunity)
1) extrafollicular response
| 2) the germinal centre response
41
Where does somatic hypermutation take place?
germinal centres
42
What happens in the dark zone and light zone of the germinal centre reaction
darkzone
does not contain any FDC or T cells
It is densely packed with rapidly proliferating B cells,
in the light zone
the small non-dividing progeny of B cells migrate to the B cells
They come into close contact with the process of the abundant Follicular dendritic cells and T follicular helper cells
(somatic mutation and affinity maturation/isotype switching happens in the light zone)
43
Where are follicular dendritic cells found?
They are only found in the lymphoid follicles
44
How are follicular dendritic cells different to normal dendritic cells
They present antigen on MHC to T cells
| I think this is a typo, FDCs should only be presenting to B cells
45
Follicular Dendritic cells role
involved in displaying antigens for the selection of germinal centre B cells
They present the antigen bound antibody complex
They provide survival signals to the B cells withich would outcompete others for binding to the antigen being presented. B cells that receive no signal die.
46
What is the most common kind of white blood cell in the blood
neutrophils, accounting for 40 to 60%
47
how do immunologists identify immune cells
cell morphology
expression of surface molecules
48
Do mast cells have a myeloid progenitor
no, they enter tissues as immature mast cell progenitors
49
Where are mast cells found and what do they do
They are found in peripheral tissues exposed to environment and degranulate cytokines/histamine
50
What do eosinophils fight
parasites and helminths
51
Where are eosinophils found
mucosal linings of respiratory, gastrointestinal and genitourinary tracts
52
how are basophils different to mast cells
usually not found in peripheral tissues
| and has to be recruited,
53
neutrophils
```
not normally found in tissues,
infiltrate inflamed peripheral sites
phagocytosis
cytokines that promotes inflammation and recruitment of other cells
promotes phagocytosis by macrophages
```
can kill bacteria by entrapping them in extracellular structures called NETs
54
innate lymphoid cells
like T cells, they can provide early defense against infections and interact with adaptive immune system
ILC1 provides defense against viruses
ILC2 promote allergic inflammation
ILC3 provide intestinal barrier function
55
NK cells
if microbes breach epithelia
| they can play a very important role in antiviral and tumour immunity
56
What are the 2 only primary lymphoid tissues
bone marrow and thymus
57
what happens in the primary lymphoid tissues
lymphocytes first express antigen specific receptors
lymphocytes attain functional maturity
58
What happens in the secondary lymphoid tissues
lymphocyte response to antigen initiated and developed
59
In adults where do most blood cells come from
flat bones
60
What happens in the bone marrow for B cells
B cell maturation
gains antigen specific receptors
plasmablasts (mature antibody secreting B cells) also come back to the bone marrow
61
What happens in the thymus?
cortex-contains dense T cells
medulla-T cells, DCs and macrophages
central tolerance is acquired for T cells.
There are cells called MECs which express autoimmune regulators that cause the clonal deletion of reactive T cells
62
what happens in the spleen
blood recirculation, lots of blood borne antigens are trapped. Lots of phagocytes as well
63
the spleen architecture
t cell rich, b cell rich, red pulp, white pulp
The B cell zones are further away from the blood vessel of the T cell zone.
64
What happens in the marginal zone
marginal sinus, has a few dendritic cells.
Transit zone. Cell moving from blood to white pulp.
We have macrophages
65
adaptations of the epithelium that helps us
```
stratification adds cellular layers
Keratinisation hardens uppermost layer
mucus secretion
cilia
tight junctions
antimicrobial peptides
```
66
alpha and beta defensins
alpha defensins
small cationic proteins that could basically activate immune signalling or directly kill stuff
alpha is produced by antimicrobial cells like paneth cells or leukocytes
mucosal epithelial cells generally secrete beta
67
structure of defensins
cationic, beta sheet rich
68
TLR structure
leucine rich repeat ectodomain
for ligand binding.
A transmembrane domain for anchoring
and toll interleukin 1 receptor for cytosolic signalling
69
In flies, tlr has
developmental roles and immune roles
70
what is the TLR signalling pathway
TLR=>TIR
recruits adaptor proteins such as MAL and MyD88 which cleaves IKKa to p65 and p50 which then go activates the nucleus (NFkB pathway)
can also activate TRIF/TRAm pathway for IRF3
71
What does NOD1 sense
mesodiaminopimelic acid
mainy gram negative bacteria
NOD1 is expressed in gut epithelia
72
NOD2
senses mostly muramyl dipeptide
gram -ve and gram positive bacteria
typically expressed by leukocytes and specialised immune cells
73
RIPK2
phosphorylate stuff to activate NFkB
74
body guard concept
you could have these nod like receptors activate innate immune system like NOD receptors
They use the same is LRR
75
NFkB
IKK complex formed.
| This then phosphorylate IKb subunit and then release p50 and p65.
