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BMS 301 > IgE and its Receptors > Flashcards

IgE and its Receptors Flashcards

1
Q

What are the “bad” interleukins?

A

IL 4 and IL 13

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2
Q

Who is the sentinels of the adaptive and innate immune system

A

mast cells

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3
Q

why do we want to study about membrane receptor?

A

Favourite target for drug treatment of diseases

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4
Q

xolair

A
  • treat asthma
  • block IgE
  • IgE can NOT react with allergen
  • free from asthma attack
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5
Q

Allergy

A

Disease due to immune response to allergen and mostly IgE mediated

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6
Q

Hypersensitivity reactions

A

Inappropriate or exaggerated immune responses that causes inflammation, tissue injuries and disease

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7
Q

hayfever aka allergic rhinitiis

A

allergen activates mast cells in nasal mucosa and conjunctivae causing

  • nasal congestion
    sneezing
    allergic conjunctivitis
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8
Q

allergic asthma

A

allergen activates mast cells in lower respiratory tract

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9
Q

Early phase of asthma

A
  • 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
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10
Q

Late phase of asthma

A

cytokines leads to leukocyte-wbc- accumulation (infiltration)

inflammation

some develop chronic asthma ( chronic inflammation and tissue damage)

asthma attack can be fatal

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11
Q

What are the mechanism of asthma

A
  1. sensitisation to allergen
  2. IgE receptor crosslinking
    late phase
  3. recruitment and activation of other immune cells by chemokines and cytokines
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12
Q

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
A

*sensitisation mechanism

  1. dendritic cells are activated
  2. migrate to lymph node
  3. becomes an APC vic MHC and present the antigen to naive T-cell
  4. T cell –IL4–> Th2 cell
  5. Th2 produce IL4 and IL13
  6. Th2 binds/ligation to B cells via (CD40 Ligand on TH2, CD40 Receptor on B cell)
  7. B cells undergo immunoglobulin class-switch recombination ( when cytokines 1L4,1L13 and ligation
  8. B cells produce IgE type antibodies
  9. IgE binds to FcRI on mast cells [SENSITISATION is happening here]
  10. sensitised mast cell can respond rapidly when re-exposed to allergen
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13
Q

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

A

IgE crosslinking and Fc3RI signalling in mast cells

  1. crosslinking = Fc3RI (mast cell) + IgE + Antigen
  2. induces aggregation of Fc3RI moleucles on the plasma membrane of the mast cells
  3. activates protein tyrosine kinase (LYN and FYN)
  4. LYN phosphorylate ITAM motifs on Fc3RI and activate SYK ( already bound to ITAM)
  5. FYN phosphorylate Gab2 and activate the PI3K pathway
  6. LYN and SYK phosphorylate LAT and other enzymes
  7. hence regulating the RAS-MAPK , PLC gamma, and PI3K pathway
  8. mast cells secretes preformed mediators
    - granules
    - histamines
    - peptidase -etc-

and lipid mediators such as prostaglandin

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14
Q

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
A

Late phase recruitment and activation of other immune cells by chemokines and cytokines

  1. activated mast cells release cytokines, chemokines and growth factors
  2. mast cells products can recruit other immune cells thus
    a) activating innate immune cells
    b) anti-inflammatory effect
  3. in late phase, T cell also produce molecules that recognized allergen-derived peptides
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15
Q

Fc3RI

A

High affinity receptor for IgE

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16
Q

Chronic stage of allergen0induced airway inflammation

A

Remodelling of the airways

  1. Increased resident mast cells
  2. increased smooth muscle lining the airways
  3. adaptive immune cells now lives in lungs rather than in circulation
  4. increased goblet cells

5 congestion in airways due to mucus

17
Q

Why do doctors prescribed steroid for asthma patient?

A
  1. Its a transcription inhibitor

so cannot be prescribed all the time

18
Q

What are the roles of these immune cells

  • Eosinophil
  • neutrophils
  • basophils
A

eosinophil ( the ultimate killer cells)
- can kill healthy cells such as epithelial cells

neutrophils
-can kill cells by secreting substance

basophils
- secrete more histamines

19
Q

What are the drugs for asthma?

