Quiz 7 Flashcards
What is an autoimmune reaction?
immune response to self antigen
What is central tolerance?
T cell development/selection (removing auto reactive T cells)
What is peripheral tolerance?
Tregs and suppression/anergy of self-reactive T cells
What are the polarizing cytokines for Tregs?
IL-2 and TGF-B
What are the effector cytokines for Tregs?
IL-10 and TGF-B
What are the 4 outcomes of Treg–MHC interaction?
- IL-10 expression
- CTLA-4 expression
- IL-2R upregulation
- linked expression
When Tregs and MHC interact, what is the purpose of IL-10 expression?
inhibits MHC on APCs
inhibits B7/CD28
inhibits TNF-a and IL-6
When Tregs and MHC interact, what is the purpose of CTLA-4 expression?
binds with B7 on APC to induce anergy
When Tregs and MHC interact, what is the purpose of IL-2R (CD25) being up regulated?
binds IL-2 = outcompetes for T cell activation
When Tregs and MHC interact, what is the purpose of linked expression?
Treg can bind and inhibit 2 T effectors bound to an APC
What is the steps of central tolerance for T cells?
- HSC
- blood
- double negative
- thymus cortex (positive selection)
- double positive
- thymus medulla (negative selection)
- single positive
- blood
Where does positive selection happen?
thymus cortex
Where does negative selection happen?
thymus medulla
What is positive selection?
T cell is functional and equipped to make a response against foreign antigens
What is negative selection?
deletes T cells with high affinity for self-peptides via apoptosis, thus ensuring self tolerance
What presents to double positive T cells in positive selection?
cTEC/DC/macrophage
What presents to single positive T cells in negative selection?
AIRE + mTECs
What are the three fates of double positive T cell in positive selection?
- intermediate affinity = single positive
- high affinity for MHC = apoptosis
- no recognition = death by neglect
In negative selection what affinity do you want the TCR to have?
intermediate affinity
How does AIRE+ mTEC present self antigen?
opens DNA region
Transport of single positive T cells out of thymus is mediated by ________
S1P and S1PR (on T cell)
How does S1P mediate SP T cell transport out of the thymus?
T cell follows the concentration gradient
(S1P is high in the blood and low in the thymus)
What does the drug FTY720 prevent autoimmunity?
binds to S1PR on T cells to prevent them from leaving the thymus (prevents auto reactive T cells from leaving the thymus)
Peripheral tolerance follows ___________
central tolerance
What is the purpose of peripheral tolerance?
sometimes auto reactive T cells make it through the selection process and into the blood and they need to be eliminated
What is the disorder APECED?
mutation in AIRE causing there to be not presentation of self during negative selection
Why are people with APECED prone to yeast infections?
IFN-a and IL-17 activity id blocked which is important for Th17 functions of protection against fungi
What is the ELISA test for?
tests for autoantibodies in APECED patients (typically IgG)
What are 3 trademarks for APECED?
- reduced expression of self-antigen
- reduced IFN-a (due to anti-cytokine Ab)
- reduced IL-17 (due to anti-cytokine Ab)
APECED patients also have loss of B cell tolerance, how does this happen?
B cells depend on T cells for SHM
auto-reactive T cells make conjugate pair with B cells = auto-reactive Ab
What T cells mediate psoriasis?
Th17
Th23
Th1
What are 3 alterations of skin in psoriasis?
- redness
- skin thickening
- white scales
What causes the redness in psoriasis?
vasodilation and inflamed endothelial cells
What causes the skin thickening in psoriasis?
hyper-proliferation of keratinocytes
What causes the white scalees in psoriasis?
parakeratosis (top layer of keratinocytes won’t loose nucleus and die)
What is parakeratosis?
top layer of keratinocytes won’t loose nucleus and die
Where does all of the skin affects of psoriasis occur?
stratum corneum
Because of the dysfunction of skin in psoriasis what 3 things occur making it a skin barrier dysfunction disease?
- improper skin stacking
- improper secretion of lipids
- improper adherence of keratinocytes
What is psoriasis area and severity index (PASI) score?
observational score determined by severity and amount covering skin
What are the 3 things determining severity on the PASI score?
- redness
- thickness
- scaling
What are the 4 histological changes in psoriasis?
- corneum becomes thick and broken
- epidermis is much larger than normal
- dermis has enlarged blood vessels
- immune infiltrates (DC and T cell clusters)
Are keratinocytes or T cells the driving force of psoriasis and why?
T cells
IL-2R on T cells is important for T cell proliferation
What experiment determined that T cells are the driving force of psoriasis?
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
What molecule produced by keratinocytes causes inflammation of blood vessels?
VEGF
What 4 ways do keratinocytes aid in barrier protection?
- hyper-proliferation
- recruit immune cells
- produce AMP
- produce VEGF
What 4 ways do TH17 cells aid in barrier protection?
- hyper-proliferation
- produce IL-1, IL-6, TNF-a, IL-17, IL-22
- produce AMP
- produce VEGF
What 2 cytokines heavily affect keratinocytes?
