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Lecture 4 Flashcards

1
Q

why is microbial dna recognized in our immune systems but our host rna not usually

A

methylation: bacterial dna is methylated

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2
Q

what would happen if you take foreign rna and then you inject it into a mice

A

If you took rna and youin ject into a mice, it would develop a robust immuneresponse aka that’s problematic= compromises its ability to be transcribed into proteins that can be used for vaccination or vaccine candidate

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3
Q

How can we suppress the immune response to foreign RNA?

A

-use tnf-a in a cell line
-lipifectin : detergent, lipophilic, so that it can get into the cell: was the empty vector to carry the rna into the cell
-We need the rna to get into the cell so that it can then be translated

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4
Q

Mammalian RNA was pretty much the same as us except for…

A

Mammalian RNA was pretty much the same as us except for mitochondria rna because it is the closest to bacterial rna aka the powerhouse. If the mitochondria is in trouble, then the cells are in trouble

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5
Q

experiment with the immune response and foreign rna: results

A

-They had basically no baseline induction of TNF-a and when they gave PolyIC which is a agonist of different TLR like tlr 7and R-848 which is another agonist that activates TLR-7 and TLR-8 to mimic a viral sensing that induce a robust TNF-a response
-If they just generated naked RNA in vitro and then gave rnase to degrade that rna, they don’t get a response, it is a nice control
-When they looked at mammalian rna, they found very similar effect of the lack of a response to this, except for mitochondrial rna because we acquired mitochondria from bacteria

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6
Q

what happens if the mitochondrial membrane is compromised

A

got compromised and that the mitochondrial DNA got out of the mitochondria, we would get a strong immune response

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7
Q

true or false: rna modifications have different immunostimulatory capacities

A

true

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8
Q

rna can be modifies through…

A
  • different processes like methylation and that this could then shape how it is able to become recognized by different TLRs
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9
Q

true or false: viruses can alsi modify their rna to be able to not be sensed by bacteria ex: bacteriophages

A

true

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10
Q

true or false: tlrs only respond to one thing

A

false they respond to different modifications

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11
Q

Different modifications to a greater extend lead to ….

A

Different modifications to a greater extend lead to certain TLR activation ( TLR 3,7 and 8)

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12
Q

what are the advantages of cell lines

A

-highly control systems: we know exactly what they are going to express
-primary cells are harder to get
-easier to to access

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13
Q

disadvantages to cell lines

A

-we don’t have the normal beig activated in cell lines
-We basically fuse them to a tumor cell which makes them proliferate but we don’t get the normal pathways because they are disturbed due to the tumor cell
-We dunno if these signaling pathways that are working in cells lines will be able to work in primary cell lines
-Primary cell like: use your blood or tissue

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14
Q

true or false: certain modifications to rna will completely eliminate responses

A

true

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15
Q

Certain modifications to RNA will completely eliminate response because some of the modifications: how did they come to that conclusion

A

-There was this particularly this modification where they combines the methylation of the arginine M6A and the pseudo uridine, when they put those 2 thing together on the same rna they completely eliminated the response
-But if they took rna that had the either of these modifications and then mixed these 2 cells: they still got a response
=There is an additional signal that is inhibited by the combination of the pseudo uridine and the methylated arginine on the same rna as opposed to individual because just mixing the 2 together still elicited the response too
=Whatever happened with the pseudo uridine was not sufficient to inhibit the response same with the methylated arginine

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16
Q

what are rlr able to recognize?

A

viral dsdna that has the M6A modification

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17
Q

true or false: there is only one type of DCs

A

false there are 2

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18
Q

true or false: different dc respond differently depending on the stimulus they receive

A

true

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19
Q

dc2 usually produce…

A

Dc2 will usually produce INF-a and not type one interferon

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20
Q

true or false: one modification will elicit one type of response in one dc but to in the other type

A

true

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21
Q

The capacity of RNA to induce DCs to mature and secrete cytokines depends ….

