Final Exam Flashcards
What is the hygiene hypothesis?
lack of exposure in early childhood to infectious agents and possible allergens results in a higher likelihood of developing hypersensitivity issues
Type I HSR are mediated by what Ab isotype?
IgE
Type ___ HSR is responsible for allergies
type 1
What are the polarizing and effector cytokines of Tregs?
polarizing: IL-2, TGF-B
effector: IL-10, TGF-B
What are the polarizing and effector cytokines of TH17?
polarizing: IL-1, IL-6, IL-23, TGF-B
effector: IL-17, IL-22
What are the polarizing and effector cytokines of TH2?
polarizing: IL-4
effector: IL-4, IL-5, IL-13
What are the polarizing and effector cytokines of TH1?
polarizing: IL-12, IL-18, IFN-g
effector: IFN-g, TNF
Atopic individuals have a skewed _____ response
TH2
What T cell subset is important for type I HSR?
TH2
What is tonic signaling?
immune skewing above the baseline set by barrier surface microbiome and other factors (sex, age, weight, …)
What are 4 types of non-covalent interactions?
- hydrogen bonds
- ionic bonds
- van der Waal interactions
- hydrophobic interactions
What unit is the Kd measured in?
M
What unit is the Ka measured in?
M-1
Kd and Ka are _________ of each other
inverses
What is the Kd?
concentration of L when 50% of RL complex is formed
When 10% of RL is formed = ____xKd
0.1
When 50% of RL is formed = ____xKd
1
When 90% of RL is formed = ____xKd
10
When 100% of RL is formed = ____xKd
100
If Ka is a constant, why does binding increase with increasing concentration?
increasing concentration increases the probability of an interaction between R and L
The smaller the Kd the better or worse the affinity?
better
What is avidity?
enhanced affinity interaction due to multiple binding interactions
What 2 things are required for avidity?
- R of L attached to surface
- requires other complement to have multiple binding sites
What non-covalent interaction is important for specificity?
van der Waal
What is a hypersensitivity reaction?
when the immune system responds inappropriately to innocuous antigens
What is the effector mechanism of type I HSR?
degranulation
What are the 3 phases of type I HSR?
- sensitization phase
- early effector phase
- late phase response
What happens in the early effector phase of type I HSR?
IgE + allergen binds to FCERI on mast cells = release of primary and secondary mediators
What happens in the late phase of type I HSR?
TH2 and granulocyte recruitment and cytokine release
What 2 things are special about IgE?
- low in serum
- binds high affinity to FCERI
Mast cells, TH2 cells, and eosinophils produce _____ to induce IgE class switching
IL-4
What high affinity receptor does IgE bind to?
FCERI
Where are mast cells found?
tissue
Why are mast cell usually the first granulocyte to encounter IgE bound to an allergen?
they are stored in the tissue close to sites of entry
What are the 3 products of IgE–FCERI signaling cascade?
- degranulation
- PLA
- cytokine production
What is an example of primary mediator of type I HSR?
histamine
What are 2 examples of secondary mediators in type I HSR?
leukotrienes
prostaglandins
PLA —> _______ —–> prostaglandins and leukotrienes
arachidonic acid (AA)
What pathway does prostaglandin synthesis use?
COX2
What pathway does leukotriene synthesis use?
lipoxygenase
What is the product of leukotriene synthesis?
cys LTR1
What is the product of prostaglandin synthesis?
DP1 and CRTH2 receptors
Montelukast (Singulair) blocks synthesis of ________ which aids in asthma symptoms
cys LTR1 (leukotrienes)
Eosinophils produce ______ in their granules
MBP
ROS in granulocytes produce _________
myeloperoxidasee
Neutrophils produce ______ in their granules
MPO
RNS combined with ROS in granulocytes produce ________
peroxynitrite
What are the 3 results of iNOS exposure?
- apoptosis
- protein damage
- necrosis
RNS in granulocytes produce _________
iNOS
What cytokine initiates the transition to the late phase response of type I HSR?
TNF-a
What are some things that affect the severity of type I HSR?
route
concentration
prior exposure
predisposition
Epinephrine binds to ___________ to counter act meditators and improves cardiac output
a+B adrenergic receptor
Steroids inhibit _______ signaling to stop inflammation
NfkB (pro-inflammatory transcription factor)
What is the goal of SCITs?
divert the TH2 response in atopic individuals
How do SCITs divert the TH2 response?
