Quiz 3 Flashcards
What is a hypersensitivity reaction?
when the immune system responds inappropriately to innocuous antigens
What does anaphylaxis mean?
against protection
What is the recognition molecule for type I HSR?
IgE
What is the effector mechanism of type I HSR?
mast cell, basophil, and eosinophil degranulation
What are the 3 phases of type I HSR?
- sensitization phase
- early effector phase
- late phase
What happens during the sensitization phase of type 1 HSR?
first exposure to antigen
What happens during the early effector phase of type 1 HSR?
primary and secondary mediators are released and granulocytes are activated
When does IgE–FcERI binding happen in type 1 HSR?
early effector phase
What is the difference between primary and secondary mediators?
primary are stored in granules
secondary have to be synthesized
What happens during the late phase of type 1 HSR?
Th2 cells involvement
- recruit granulocytes
- increased cytokine production
Where are FcERI receptors found?
on granulocytes to induce degranulation
What are the steps of the early phase of type 1 HSR?
- free IgE binds to high affinity FcERI on granulocytes
- IgE binds to multivalent antigens
- IgE–FcERI interact and induce receptor clustering and signaling
- degranulation (primary and secondary mediators released)
_____ cells promote class switching of B cells to IgE
Th2
Where does somatic hypermutation occur on an antibody? What about isotype switching?
somatic: Fab region
isotype switching: Fc region (bottom)
What cytokine promotes IgE class switching?
IL-4/13
IgE has an unique 3 domain ____ region
Fc
What Ig has the same 3 Fc domain but is pentameric?
IgM
What part of IgE binds to the FcERI?
Fc region
Ig___ is low in the serum compared to other Igs
IgE
Where are mast cells found?
tissue (final epithelial layer)
Where are basophils found?
blood
Where are eosinophils found?
blood (migrate to tissue)
What phase of type I HRS are eosinophils and neutrophils the most important?
late phase
What molecules does IgE bind to?
proteins or glycoproteins
What is the IgE signaling cascade?
- allergen binds to IgE which is bound to FcERI
- FcEREI clusters = activation of Lyn tyrosine kinase
- Lyn phosphorylates ITAMs
- Syk recruits SH2 to ITAMS
- Syk is autophosphorylated = activation of PLC-gamma
- degranulation, PLA activation, cytokine production.
What is the result of the IgE signaling cascade?
degranulation
PLA (phospholipase A) activation
cytokine production
What phase of type 1 HSR do primary and secondary mediators play a role?
early phase
What are primary mediators derived from?
decarboxylated histidine
How many histamine receptors do cells have?
4
Which histamine receptor do anti-histamines target?
H1
Binding of H1 (histamine) receptor induces what?
smooth muscle contractions
increased vascular permeability
mucus
Binding of H2 (histamine) receptor induces what?
increased vascular permeability
vasodilation
release of acid into stomach
What are 2 examples of primary mediators?
histamine
heparin
Degranulation of secondary mediators is induced by ________ that generates ________ to produce leukotrienes and prostaglandins
phospholipase A2
arachidonic acid
What are 3 examples of secondary mediators?
- leukotrienes
- prostaglandins
- IL-1/TNF-a
What enzyme pathway synthesizes leukotrienes?
lipoxygenase
What enzyme pathway synthesizes prostaglandins?
COX2
What are the steps of the leukotriene synthesis pathway?
- cPLA2 +membrane phospholipids
- AA (arachidonic acid)
- LOX
- Cys LTR1(receptors)
What are the steps of the prostaglandin synthesis pathway?
- PLA2 +membrane phospholipids
- AA (arachidonic acid)
- COX 1&2
- DP1 & CRTH2 (receptors)
What is TNF-a?
inflammatory cytokine
Where is TNF-a stored?
mast cell granules
What does expression of TNF-a increase?
selectin and integrins
permeability
vasodilation
What do eosinophils release to kill pathogen?
MBP (major basic protein)
-reactive O2 species
What do neutrophils release to kill pathogen?