76
homing definition
blood to specific site
77
migration or recruitment
general leukocyte movement from blood into tissues
78
recirculation
blood into secondary lymphoid organs into blood
79
What does TNF and IL1 do to endothelial cells
They stimulate endothelial cells to rapidly express E selectin and P selectin, and this causes leukocytes which express selectin ligand to roll. Leukocytes therefore then express integrins which further causes the cells to roll
80
How do leukocytes bind to High endothelial venules
HEVs have addressins such as PNAd -a ligand for L selectin
81
how do naive T cells return to blood anatomically
efferent lymphatics,
through the lymphatic vasculature
finally into the superior vena cava or subclavian vein
82
How do naive T cells find their way into lymph nodes?
L selectin receptor on HEV binds to L selectin on naive T cells
Naive T cells express a CCR7 receptor
that is attracted to CCL19/21 expressed by HEV
T cells express LFA1 integrin that can also bind to ICAM 1 on HEV
83
chemokine common functions
+ve charge so they could bind to extracellular matrix and remain localised near secreting cells
they create a chemokine gradient
84
general features of tumour necrosis factors
trimeric complexes
membrane bound and soluble forms
cytokine ligands are expressed as membrane bound proteins and released by proteolytic cleavage
85
What is TNF a
a powerful pro inflammatory cytokine
86
What are the main producers of TNF a
macrophages
87
What do TNF a bind to
TNFR1 most mammalian cells
| or TNFR2 restricted to immune cells
88
TRADDs
TNF receptor associated death domain-activates caspase pathway
89
TRAFs
TNF receptor associated factors
| activate NFKB transcription factors that can cause survival and cytokine expression
90
Interferon function
up regulate genes that protect neighbouring host cells from infection like
proteases and nucleases
they can activate immune cells-kill me signal
they can upregulate antigen presentation to T lymphocytes
91
interleukins
communicate between leukocytes.
signal through receptors and jak stat pathway
92
What are the hallmarks of the innate immune system
```
speed
duration
repetitive
interactive
non-reactive
```
93
haustoria
feeding structures of stuff like rust which do not penetrate through plasma membrane
94
PTI
weak immune response that commonly involves callose deposition, production of antimicrobial compounds and defence proteins
95
ETI
rapid/robust and causes the hypersensitive reaction also known as programmed cell death
96
gene for gene hypothesis
if the antigen is avirulent and the host is resistant, there is low immunocompatibility and the host could be infected.
avr1avr1 is the virulent strain
97
Why is the gene to gene hypothesis important?
a low IT (incompatible) suggest the presence of at least one pair of either the avirulence and resistance genes in the host and pathogen
98
resistance exists on a continuum
host
intermediate host
intermediate nonhost
nonhost
99
Complementarity determining region
where the antigen binds
100
how many different kinds of light chains are there?
kappa and lambda, they differ in constant domain
101
how are different epitopes of protein antigens recognised?
sequence of amino acids
3D shape of protein antigen-conformational epitopes
102
affinity
strength of binding between one antigen binding site on an antibody molecule and its corresponding epitope
Affinity is often expressed as the dissociation constant
The lower the Kd, the higher the affinity
103
avidity
overall strength of the interaction between the antibody and its antigen
depends on both the affinity and valency of interactions.
cross reaction
104
how many valencies does have IgA have
4?
105
What affects avidity
valency
affinity of antibody for the epitope
structural arrangement of the parts that interact.
106
rheumatic fever
some people are infected with strep throat
after such infections, individuals produce anti-strep throat antibodies that cross react with an antigen in heartmuscle
and this may cause an inflammatory disease called rheumatic fever.
Other individuals making anti-streptococcal antibodies that deposit in kidney glomeruli causes post streptococcal glomerulonephritis
107
in what ways are the T cell receptors for antigen similar to BCR
membrane bound, constant regions
| variable regions
108
What unique features of the TCR make it different to BCRs
two chains, alpha and beta chains
| no heavy and light chains. Slow on rate, slow off rate.
109
How are DCs activated
after sensing TNF or IL1, the DC migrate from the periphery to draining lymph nodes
110
What are the steps in which lymphocytes are activated?
1) recognition of peptide and MHC
2) Co-receptors
3) adhesion molecules like LFA1 and ICAM1
4) positive costimulation
111
where are follicular B cells found
in secondary lymph nodes in follicles
they are t dependent
112
where are marginal b cells found
in the peripheral region of the splenic white pulp
113
what are B1 cells
B cells that are responsive to mostly polysaccharide and lipid
mostly express IGm and are found in mucosal tissues and peritoneum
114
how do T cells move towards periphery
activated effector T cells lose CCR7 and up regulate other chemokine receptors that allow them to home to the periphery: they respond to either CCL19 or CCL21
They upregulate CXCR5 which basically gets them to move closer to CXCL13 expressed in B cell follicle
115
What do activated B cells express to make them move towards the margin
activated b cells lose CXCR5 and upregulate CCR7. The same chemokine expressed by naive T cells
This enables B cells to home to the T cell zones by migrating towards either CCL19 or CCL21
116
What is the effect of the upregulation of CD40 on activated B cells?
allows the B cells to receive additional help from the already activated T cells
T cell provides CD40L TO cd40 on b cells causing class switching and shit to happen
117
similarities and key differences between marsupial with monotremes(platypus) and eutherian mammals (like humans)
similarities: bone marrow, spleen, lymph node, MALT
key differences: thymuses, spleen, timing of immune development
118
Thymus differences between polyprotodont marsupials (like devil and opossum) against diprotodont marsupials (like wallaby and wombat)
polyprotodont have thoracic thymus vs
diprotodont which have a cervical and thoracic thymus.