A

The capacity of RNA to induce DCs to mature and secrete cytokines depends on the DC subtype and the characteristics of nucleoside modifications present in RNA

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22
Q

The Rig like receptor activated a unique pathways independent of….

A

The Rig like receptor activated a unique pathways independent of MyD88 that acts through MABS which then stimulate mitochondrial activation to release factors from the mitochondrial membrane go to the nucleus and then stimulate type 1 interferon production, but this has no antiviral activity in and of itself, this is a 2 step process: fundamental to understand how we fight viral infections

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23
Q

what is a paracrine system

A

it is basically when one infected cell is like omg I am infected by secreting type 1 interferon so that the other cells can kill it

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24
Q

Type 1 interferons signals to other cells that

A

Type 1 interferons signals to other cells that secrete interferon stimulated genes, those genes have direct antiviral activity to kill the infected cells

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25
name 2 polarizing cytokines for th1 differenciation
IL-12 and TNF-a they are polarizing cytokines that promote TH1 differentiation, promote cytotoxic T cells to kill virally infected cells which is enhanced by type 1 interferons
26
what is signal one?
when apcs present the antigen on their mhc
27
When you add modified RNA, the getting ready for action is taking... and what happens
-When you add modified RNA, the getting ready for action is taking more time? So you get less costimulatory cytokines -It downregulates MHC expression and the expression of costimulatory cytokines
28
What would be the gold standard of really identifying whether these cells can activate T cells?
-Coculture them with T cells to see if they would activate T cells -An antigen to activate the T cells: they use basic antigens that are recognized easily by pretty much mhc ex: covid -The RNA is not the antigen because it is not a peptide which is what is presented on MHCs
29
true or false: the covid vaccine was based on the fact that a single rna modification would turn off the immune system
true The covid vaccine was based on that since they made only one modification so that the vaccine can kinda hide from the immune system so that it can proliferate
30
Explain the difference between gain of function and loss of function experiment: and why do we use that
-Loss of function: You ko smth out and you see if it did smth that you wanted or not: only says that it is necessary or not for the response that we are testing -Gain of functions, it shows that it is only that that can get smth to happen, whether it is sufficient
31
What are 3 tests that one could perform in vitro to assess the immunogenecity of a vaccine candidate
-Cytokine production by DC -Flowcytometry to measure costimulatory molecules -Meseasing t cell activation by DC
32
Kariko paper: what are the 3 factors that dictate whether the cells produce inflammatory cytokines to dna or rna
-Modification to rna/dna -Presence of correct tlr in the cell -Location of where the cell is because some will have different attributes in the tissues -How the cell is exposed to the rna ex: extracellular, intracellular
33
Define physiological inflammation and how it i helpful
-Baseline inflammation of your body: baseline of inflammation where our body sense -Gut and the mucus layer: it was always activated and would always make mucus and new cells to keep our commensal microbes and pathogens at bay
34
what is natures little secret and why
-Dendritic cells because they are natures adjuvants -They have the ability to boost the adaptive immune response
35
which type of t cell mediated the expulsion of helminths
th2
36
what is a common mouse helmintsh model for human for human hookworm infections
nippostrongylus Brazil lens is a model of human hookworm infection hookworms
37
facts about nippostrongylus Brazil lens
Don’t replicate in the host the larvae will sit in the skin and then get into bloodstream and into lungs because you will cough them up and swallow them back, and then we get them back into us into the intestines and make eggs and then we poop the eggs and then the cycle starts again There are some worms that we can swallow the larvae and they embed into our intestinal wall, they grow as adult worms and the reemerge as adult works and lay eggs
38
true or false: nippo is a rat parasite
true
39