IL-17
IL-22
Immune signaling in psoriasis…
LC–Cd1a produces ______
Th17
Immune signaling in psoriasis…
neutrophils produce ______
Th17
Immune signaling in psoriasis…
T1 and T17 cause _________
cell damage
Immune signaling in psoriasis…
pDCs produce __________
lots of IFN-a
Immune signaling in psoriasis…
dDCs produce _____, ______, and ______ as well as activate _______
IFN-a
IL-22
IL-12
mDCs
Immune signaling in psoriasis…
TH1 cells produce _____ and recruit ______
TNF-a
macrophages
Immune signaling in psoriasis…
keratinocytes produce _____, ____, and ______
IL-1
IL-6
TNF-a
What is the specific antigen for psoriasis?
unknown
What is the transition from psoriasis to PsA?
unknown
The basic dysfunction of psoriasis is _________ imbalance
lipid
IL-___ is the most important cytokine for psoarisis
IL-17
What is it significant that PsA is associated with MHC I alleles?
co-morbidities
What 2 T helper cells are important for psoriasis?
Th17
Th1
What are the polarizing and effector cytokines for TH17?
polarizing: IL-1, IL-6, IL-23, TGF-B
effector: IL-17, IL-22
What are the polarizing and effector cytokines for TH1?
polarizing: IL-12, IFN-a, IL-18
effector: IFN-a, TNF
What are the 2 types of IL-2 receptors?
type I: low affinity
type II: high affinity
What is type I IL-2 receptor made of?
low affinity
IL-2R beta + IL-2R gamma
What is type II IL-2 receptor made of?
high affinity
IL-2R alpha + IL-2R beta + IL-2R gamma
What is IL-2R common chain?
IL-2R gamma
What chain in IL-2R type II makes it high affinity?
IL-2R alpha
Autocrine IL-2 promotes T cell proliferation in what 2 ways?
activated T cells produce IL-2
activated T cells up regulated IL-2R alpha
What 3 interactions/signals are required for T cell activation?
- MHC–TCR
- B7–CD28
- autocrine IL-2
What is DAB389 IL-2 (TOX)?
toxin that shuts down T cell clonal expansion
What is the target of DAB389 IL-2 (TOX)?
activated T cells expressing IL-2R alpha
How does DAB389 IL-2 (TOX) stop T cell proliferation?
binds to IL-2R alpha which internalized by T cell and protein synthesis is shut down = cell death
Where are CD8+ cells located in psoriasis skin?
epidermis
Where are CD4+ cells located in psoriasis skin?
dermis
A proposed mechanism of psoriasis is that specific HLA class I alleles are expressed what other mechanism backs up this claim?
CD8+ cells (T17 or T1 cells) found in lesions
HLA I C___ and B___ are common in psorasis patients
C06
B07
HLA-B___ is a risk factor for psorasis
HLA-B27
What are 4 characteristics of IFN-a?
- pleiotropic (multiple functional cytokine)
- anti-viral
- immunomodulator (up-regulates MHC)
- anti-proliferative (shuts down protein synthesis)
What subtype of IFN is expressed on keratinocytes?
kappa
All type I IFN binds to IFNR1 and R2 which are expressed on…
all nucleated cells
What signaling cascade does IFN-a R1 and 2 use?
JAK/TYK/STAT
Is JAK/TYK/STAT unique to IFN?
no IL-10 uses it
What are 3 psoriasis therapeutics we talked about that targets IFN-a?
- TYK2 inhibitor
- anti-IFNa R1 Ab
- anti BCDA2 Ab
How does TYK2 inhibitor prevent psoriasis?
blocks IFN-a receptor signaling pathway in cells
How does anti-IFNa R1 Ab prevent psoriasis?
blocks all IFN signaling because it cannot bind to its receptor
How does anti BCDA2 Ab prevent psoriasis?
prevents them from activating and secreting IFN
What are 3 ways to measure IFN signaling?
- measure MHC up-regulation
- measure STAT phosphorylation
- detect expression of ISG (IFN stimulated gene)
What are 3 pieces of evidence what pDCs are important in psorasis?
- psoriatic skin has active IFN-a signaling pathways
- excessive IFN signaling
- treatment with IFN-a will make psoriasis worse
What are 2 markers for pDCs?
- BDCA-2/CD123
- CD86
Why is BDCA-2/CD123 important marker for pDCs?
moves pDCs from blood to skin
How do pDCs produce so much IFN-a?
pDCs TLR-7/9 (endosomal receptors) sense DNA/RNA inside of cell endosome (where viral DNA is sensed)
How do pDCs recognize self-DNA if its inside the endosome in the cell?
LL37 converts self-DNA by binding to DNA, causing it to aggregate and cluster, triggering TLR-7
What induces LL37 function?
IL-17 mediated keratinocyte damage
Entry of LL37/DNA complex induces activation of _____ of pDCs
TLR-7
What does IL-17 recruit?
neutrophils
What is angeogenesis?
growth of blood vessels (due to VEGF production)