119
thymus of different animals with us and rats
basically the same thing,
cervical and thoracic thymus structurally and functionally similar to eutherians
mature thymus-cortex/medulla and Hassal's corpuscles
T lymphocyte development:
gene expression studies
thymectomy-lymphocyte depletion and delayed antibody response
120
Development of the immune system between monotremes, marsupials and eutherians
marsupials are immunonaive at birth and the immune system develops within non-sterile pouch
born early developmental stage
mammals are born at a late developmental stage
immunocompetent and birth
immune system develops within sterile uterus
121
Development of marsupial immune system in more detail
1 month: thymus and bone marrow
3 months: spleen and lymph node
4-5 months: MALT
122
how are marsupial newborns protected in the pouch
They are protected via passive immunity by milk
which transfers IgA in the first phase
Then they start getting IgG transfer.
123
protection in the pouch
expansion of antimicrobial peptide genes in marsupials and monotremes.
e
124
are immune cell populations in marsupials and monotremes same as mammals
yup pretty much exactly same. Have CD4, CD4 and CD8.
They do have different antibody markers.
125
functional difference between mammal and marsupials/monotremes
the level of response differs
mouse=800
platypus=30
126
difference between marsupial and monotreme TCR
they have a fifth TCR chain-mu
this is unique to marsupials and monotremes
we don't have a gene that produces mu
mu gene has no vdj recombination.
2 isofroms of mu TCR in marsupials and only 1 isoform in monotreme
127
difference between eutherian and (marsupial and monotreme TLRs)
they have the same TLR repertoire as eutherians except TLR1 and TLR6 could not be identified
Unique TLR1/6 like not found in eutherians
Ancestral gene
Duplicated and evolved into TLR1 and TLR6
tlr1 and tlr6 basically combined.
128
difference in mhc
mhc class 1 gene UT only found in marsupials and monotremes. They are highly duplicated
MHC genes for marsupials and monotremes dispersed everywhere. For monotremes some are located on sex chromosomes
129
difference between immunoglobulins
marsupials don't have IgD.
montremes have the same as humans
Diversity in the other animals are lower:
marsupials have limited heavy chain diversity so the light chain compensates
The platypus have limited heavy and light chain diversity
130
DFTD
clonal cell line
arose from a schwann cell in a female devil
we know its from a female because it has genes normally found on x chromosome and no sry gene
131
Why is DFTD not recognised?
hypothesis 1: DFTD is seen as self because devils lack diversity at MHC genes
hypothesis 2: DFTD evades the immune system by down regulating MHC expression
132
is MHC diversity low
yup they gone through lots of bottlenecks and lots of alleles have been lost. Lots of Devils are like clones, very limited pool of MHC
3 population crashes in european arrival.
133
What devils are more susceptible
angiogenesis
134
skin graft histology
allograft rejected even though MHC of the 2 devils were almost identical
lymphocyte infiltration-immune activation and rejection of foreign cells
they have functional MHC diversity and can distinguish self from non-self
135
DFTD downregulates MHC1 expression
MHC 1 and genes essential for antigen loading and presentation (TAP 1, TAP2 and B2M) show low/no expression in DFTD.
it basically acetylate the chromatin on these cells
136
devil immune system and age
lymphocytes in devils decline with age
lower anti cancer response
TCR diversity declines with age
137
NK cells DFTD
devil NK cells may require anti DFTD antibodies for activation resulting cytotoxic response. So no anti DFTD means that there may be no NK cell response
138
DFTD immunotherapy
DFTD-treat DFTD cells with interferon gamma which induces MHC 1 expression and makes stuff visible to the immune system. Testing in captive and reintroduced devils the antibody response.
current formulations require multiple injections and trapping is difficult
devils are elusive and trap shy.
139
why is DFTD so difficult to treat
it could evolve
are DFTD functionally different? nope
Is DFTD more or less aggressive. Double the amount of genetic material-slows tumour development, increase in polymorphism, and masks deleterious mutations
slow growing tumour more aggressive
140
insurance program
intensive program
free range closure
peninsula islands
genetic
141
controlling plant diseases
cultural practices
breeding
fungicides
142
what is wheat
a hexaploid: A, B, and D
aabbdd
3 hybridisation events
143
Sr26
gene for stem rust resistance gene.
Sr26 is transgenic...
cultivated from a different cultivar.
144
How do breeders select how to breed stuff
breeders want resistance that is easy to select, minimise yield loss and is durable
do it by phenotyping.
basically you infect them with rust then phenotyping.
backcrossing/germplasm
iterative resistance gene try to get into the plants.
145
multigenic resistance
massive populations reached
this is done by genetic engineering
genome sequencing
pull out eti and stick them together.
isolate 5 resitsance genes and then reinsert them as basically one large glued chunk into the wheat genome
it is considered cisgenic, because it is a gene from the same kind of plant.
