Quiz 7 Flashcards

1
Q

What is an autoimmune reaction?

A

immune response to self antigen

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2
Q

What is central tolerance?

A

T cell development/selection (removing auto reactive T cells)

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3
Q

What is peripheral tolerance?

A

Tregs and suppression/anergy of self-reactive T cells

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4
Q

What are the polarizing cytokines for Tregs?

A

IL-2 and TGF-B

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5
Q

What are the effector cytokines for Tregs?

A

IL-10 and TGF-B

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6
Q

What are the 4 outcomes of Treg–MHC interaction?

A
  1. IL-10 expression
  2. CTLA-4 expression
  3. IL-2R upregulation
  4. linked expression
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7
Q

When Tregs and MHC interact, what is the purpose of IL-10 expression?

A

inhibits MHC on APCs
inhibits B7/CD28
inhibits TNF-a and IL-6

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8
Q

When Tregs and MHC interact, what is the purpose of CTLA-4 expression?

A

binds with B7 on APC to induce anergy

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9
Q

When Tregs and MHC interact, what is the purpose of IL-2R (CD25) being up regulated?

A

binds IL-2 = outcompetes for T cell activation

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10
Q

When Tregs and MHC interact, what is the purpose of linked expression?

A

Treg can bind and inhibit 2 T effectors bound to an APC

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11
Q

What is the steps of central tolerance for T cells?

A
  1. HSC
  2. blood
  3. double negative
  4. thymus cortex (positive selection)
  5. double positive
  6. thymus medulla (negative selection)
  7. single positive
  8. blood
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12
Q

Where does positive selection happen?

A

thymus cortex

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13
Q

Where does negative selection happen?

A

thymus medulla

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14
Q

What is positive selection?

A

T cell is functional and equipped to make a response against foreign antigens

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15
Q

What is negative selection?

A

deletes T cells with high affinity for self-peptides via apoptosis, thus ensuring self tolerance

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16
Q

What presents to double positive T cells in positive selection?

A

cTEC/DC/macrophage

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17
Q

What presents to single positive T cells in negative selection?

A

AIRE + mTECs

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18
Q

What are the three fates of double positive T cell in positive selection?

A
  1. intermediate affinity = single positive
  2. high affinity for MHC = apoptosis
  3. no recognition = death by neglect
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19
Q

In negative selection what affinity do you want the TCR to have?

A

intermediate affinity

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20
Q

How does AIRE+ mTEC present self antigen?

A

opens DNA region

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21
Q

Transport of single positive T cells out of thymus is mediated by ________

A

S1P and S1PR (on T cell)

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22
Q

How does S1P mediate SP T cell transport out of the thymus?

A

T cell follows the concentration gradient
(S1P is high in the blood and low in the thymus)

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23
Q

What does the drug FTY720 prevent autoimmunity?

A

binds to S1PR on T cells to prevent them from leaving the thymus (prevents auto reactive T cells from leaving the thymus)

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24
Q

Peripheral tolerance follows ___________

A

central tolerance

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25
Q

What is the purpose of peripheral tolerance?

A

sometimes auto reactive T cells make it through the selection process and into the blood and they need to be eliminated

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26
Q

What is the disorder APECED?

A

mutation in AIRE causing there to be not presentation of self during negative selection

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27
Q

Why are people with APECED prone to yeast infections?

A

IFN-a and IL-17 activity id blocked which is important for Th17 functions of protection against fungi

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28
Q

What is the ELISA test for?

A

tests for autoantibodies in APECED patients (typically IgG)

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29
Q

What are 3 trademarks for APECED?

A
  1. reduced expression of self-antigen
  2. reduced IFN-a (due to anti-cytokine Ab)
  3. reduced IL-17 (due to anti-cytokine Ab)
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30
Q

APECED patients also have loss of B cell tolerance, how does this happen?

A

B cells depend on T cells for SHM
auto-reactive T cells make conjugate pair with B cells = auto-reactive Ab

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31
Q

What T cells mediate psoriasis?

A

Th17
Th23
Th1

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32
Q

What are 3 alterations of skin in psoriasis?