true or falseL: IL-4 is important for anti-helminth immunity
true
40
what happens if you ko IL-4 and IL-13 in the mouse
-you can see that at day 6, 10 and 14 that there still worms in their intestine -IL-13 is the most important to yeet out these worms -IL-4 and il-13 are mostly produced by cd4 T cells
41
which cytokine that is not il-4 and il-13 is also induced in nippo infection
IL25 infection but it was only produced by epithelial cells, if deleted then the same phenotype as if we ko il4 and il13. You still had lots of worms
42
il25 if made by epithelial cells then it must activate....
il25 if made by epithelial cells then it must activate TH2 cells to make IL-4 and IL-13 which will lead to worm infection
43
If we take wt cells and infect them compared to rag KO cells, these rag cells willll......
still have lots of worms in their intestines after 10 days
44
what does rag do?
it does vdj recombination on the T and B cell receptor so if we don't have it then B and T cell can't be selected
45
what happens if you give il-25 to the wt mice that are infected for nippo from day 0
it enhanced the expsulsion of worms in wt mice
46
what happens if you give il-25 to the wt mice that are infected for nippo from day 0
it enhanced the expulsion of worms in wt mice
47
what happens if you give il-25 to rag ko mice
the worms are also expelled
48
true or false: if you give il-25 then there is no need for T and b cells
true
49
true or false: there was a mysterious cell in the helminth expulsion that released IL-22
false it was a mysterious cell that released il-13
50
where was the mysterious cell located that secreted il13
she saw weird lumps in mesoteric fats that lines that the lymphatics ans the vasculature that drain from the gut to the liver
51
what did the weird lumps look like
that looked like lymph nodes: fat associated lymphoid clusters
52
what is the granularity amd size of lymphocytes
they are not so big and not so granular
53
true or false: phagocytic cells have cytoplams while lymphocytes don't
true
54
what was the conformation that the wuirky cells were in fact lymphocytes
they expressed cd45 so that means they are lymphocytes and that they are derived from the bone marrow
55
which cytokines do the quiky cells express
il-7 which are expressed in all lymphocytes
56
IL-7 receptors are part of a family of the common.....
IL-7 receptors are part of a family of the common gamma chain cytokine family
57
mice that are ko for IL-7 have what?
they don't have lymphocytes
58
why do il-7 ko mice don't have lymphocytes
that's because common gamma means that this receptor unit is shared by a lot of different cytokines and that it is important for lymphocytes development
59
Mice that are KO for these cytokines do not have lymphocytes, why?
That’s because common gamma means that a lot of different cytokines shares this receptor unit and that it is important for lymphocyte development
60
common mechanism of cyokine signalling
-cytokine binding cross links adjacent receptors and tyrs/jaks crpps phosphorylate eachother on tyrosines -activated jaks phosphorylated receptors on tyrosines -after stats dock on specific phosphotyrosines on the receptor, the jaks phosphorylate them -stats dissociate from receptor and dimerize via their sh2 domains -stats migrate to nucleus, bind to DNA and other gene regulatory proteins -target gene expression
61
how many cytokines shate the common gamma chain receptor subunit
6 -They all have that subunit but they all have unique specific receptor subunits that pair with it and signal uniquely through the cell -And because they have these specific sububits that not only determine specificity of their binding to the cytokine but also determines the specificity of thet stat(signal transduction activator of transcription) that they can use
62
which cytokines are important for the devlopment and maintenance of naive lymphocytes T and B
il-2 and il-7
63
They found that when they stimulated these quirky cells with IL-2
it did not do much, it expanded the cells and that’s it aka activated but not differentiated
64
what happened when the quirky cells got added il-2, 25 and 33
Added IL-25 and IL-33, it potently induced IL-5 and IL-13 but did not induce interferon gamma expression
65
true or false: th1 cells make inf gamma
true
66
what are the characteristics of the quirky cells
-not macrophage, T or B cell Small Not much cytoplasm agranular Expressed CD45 means they are from bone marrow Expressed the IL-7 receptor alpha high : expressed on all lymphocytes
67
true or false the quirky cells responded too typical chemokines like IL-1 and Il-7 and but not IL-2