A

B2 Adrenoreceptor

  • anti histamine
  • anti-leukotrienes
  • anti-IgE
  • corticosteroid
20
Q

corticosteroid

A
  • inhibit induction of Cox2&raquo_space; so repress transcription of chemokines, cytokines, prostanoids
21
Q

MacGlashan 2012

A

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 []
22
Q

FcR1 signalling event

A
  1. Crosslinking between Fc3RI , IgE and Allergen
  2. Activation of Lyn Kinase
  3. Lyn phosphorylate ITAMS on BG subunit and activate SYK
  4. SYK and LYN phosphorylate LAT
  5. phosphotyrosine on LAT creates binding sitefor adaptor protein such as PLC and Grb2
  6. PLC breaks down phospholipid PIP2 to IP3
  7. IP3 causes increased in Intracellular Ca2+
  8. Ca2+ causes increased granulation
  9. Increased secretion of preformed and lipid mediators by amst cells
23
Q

How do we find out about the Fc3RI signalling pathways?

A
  1. use of model systems such as
    a. Immortal cell lines
    b. primary cultures
    c. haematopoeitic stem cells
    d. transgenic mice ( KI/KO/KD)
  2. Immunoprecipitation and yeast2hybrid experiments
    * identifyin binding partners
  3. RNAi screens
  4. Kinase assays
    * check for phosphorylation(western blotting of anti-tyrosine
  5. fucntional assays in vitro
    * calcium imaging
    - GFP tagged protein
  • Functional assays in vivo
  • systemic anaphylaxis - measure histamine in blood
  • passive cutaneous anaphylaxis * ear
24
Q

activation of mast cells is dependent on

A
  • calcium influx

* via CRAC

25
Q

How do we find out about CRAC channel?

A

1st clue - SCID patient > Ca2+ store depletion does not trigger ca2+ entry in T cells (hence no granulatiom, hence no mediators secreted , hence immunodeficient?)

2nd clue - the gene STIM-homologue in drosophila is needed for CRAC to function

3rd clue - Ca2+ store depletion induces STIM1 translocation to plasma membrane

4th clue - mutation of CRAC gene (ORAI) causes immunodeficiency in SCID patient due to failure of CRAC channel to function

26
Q

What is STIM

A
  • found in endoplasmic reticulum
  • act as Calcium sensors ( have EF hand)
  • signals to CRAC to open and let Ca2+ influx when the store of ca2+ is depleted
27
Q

CRAC

A
  • ca2+ channel found in plasma membrane
28
Q

SERCA

A
  • Sarco-endoplasmic Reticulum Calcium Channel
  • found in sarcoplasmic or endoplasmic reticulum
  • Let Ca2+ enter the store from the cytoplasm
  • Blocked by Thapsigargin
29
Q

Describe the experiment with SCID patient by Feske et al 2005

A
  1. Collect healthy and SCID T cells culture
  2. Put in a solution without calcium (calcium will eventually depleted from the store due to er being leaky)
  3. Add Thapsigargin, a SERCA inhibitor (so that when we put calcium back into the solution, calcium cannot enter store)
  4. Replace calcium free solution to solutions containing calcium
  5. measure Ca2+ influx into the CELL (cytoplasm, not ER)
  6. in healthy t cell, after ca2+ addition, there is an INFLUX of Ca2+ inside the cell
  7. i SCID, no influx eventhough calcium in ER is low and we have now calcium in the solution.

– behaves as if the cell does not know that it is depeleted of calcium and it doesn’t want to take up more calcium

30
Q

SCID

A

SEVERE COMBINED IMMUNO-DEFICIENCY

impaired T cell function

acts like DOMINANT NEGATIVE inhibitor of CRAC

31
Q

Describe the experiment on STIM homologue by Roos J et al 2005

A
  1. Basically the same experiment as Feske
  2. But using healthy T cells
  3. and adding dsRNA for STIM to suppress gene expression
  4. in dsRNA treated, no CRAC current detected after adding calcium
  5. IV curve in normal cells shows inward rectification
    * this experiment does not involve thapsigargin
32
Q

Evidence that STIM is not a channel?

A
  • only ONE transmembrane domain

- found in ER ( not in plasma membrane)

BMS 301 (5 decks)

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