A
  1. redness
  2. skin thickening
  3. white scales
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33
Q

What causes the redness in psoriasis?

A

vasodilation and inflamed endothelial cells

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34
Q

What causes the skin thickening in psoriasis?

A

hyper-proliferation of keratinocytes

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35
Q

What causes the white scalees in psoriasis?

A

parakeratosis (top layer of keratinocytes won’t loose nucleus and die)

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36
Q

What is parakeratosis?

A

top layer of keratinocytes won’t loose nucleus and die

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37
Q

Where does all of the skin affects of psoriasis occur?

A

stratum corneum

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38
Q

Because of the dysfunction of skin in psoriasis what 3 things occur making it a skin barrier dysfunction disease?

A
  1. improper skin stacking
  2. improper secretion of lipids
  3. improper adherence of keratinocytes
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39
Q

What is psoriasis area and severity index (PASI) score?

A

observational score determined by severity and amount covering skin

40
Q

What are the 3 things determining severity on the PASI score?

A
  1. redness
  2. thickness
  3. scaling
41
Q

What are the 4 histological changes in psoriasis?

A
  1. corneum becomes thick and broken
  2. epidermis is much larger than normal
  3. dermis has enlarged blood vessels
  4. immune infiltrates (DC and T cell clusters)
42
Q

Are keratinocytes or T cells the driving force of psoriasis and why?

A

T cells
IL-2R on T cells is important for T cell proliferation

43
Q

What experiment determined that T cells are the driving force of psoriasis?

A

IL-2 was infused with a toxin and is taken up by T cells causing them to die = decreased psoriasis

** IL-2R on T cells is important for T cell proliferation

44
Q

What molecule produced by keratinocytes causes inflammation of blood vessels?

A

VEGF

45
Q

What 4 ways do keratinocytes aid in barrier protection?

A
  1. hyper-proliferation
  2. recruit immune cells
  3. produce AMP
  4. produce VEGF
46
Q

What 4 ways do TH17 cells aid in barrier protection?

A
  1. hyper-proliferation
  2. produce IL-1, IL-6, TNF-a, IL-17, IL-22
  3. produce AMP
  4. produce VEGF
47
Q

What 2 cytokines heavily affect keratinocytes?

A

IL-17
IL-22

48
Q

Immune signaling in psoriasis…
LC–Cd1a produces ______

A

Th17

49
Q

Immune signaling in psoriasis…
neutrophils produce ______

A

Th17

50
Q

Immune signaling in psoriasis…
T1 and T17 cause _________

A

cell damage

51
Q

Immune signaling in psoriasis…
pDCs produce __________

A

lots of IFN-a

52
Q

Immune signaling in psoriasis…
dDCs produce _____, ______, and ______ as well as activate _______

A

IFN-a
IL-22
IL-12

mDCs

53
Q

Immune signaling in psoriasis…
TH1 cells produce _____ and recruit ______

A

TNF-a

macrophages

54
Q

Immune signaling in psoriasis…
keratinocytes produce _____, ____, and ______

A

IL-1
IL-6
TNF-a

55
Q

What is the specific antigen for psoriasis?

A

unknown

56
Q

What is the transition from psoriasis to PsA?

A

unknown

57
Q

The basic dysfunction of psoriasis is _________ imbalance

A

lipid

58
Q

IL-___ is the most important cytokine for psoarisis

A

IL-17

59
Q

What is it significant that PsA is associated with MHC I alleles?

A

co-morbidities

60
Q

What 2 T helper cells are important for psoriasis?

A

Th17
Th1

61
Q

What are the polarizing and effector cytokines for TH17?

A

polarizing: IL-1, IL-6, IL-23, TGF-B
effector: IL-17, IL-22

62
Q

What are the polarizing and effector cytokines for TH1?

A

polarizing: IL-12, IFN-a, IL-18
effector: IFN-a, TNF

63
Q

What are the 2 types of IL-2 receptors?

A

type I: low affinity
type II: high affinity

64
Q

What is type I IL-2 receptor made of?

A

low affinity
IL-2R beta + IL-2R gamma

65
Q

What is type II IL-2 receptor made of?