They noticed that the cells responded to typical chemokines like IL-2 and Il-7 and but not IL-1
68
true or false: the quirky cells produce inf gamma
true
69
Indirect evidence of ILC2 function in vivo
-They injected recombinant IL-33(potent inducer of type 2 cytokines) and PBS into a mouse that is rag KO aka they don’t have T and B cells-> they could detect IL-5 and IL-13 in the sirius -When they did the same in mice that were rag 2 deficient and gamma C ko aka no T and B cells and no IL-2,4,7,21 signalling they no longer saw IL-5 and IL-13 -This suggested that these cells were responsible for this because they induced the cytokines in the absence of T and B cells butr they still needed the common gamma chain since these cytokines drive T and B cell development
70
true or false: il-33 stimulated il-13 and what does it do
true Because IL-33 stimulates IL-13 to be secreted by these cells to then act on the intestinal cells to differentiate into goblet cells and mucus produced by the goblet cells is a part of the weep and sweep response, the weeping being the mucus being secreted into the gut to help push out the worms and the sweep is the rapid turnover of the inertinal epithelial to push down the waste through the intestines
71
direct evidence of ilc2 function in vivo : types of ko they used
Instead of only injecying IL-33, they infected mice with nippo and they looked at various times in the serum for IL-5 and IL-13 and they saw after infection of -WT they saw a nice induction of IL-5 and IL-13 -Rag ko: still saw IL-5 and IL-13 -double KO (rag and gamma chain) they did not
72
Can we take these cells and put them into gamma C and rag KO to see if it restores to get IL-5 and IL-13?
-Yes they used infected nippo mouse and the special cells -Ended up having induction of IL-5 and IL-13 -This shows that these cells are required and sufficient to drive the production of IL-13 in these animals
73
what is the difference with direct and indirect
-direct: when you KO rag and gamma c you are KO other cells that we dunno what they are the mice get severely immuno suppressed, humans would probs die too -direct you take the same mice that is KO and you simply restaure one population that you ate interested in and that's sufficient
74
The helminth is inducing IL-33 or IL-25 by a subset of cells called .....
The helminth is inducing IL-33 or IL-25 by a subset of cells called tuft cells and those cells sense the worm, secrete IL-25 and activate ILCs to act back on the epithelium to induce goblet cells differentiation
75
ILC are receiving signals such as......from the .... in the context in helminth infection, and allergic immunity and then stimulated these IL-32 which are ... to produce rapidly and tons of cytokines which can then do lots of things to the intentional environment
ILC are receiving signals such as IL-25 and IL-33 from the epithelium in the contect in helminth infection, and allergic immunity and then stimulated these IL-32 which are tissue resident to produce rapidly and tons of cytokines which can then do lots of things to the intentional environment
76
which type of cells cam ilc help differenciate
Can induce goblet cells differenciation, can activate macrophage to take in more and more of a wound healing phanotype, can recruit the eosinophils through IL5, it can promote class switching of B cell to IgA producing B cells
77
true or false: ilc2 looks like th1
false they look like th2
78
ILCs (group 1) which included .....but also a subset of ILCs that express .... and T bet that are able to produce I...and TNF alpha
ILCs (group 1) which included NK cells but also a subset of ILCs that express eomesodermin and T bet that are able to produce interferon gamma and TNF alpha
79
what do ILC2 express
ILC2 express lineage specific TF GATA 3 which then drive induction of IL-5 and -13
80
ilc3 are able to produce:
: il 17 and 22
81
true or false: ilcs are tissue resident
true
82
true or false: ilcs are responsive to epithelial derived cytokines and alarmins secreted from dead or dying cells (ex:IL-1, IL-33)
true
83
ilcs are sensors of:
tissue stress/health
84
true or false: ILCS AREpotent cytokine producers
true
85
A common feature of PRR activation is intracellular signaling mediated by the NFkB TF. What are3 factors related to PRR sigbnaling that may determine which genes are expressed by NFkB signalling?
-TF binding partners -Complementary signaling pathways or anti-inflammnatory pathways that may activate NFkB differently -Accessibility of chromatin to bind NFkB certain cell types
86
Does Kariko and WeissmN STUDY REFINE Janeways non-self hypothesis and/or Matzingers danger theory and if so how?
