IgE and its Receptors Flashcards
(32 cards)
What are the “bad” interleukins?
IL 4 and IL 13
Who is the sentinels of the adaptive and innate immune system
mast cells
why do we want to study about membrane receptor?
Favourite target for drug treatment of diseases
xolair
- treat asthma
- block IgE
- IgE can NOT react with allergen
- free from asthma attack
Allergy
Disease due to immune response to allergen and mostly IgE mediated
Hypersensitivity reactions
Inappropriate or exaggerated immune responses that causes inflammation, tissue injuries and disease
hayfever aka allergic rhinitiis
allergen activates mast cells in nasal mucosa and conjunctivae causing
- nasal congestion
sneezing
allergic conjunctivitis
allergic asthma
allergen activates mast cells in lower respiratory tract
Early phase of asthma
- reversible airways obstruction and inflammation
- increased number of mast cells in bronchi
- within 5 minutes of allergen exposure
- mast cell secrete mediators at affected sites
Late phase of asthma
cytokines leads to leukocyte-wbc- accumulation (infiltration)
inflammation
some develop chronic asthma ( chronic inflammation and tissue damage)
asthma attack can be fatal
What are the mechanism of asthma
- sensitisation to allergen
- IgE receptor crosslinking
late phase - recruitment and activation of other immune cells by chemokines and cytokines
describe the first step
mechanism of asthma 1. sensitisation to allergen 2. IgE receptor crosslinking late phase 3. recruitment and activation of other immune cells by chemokines and cytokines
*sensitisation mechanism
- dendritic cells are activated
- migrate to lymph node
- becomes an APC vic MHC and present the antigen to naive T-cell
- T cell –IL4–> Th2 cell
- Th2 produce IL4 and IL13
- Th2 binds/ligation to B cells via (CD40 Ligand on TH2, CD40 Receptor on B cell)
- B cells undergo immunoglobulin class-switch recombination ( when cytokines 1L4,1L13 and ligation
- B cells produce IgE type antibodies
- IgE binds to FcRI on mast cells [SENSITISATION is happening here]
- sensitised mast cell can respond rapidly when re-exposed to allergen
describe the second step
mechanism of asthma
1. sensitisation to allergen –T cells and mast cells
2. IgE receptor crosslinking - mast cells
late phase
3. recruitment and activation of other immune cells by chemokines and cytokines
IgE crosslinking and Fc3RI signalling in mast cells
- crosslinking = Fc3RI (mast cell) + IgE + Antigen
- induces aggregation of Fc3RI moleucles on the plasma membrane of the mast cells
- activates protein tyrosine kinase (LYN and FYN)
- LYN phosphorylate ITAM motifs on Fc3RI and activate SYK ( already bound to ITAM)
- FYN phosphorylate Gab2 and activate the PI3K pathway
- LYN and SYK phosphorylate LAT and other enzymes
- hence regulating the RAS-MAPK , PLC gamma, and PI3K pathway
- mast cells secretes preformed mediators
- granules
- histamines
- peptidase -etc-
and lipid mediators such as prostaglandin
describe the third step
mechanism of asthma 1. sensitisation to allergen 2. IgE receptor crosslinking late phase 3. recruitment and activation of other immune cells by chemokines and cytokines
Late phase recruitment and activation of other immune cells by chemokines and cytokines
- activated mast cells release cytokines, chemokines and growth factors
- mast cells products can recruit other immune cells thus
a) activating innate immune cells
b) anti-inflammatory effect - in late phase, T cell also produce molecules that recognized allergen-derived peptides
Fc3RI
High affinity receptor for IgE
Chronic stage of allergen0induced airway inflammation
Remodelling of the airways
- Increased resident mast cells
- increased smooth muscle lining the airways
- adaptive immune cells now lives in lungs rather than in circulation
- increased goblet cells
5 congestion in airways due to mucus
Why do doctors prescribed steroid for asthma patient?
- Its a transcription inhibitor
so cannot be prescribed all the time
What are the roles of these immune cells
- Eosinophil
- neutrophils
- basophils
eosinophil ( the ultimate killer cells)
- can kill healthy cells such as epithelial cells
neutrophils
-can kill cells by secreting substance
basophils
- secrete more histamines
What are the drugs for asthma?
B2 Adrenoreceptor
- anti histamine
- anti-leukotrienes
- anti-IgE
- corticosteroid
corticosteroid
- inhibit induction of Cox2»_space; so repress transcription of chemokines, cytokines, prostanoids
MacGlashan 2012
Fc3RI is the high affinity receptor that binds to IgE
IgE dependent signalling as therapeutic target for allergies
- omalizumab binds to IgE*
2. reduced free IgE
3. Reduced Fc3RI expression on mast cells
4. but omalizumab have low affinity to IgE, so need high []
FcR1 signalling event
- Crosslinking between Fc3RI , IgE and Allergen
- Activation of Lyn Kinase
- Lyn phosphorylate ITAMS on BG subunit and activate SYK
- SYK and LYN phosphorylate LAT
- phosphotyrosine on LAT creates binding sitefor adaptor protein such as PLC and Grb2
- PLC breaks down phospholipid PIP2 to IP3
- IP3 causes increased in Intracellular Ca2+
- Ca2+ causes increased granulation
- Increased secretion of preformed and lipid mediators by amst cells
How do we find out about the Fc3RI signalling pathways?
- use of model systems such as
a. Immortal cell lines
b. primary cultures
c. haematopoeitic stem cells
d. transgenic mice ( KI/KO/KD) - Immunoprecipitation and yeast2hybrid experiments
* identifyin binding partners - RNAi screens
- Kinase assays
* check for phosphorylation(western blotting of anti-tyrosine - fucntional assays in vitro
* calcium imaging
- GFP tagged protein
- Functional assays in vivo
- systemic anaphylaxis - measure histamine in blood
- passive cutaneous anaphylaxis * ear
activation of mast cells is dependent on
- calcium influx
* via CRAC