- induce IL-10 signaling to inhibit IL-4 (TH2)
- shifts IgE–>IgG which can bind to inhibitory receptor = block degranulation
What is SHIP phosphatase?
inhibits IgE-Lyn phosphorylation and blocks mast cell activation
* uses ITIMs
beta-2 agonists use the same receptor as __________
epinephrine (a+b adrenergic receptor)
What is FEV?
forced expiratory force
What is PEF?
peak expiratory flow
What are 2 biomarkers for asthma?
FeNO (nitric oxide)
eosinophil levels
What are anticholinergics?
allows acetylcholine to bind to M2 in airways (inhibitory receptor) instead of eosinophil MBP
Type II IL-4/13 receptors are found on _________, __________, ________
epithelial cells, smooth muscles, and endothelial cells
What happens when acetylcholine is not able to bind to M2 in airways and MBP from eosinophils take place?
bronchial spasms and hyper reactivity
Type I IL-4/13 receptors are found on _________
lymphocytes
Type I IL-4/13 receptor is made of what chains?
IL-4R a
gc
Type II IL-4/13 receptor is made of what chains?
IL-4R a
IL-13R a
Is type I or II IL-4/13 receptor unique for IL-4?
type I
Atopic dermatitis is IL-___ dominant
IL-13
Asthma is IL-_____ dominant
IL-4
What is the genetic mutation in AD?
FLG gene
What does the FLG gene do?
crosslinks epidermal layer so its strong
FLG mutation is common in what race?
europeans and asians
What race has higher IL-17/TH17 levels in AD?
asians
FLG mutation is less common in _____________ but their AD is just as severe
african americans
What race has the highest IgE/Th2 response and a very low Th17/22 response?
african americans
Why is it important that AD is mediated differently in different races?
AD is not just mediated by TH2 but also TH17 due to polymorphisms
What is the polymorphism in AD regarding races?
(Q576R) IL-4 Ra gene mutation
What does atopic mean?
predisposition to allergic responses involving IgE
What is the atopic march?
AD showing up early in life opens the door for food allergies –> asthma —> rhinitis
What are the 3 distinct features of AD?
- epithelial barrier dysfunction
- susceptibility to infections
- atopic features (rhinitis and asthma)
What is the role if IL-5 in type I HSR?
eosinophil activation
What is the role if IL-4 in type I HSR?
IgE class switching
What are the 4 major steps in the primary immune response?
- antigen–DC
- DC–T cell
- antigen–B cell
- T cell – B cell
MHC class 1 is presented on _______ cells
all cells
MHC class II is presented on _____, _____, _____ cells
macrophages, DC, B cells
What 3 protein interactions are required for T cell–DC?
B7—CD28
MHC—TCR
CD4/8
What cytokine aid in T cell proliferation?
IL-2
What 3 protein interactions are required for T cell —-B cell?
TCR — MHC II
CD40L—CD40
CD4
Ig___ is highly efficient in complement activation
IgM
Ig__ and Ig__ are high efficient in activating NK cells
IgG1
IgG3
Ig___ all function as opsins
IgG
What is a type II HSR?
IgM/IgG recognition of innocuous cell surface molecules as foreign leading to Ab-mediated death
What are the 3 mechanisms of Ab-mediated death in type II HSR?
- MAC
- ADCC
- phagocytosis
What binds to IgM first in complement activation?
C1q
NK cells express _____ and bind to antibodies Fc region to induce ADCC
FCgRIII
Ig___ is the most common isotype promoting ADCC
IgG1
What is released when NK cells kill?
- FASL
- granzymes
- perforins
How does Ab-mediated phagpcytosis work?
Ab binds to antigen on cell surface and Fc receptor on phagocytes detect and engulf it
What are 3 examples of type II HSR?
- mismatched blood transfusion
- hemolytic disease in newborns
- drug induced anemia
What is mismatched blood transfusions?
IgM binds to blood antigens recognized as foreign resulting in MAC lysis
What is hemolytic disease of newborns?