-Danger theory: If mitochondrial membrane is damaged, it is bad for the cell since the bacterial contents gets out and will activate an immune response -Janeway: not really cuz like even if we have self RNA it could be dangerous. Not all rna is created equal and even if its from a microbe, there ate rna modifications, will determine the immune response and if the rna is self or non self
87
Your lab just discovered a new adjuvant. How would u test whether it has potential to be used in a vaccine
-Inject it in a mice to see if it gonna induce the production of cytokines by dendrites by costimulatory expression in response to this new adjuvant -Measure if dendritic cells are able to activate T cells you need to add smth else that I could not find what she said
88
What is the difference between an IL-2 and an IL-4 receptor
-They bind different stats/ activate different stats -Half of the receptor is common aka common gamma chain and the other is unique to each cytokine
89
why do il2 and il4 activate different stats
Those subunits bind to different kinases and the combination of those we have the jaks abd then those determine what stats are activated
90
The relationship between IL-25 and ILC2 has become known as the tuft-ILC circuit. Why was it given this name and what is its function
Il-25 is produced during an helminth infection by the tuft cells that sense the helminths and then secreted il-25 to act on ilcs which then will make IL5 and iL 13 which will act back on the epithelium to induce goblet cell differentiation and mucus production and IL-13
91
th2 cells classically produce il...
il-4,5,8 and 13
92
th17 and th22 produce:
We have tH17 and TH22 they produce TL-22 and IL-17 and Rig gamma positive T cells that are producing cytokines
93
ata 3 is a TF that is activated in response to:
Gata 3 is a TF that is activated in response to stimuli that we don’t understand yet and then bind to DNA to promote the expression of these cytokines
94
true or false: gata 3 is required for all ilc development
true
95
true or falseTH2 cells, make IL-4,5 and 13 but ILC2 only makes IL-4 and 13
TH2 cells, make IL-4,5 and 13 but ILC2 only makes IL-5 and 13
96
The more methylation the DNA has the more...
the more methylation the DNA has the more closed it is and we call it heterochromatin
97
acetylation is related to
acetylation is associated with the openend chromatin and we call it euchromatin to make it more accessible
98
if you stimulate a T cell, it expands and contracts and it forms
if you stimulate a T cell, it expands and contracts and it forms memory T cells that are imprinted, they are epigenetically changed though signalling through cytokines and TCRs in the memory phase as opposed to the initial activation phase
99
true or false: every T cell has antigen specificity
true
100
true or false: memory T cells need co stimulatory moleculted
false they don't, they are faster and stronger all it needs is to see the antigen because its genome has already been imprinted
101
epigenetic change confer:
memory to the innate immune sustem
102
true or false: history of microbial exposure may impact you I react to subsequent infections even in an antigen independent
true
103
true or false: monocytes live long
they don't live long
104
What if you train the stem cells in bone marrow and this can be epigenically modified to that any cell that they give rise to in your life,they will change their function in response to .....
they will change their function in response to subsequent challenges
105
If we can immunize with BCG(tuberculosis vaccine) so that it get to the bone marrow and it infects it(non-pathogenetic) it mayb be able to train ...
hematopoietic stem cells, epigenetically imprint those cells to give rise to monocytes and macrophages that are more more protective against virulent MTB
106
what does bcg do
Bcg somehow epigenetically imprints stem cells in a T cell independent way to get more protection against TB
107
what is bcg
the vaccine for tb
108
They infected pregnant mice with a non pathogenic bacterial infection in the gut, then challenged the pups with salmonella when adult
-Found that in the mothers that were infected, the pups that come from them were more protected against salmonella infection than normal adults -Demonstrated that in those mice the mothers that were infected released IL6 imprinted stem cells in the intestinal epithelium such as when those cells were infected they gave rise to epithelial cells that were better at resisting salmonella infection

MIMM 314 (11 decks)

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