A

high affinity
IL-2R alpha + IL-2R beta + IL-2R gamma

66
Q

What is IL-2R common chain?

A

IL-2R gamma

67
Q

What chain in IL-2R type II makes it high affinity?

A

IL-2R alpha

68
Q

Autocrine IL-2 promotes T cell proliferation in what 2 ways?

A

activated T cells produce IL-2
activated T cells up regulated IL-2R alpha

69
Q

What 3 interactions/signals are required for T cell activation?

A
  1. MHC–TCR
  2. B7–CD28
  3. autocrine IL-2
70
Q

What is DAB389 IL-2 (TOX)?

A

toxin that shuts down T cell clonal expansion

71
Q

What is the target of DAB389 IL-2 (TOX)?

A

activated T cells expressing IL-2R alpha

72
Q

How does DAB389 IL-2 (TOX) stop T cell proliferation?

A

binds to IL-2R alpha which internalized by T cell and protein synthesis is shut down = cell death

73
Q

Where are CD8+ cells located in psoriasis skin?

A

epidermis

74
Q

Where are CD4+ cells located in psoriasis skin?

A

dermis

75
Q

A proposed mechanism of psoriasis is that specific HLA class I alleles are expressed what other mechanism backs up this claim?

A

CD8+ cells (T17 or T1 cells) found in lesions

76
Q

HLA I C___ and B___ are common in psorasis patients

A

C06
B07

77
Q

HLA-B___ is a risk factor for psorasis

A

HLA-B27

78
Q

What are 4 characteristics of IFN-a?

A
  1. pleiotropic (multiple functional cytokine)
  2. anti-viral
  3. immunomodulator (up-regulates MHC)
  4. anti-proliferative (shuts down protein synthesis)
79
Q

What subtype of IFN is expressed on keratinocytes?

A

kappa

80
Q

All type I IFN binds to IFNR1 and R2 which are expressed on…

A

all nucleated cells

81
Q

What signaling cascade does IFN-a R1 and 2 use?

A

JAK/TYK/STAT

82
Q

Is JAK/TYK/STAT unique to IFN?

A

no IL-10 uses it

83
Q

What are 3 psoriasis therapeutics we talked about that targets IFN-a?

A
  1. TYK2 inhibitor
  2. anti-IFNa R1 Ab
  3. anti BCDA2 Ab
84
Q

How does TYK2 inhibitor prevent psoriasis?

A

blocks IFN-a receptor signaling pathway in cells

85
Q

How does anti-IFNa R1 Ab prevent psoriasis?

A

blocks all IFN signaling because it cannot bind to its receptor

86
Q

How does anti BCDA2 Ab prevent psoriasis?

A

prevents them from activating and secreting IFN

87
Q

What are 3 ways to measure IFN signaling?

A
  1. measure MHC up-regulation
  2. measure STAT phosphorylation
  3. detect expression of ISG (IFN stimulated gene)
88
Q

What are 3 pieces of evidence what pDCs are important in psorasis?

A
  1. psoriatic skin has active IFN-a signaling pathways
  2. excessive IFN signaling
  3. treatment with IFN-a will make psoriasis worse
89
Q

What are 2 markers for pDCs?

A
  1. BDCA-2/CD123
  2. CD86
90
Q

Why is BDCA-2/CD123 important marker for pDCs?

A

moves pDCs from blood to skin

91
Q

How do pDCs produce so much IFN-a?

A

pDCs TLR-7/9 (endosomal receptors) sense DNA/RNA inside of cell endosome (where viral DNA is sensed)

92
Q

How do pDCs recognize self-DNA if its inside the endosome in the cell?

A

LL37 converts self-DNA by binding to DNA, causing it to aggregate and cluster, triggering TLR-7

93
Q

What induces LL37 function?

A

IL-17 mediated keratinocyte damage

94
Q

Entry of LL37/DNA complex induces activation of _____ of pDCs

A

TLR-7

95
Q

What does IL-17 recruit?

A

neutrophils

96
Q

What is angeogenesis?

A

growth of blood vessels (due to VEGF production)