IgG (pass barrier) binds to Rh antigen on fetal RBC (opsonization) resulting in lysis via NK cells of fetus
Why do most people possess IgM against blood carb antigens they don’t express?
common microbes express similar carb antigens
Why is lysis of red blood cells dangerous?
hemoglobin metabolizes into toxic billibrubin
How does the Rho-gam therapy work?
Rh+ fetal cells enter mothers circulation, anti-Rh Ab bind and inactivate fetal Rh antigen before mother ever sees antigens
What 2 mechanisms are used in rho gam to prevent detection of fetal Rh+ cells?
- inhibit B cell signaling via FCGRIIB
- Anti-D Ab binds to fetal RBC and is phagocytosed
In hemolytic disease in fetus, Ig___ is responsible for the primary response while Ig___ is for the secondary response
IgM
IgG
Why is a mother’s secondary exposure of D+ easier to achieve with fewer D+ RBC than the first exposure?
she has memory B cells which have a lower threshold for activation
What are delayed type 4 HSR?
skin permeable antigens activate CD4+/Th1 cells resulting in sensitization followed by DT4H on second exposure
What HSR is mediated by only T cells?
DT4 HSR
Why is type 4 HSR “delayed”?
recruitment and activation of macrophages requires time
What are the antigens for delayed type 4 HSR?
contact/skin permeable antigens
What happens during the sensitization phase of DT4 HSR?
recognition, presentation, activation via IL-2, TH1 cells created, memory T cells made
What T cell subset controls delayed type 4 HSR?
TH1 (CD4+)
What are the 3 memory T cells?
- central
- effector
- resident
Where are central memory T cells located?
circulation/SLT
Where are effector memory T cells located?
circulatioon/SLT, tissues
Where are resident memory T cells located?
tissue
What is a marker for naive T cells?
CD45RA
What is a marker for central, memory, and effector T cells?
CD45RO
What is a marker for naive T cells and central memory T cells?
CCR7
What is a marker for resident T cells?
CD103
Where are monocytes located?
blood
Where are macrophages located?
tissue
What is the most important cell in delayed type 4 HSR?
macrophages
What 2 cytokines activate and recruit macrophages?
IFN-g and TNF
Draw the TH1 inflammatory loop
a
What’s the initiator of the inflammatory loop for DT4 HSR?
Th1
What’s the function of IL-12 in the inflammatory loop?
induces more TH1 cells
What’s the function of TNF/IFN-g in the inflammatory loop?
activates macrophages
What’s the function of IL-8 in the inflammatory loop?
neutrophil recruitment
What’s the function of IL-6 & IL-1 in the inflammatory loop?
inflammation/fever
What’s the function of CCL2 in the inflammatory loop?
recruits monocytes
The inability of macrophages to clear a pathogen results in _________
granuloma formation
What 2 things can cause granulomas?
- silica
- sutures
What 2 cytokines are important for granuloma formation?
TNF-a and IFN-g
If granuloma cannot clear pathogen blood vessel and tissue damage occurs how?
persistent activation of ROS/RNS
What is in a TB skin test that induces a pure TH1 response?
PPD
TB skin test is CD___/TH__ mediated
CD4
TH1
What is the antigen in poison oak?
urushiol
Poison oak is CD___/TH___ mediated
CD4
TH17
What 2 ways can CD8+ activate DCs?
- sequential activation
- cross presentation
What is sequential activation?
DC —CD4 T cell interaction increases B7 levels, then DC interacts/activates CD8 T cell
TB skin tests and poison oak are both types of ….
DT4 HSR
DT4 HSR are CD___ T cell mediated
CD4
What is cross presentation of CD8 T cells?
DC—-CD4 T cell interactions, then changes their antigen processing to present on MHC I which can activate CD8 T cells
(present extracellular antigen on MHC I)
What is it called in cross presentation when DC switches thier antigen processing to present on MHC I?
cytosolic diversion
CD4 T cell engagement help CD8 T cells activate by providing paracrine _____ in cross presentation
IL-2
TCRs recognize just the peptide presented?