MPO (myeloperoxidase)
-reactive O2 species
What are the steps to making a reactive oxygen species?
- O2
add NADPH oxidase - super oxide anion
add superoxide dismutase - hydrogen peroxide
add myeloperoxidase
hypochlorous acid
What are the steps to making a reactive nitrogen species?
- L-arginine
add inducible nitric oxide synthease (iNOS) - nitric oxide
- nitrogen dioxide
When there is a high concentration of NO (reactive nitrogen species) what happens?
it combines with the (ROS) superoxide anion and produces peroxynitrite
When there is a low concentration of NO (reactive nitrogen species) what happens?
its a signaling molecule
What are the affects of peroxynitrite?
inactivation of mitochondria = apoptosis
protein oxidation (cysteine) = inactive enzyme
DNA damage = necrosis
What induces iNOS?
inflammatory Th2 cytokines
epithelial cell damage
What is a systemic reaction of a type 1 HSR?
anaphylaxis
What is a localized reaction of a type 1 HSR?
hives
asthma
The severity of clinical symptoms of type 1 HSR depends on what 4 things?
- route of allergen
- concentration of allergen
- prior exposure to allergen
- host pre-disposition
What does epinephrine bind to to prevent anaphylaxis?
(g-protein coupled receptor) alpha and beta adrenergic receptors
What does epinephrine block by binding to the adrenergic receptors?
primary and secondary mediators being released from granulocytes
Whats an example of a leukotriene antagonist?
Singulair
What 4 things do corticosteroids do?
- decrease inflammation: blocking inflammatory mediators
- immunosupressive: suppresses T cells
- anti-proliferative: inhibit epidermal cell turnover
- vasoconstrictive: inhibit histamine
What does glucocorticoid steroids inhibit?
NfkB nuclear factor (so it cannot enter nucleus and turn on inflammation genes)
All pattern recognition receptors activate _______
NfkB
Subcutaneous immunotherapy (SCITs) are a type of ____sentization therapy
hyposentization
What is the main goal of SCITs to prevent an immune response?
divert Th2 response from pathogenic to tolerant
How do SCITs divert the Th2 response?
T cells are redirected to produce Tregs instead of Th2 (IgE–>IgG)
What are the steps of SCITs inhibiting an immune response?
- induce IL-10 production (increase T regs and decrease Th2)
- IgE shifts to IgG
- IgG binds to FcGRIIB (inhibitory FcERI)
- no degranulation
IL-4 promotes _____ class switching
IgE
IL-10 promotes ______ class switching
IgG
What is FcGRIIB?
inhibitory version of FcERI
Does FcGRIIB use ITAMs or ITIMS?
ITIMs
How is FcGRIIB inhibitory?
prevents Lyn phosphorylation
Beta-2 agonists target the same receptor as ____________
epinepherine
What does SHIP phosphatase do for FcGRIIB?
removes phosphate from ITAMs to inactivate them
What is the mechanism of anti-IgE therapy?
bind to IgE and prevents it from binding to FcERI
What is the mechanism of anti-IL13 therapy?
blocks IL-13 or its receptor
- doesnt work very well because IL-4 picks up the pace
What is the mechanism of IL-4Ra therapy?
blocks IL-4Ra receptor because IL-13 or IL-4 both use it
- worked
What is the mechanism of anti-IL4 AMG317 therapy?
blocks IL-4Ra receptor because IL-13 or IL-4 both use it
- doesn’t work well because its outcompeted
What is the mechanism of anti-TSLP therapy?
prevent CD4 cells turning into Th2
What is the mechanism of anti-IL5Ra therapy?
blocks IL-5 receptor and induces AMCT
How does Singulair (Montelukast) prevent asthma symptoms?
prevents leukotriene pathway by blocking cysLTR1 (cys-LT antagonist) cys-leuoktrienes
What does FEV stand for?
forced expiratory volume (amount)
What is PEF stand for?
peak expiratory flow (speed)
_________ increases cardiac output (higher BP and more blood flow, dilated veins)
epinephrine
What cytokine initiates the transition to the late phase response?
TNF-a