No, interact with the MHC as well
NKT cells recognize ____ presented by ____ on APCs
glycolipids
CD1d
NKT cells DO NOT recognize…
MHC—peptide complex
What is different about NKT cell’s TCRs?
no memory or diversity
How does CD1a present lipids differently than how MHC presents peptides?
lipid is buried in CD1d and the A’ roof is what is recognized
Is CD1a activated on LC cells when the A’ roof is blocked or unblocked?
unblocked
What causes A’ roof to be blocked in CD1a?
healthy skin lipid head causes steric hinderance
In the interference model of CD1a, binding of TCR is soley based on _____ not _____
CD1a not ligand
CD1__ is highly expressed on LC DCs
CD1a
CD1__ is expressed on NKT cells
CD1d
What linkage in skin is abnormal in atopic dermatitis?
fillagrin linkages
What are corneocytes?
keratinocytes without nucleus
Where are regular LC DCs located?
epidermis
When LC DCs sample a foreign lipid with its CD1a what T cell subset is produced?
TH17
How does the skin sense PPD from TB skin test?
injected directly into dermis by passing LC DCs and being sensed by dermal DCs and macrophages
NKT cells use CD1__ and LC DCs use CD1__
NKT: CD1d
LC DC: CD1a
Only CD1___ has an A’ roof
CD1a
Why is there no diversity for TCR recognizing CD1a—lipids?
The A’ roof is the same for all receptors
What 2 things are special about NKT cells?
Invariant TCR (no diversity)
Only identified glycolipids
INF-g and TNF are important for what 2 things?
Macrophage recruitment
Granuloma formation
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?
When self-reactive T cells escape into the periphery, peripheral tolerance ensures that they are deleted or become anergic
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
Transport of single positive T cells out of thymus is mediated by ________
Transport of single positive T cells out of thymus is mediated by ________
What does the drug FTY720 prevent autoimmune T cells?
binds to S1PR on T cells to prevent them from leaving the thymus (prevents auto reactive T cells from leaving the thymus)
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 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
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)
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 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 molecule produced by keratinocytes causes formation of new blood vessels?
VEGF
What 2 cytokines heavily affect keratinocytes?
IL-17
IL-22
Immune signaling in psoriasis…
neutrophils produce ______
TH17
Immune signaling in psoriasis…
pDCs produce __________
lots of INF-a
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
The basic dysfunction of psoriasis is _________ imbalance
lipid
IL-___ is the most important cytokine for psoarisis
IL-17
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 chain in IL-2R type II makes it high affinity?
alpha
What 3 interactions/signals are required for T cell activation?
MHC–TCR
B7–CD28
autocrine IL-2
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-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 signaling cascade does IFN-a R1 and 2 use?
JAK/TYK/STAT
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 signaling pathway in cells
How does anti BCDA2 Ab prevent psoriasis?
prevents pDC 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
How do pDCs produce so much IFN-a?
pDCs TLR-7 (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 are 3 inflammatory cytokines?
TNF-a
IL-1B
IL-6
What is TNF-a main function?
master regulator
What is IL-1B main function?
fever response
What is IL-6 main function?
produces acute phase proteins
What cell produces the inflammatory cytokines, TNF-a, IL-1B, and IL-6?
macrophages
______ is required for production of IL-1B and IL-6
TNF-a
TNF-a increases what 2 things?
vascular permeability
adhesion molecules
What inflammatory cytokine activates macrophages?
TNF-a
What is an example of an acute phase protein?
CRP
What 2 things are special about IL-1B?
no gene transcription is required to make it
cannot leave the cell unless leakage occurs
What are 3 functions of neutrophils?
phagocytosis
degranulation
NETosis
What do neutrophil nets contain?
LL-37 (AMP)
histones
proteases
DNA
What does PAD4 do?
de-condenses chromatin by changing charge on Arg causing histones to release DNA
What is a type III HSR?
abnormal immune response mediated by the formation of immune complexes
Where does citrullination occur?
neutrophils
What activates PAD4?
pore forming toxins produced by bacteria
What are ACPAs?
anti-citrullinated protein antibodies
What is epitope spreading?
Ab recognizes different epitopes on the same protein causing the creation of many types of auto-Abs
What is the role if IL-13/4 in type I HSR?
promotes eosinophil trafficking
What is the antigen for Type I HSR?
innocuous/environmental antigens
What are the important cytokines for type I HSRs?
IL-13
IL-5
IL-4
Anti-citrullinated Ab indicates what disease?
RA
Anti-dsDNA Ab indicates what disease?
SLE
Anti-mylein Ab indicates what disease?
MS
What activates macrophages?
IFN-g