Cellular & Molecular Aspects of Allergy Flashcards Preview

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Flashcards in Cellular & Molecular Aspects of Allergy Deck (37)
1

Where are mast cells particular prevalent?

At sites where the body is in contact with the external environment e.g. skin/gut/lungs and near blood vessels, nerves and glands

2

What do mast cells respond to?

polybasic drugs, mechanical stimulation, UV light/heat, allergen, stings, hypertonic saline, activated complement, neuropeptides

3

What is a potential mechanism for exercise induced asthma?

Exercise causes the airway surface fluid to dry out and the hyperosmolarity triggers mast cell activation

4

What causes allergen induced mast cell degranulation?

Cross linking of IgE bound to FcepsilonR1

5

What is the structure of the FcepsilonR1 receptor?

An alpha chain which binds to Fc region of IgE, a beta chain and two gamma chains. The beta and gamma chains each have one immunoreceptor tyrosine based activation motif (ITAM).

6

How does binding of the FcepsilonR1 receptor by antigen bound IgE lead to mast cell degranulation?

There is a tyrosine kinase (Lyn) which is constitutively associated with the beta chain of the receptor. Cross linking of the receptor allows Lyn to phosphorylate the ITAMS. Tyrosine phosphorylation of the ITAMS initiates the signalling cascade. First there is recruitment and activation of other cellular tyrosine kinases. Then this leads to phospholipase C phospohrylation and activation. PLC activation leads to production of Inositol triphosphate and diacylglycerol. IP3 causes an elevation in calcium levels and DAG causes activation of protein kinase C. PKC phorphorylates myosin light chain and disassembles the actin myosin complex under the plasma membrane which allows the granules to come into contact with the plasma membrane and causes degranulation. The calcium promotes SNARE complex formation and membrane fusion.

7

How does binding of the FcepsilonR1 receptor by antigen bound IgE lead to the production of arachidonic acid metabolites?

The signalling cascade also produces MAP kinase which in turn activates phospholipase A2. PLA2 hydrolyses membrane phospholipids which releases substrates which are converted to mediators such as leukotrienes, prostaglandins

8

How does binding of the FcepsilonR1 receptor by antigen bound IgE lead to the production of cytokines?

There are preformed cytokines (TNFalpha) within the granules that are released on degranulation. But the signalling cascade also results in cytokine gene transcription. MAP kinase leads to cytokine gene transcription. This leads to the production of IL-4, IL-5 and GM-CSF

9

What do the preformed granules contain?

histamine, heparin, tryptase and TNFalpha

10

How long does it take for the contents of granules to be released after an antigen binds to IgE?

30-45 seconds

11

What are the arachidonic acid metabolites that are produced?

Cysteinyl leukotrienes and prostaglandin D2

12

How long does it take for the leukotrienes and prostaglandin D2 to be produced?

10-30 mins

13

How long does it take for cytokines IL-4, IL-5 and GM-CSF to be produced?

hours

14

What are the action of histamine?


* pain and itch
* bronchospasm
* mucus secretion
* vasodilation
* increased vascular leak
* positive inotropic and chronotropic
* gastric acid secretion
* increased wakefulness

15

What are the cysteinyl leukotrienes?

LTC4 and its degraded products LTD4 and LTE4

16

Which enzyme results in the production of LTC4?

5-lipoxygenase - an enzyme which is only present in inflammatory cells, has no role outside of inflammation and is activated by increased intracellular calcium

17

What is the receptor for cysteinyl leuktorienes?

CysLT1

18

What drug blocks the CysLT1 receptor?

leukotriene receptor antagonists

19

What is the physiological role of cysteinyl leukotrienes?

There is no physiological role outside of inflammation

20

What is the pathophysiological role of cyteinyl leukotrienes in anaphylaxis?

Causes hypotension by vasodilation, diminished cardiac output and hypovolemia by leaky vessels

21

What is the pathophysiological role of cysteinyl leuktorienes in asthma?

Causes airway obstruction by mucus production, oedema and smooth muscle shortening

22

What is the pathophysiological role of cysteinyl leukotrienes in hay fever?

Blocks the nasal passages with mucus and oedema

23

What is the action of glucocorticoids?

Inhibits phospholipase A2 - stops leukotrienes and prostaglandins

24

What are the actions of cytokines in allergy?

To induce gene expression changes for inflammatory cell infiltration and structural changes

25

Which cytokine is not down regulated by glucocorticoids?

IL-4

26

What are some endogenous inhibitors of mast cell activation?

prostaglandin E2, adrenaline, cortisol

27

What are some pharmacological inhibitors of mast cell activation?

disodium cremoglycate, nedocromil sodium (mechanism unclear)

28

What is omalizumab?

A humanised anti-IgE antibody which binds and prevents IgE from binding to the FcepsilonR1

29

How is omalizumab used?

It is administered subcutaneously in some asthma therapy to reduce sensitisation over a period of time

30

Can NSAIDs be used as anti-allergic agents?

In some allergies but not in asthma, and aspirin may provoke symptoms in asthmatics

31

What are H1 receptor antagonists used for?

urticaria, atopic dermatitis, hayfever, anaphylaxis, angiodema, bites and stings, motion sickness - not for asthma

32

What are the three generations of H1 receptor antagonists?

sedative, non sedative with cardiac effects, non sedative without cardiac effects

33

What are certirizine and loratidine?

H1 receptor antagonists that are non sedative without cardiac effects

34

Which asthma patients are leukotriene receptor antagonists useful for?

Aspirin induced asthma patients

35

What is montelukast?

A leukotriene receptor antagonist

36

What is used to treat anaphylaxis?

Adrenaline

37

What are the three ways of treating allergy?

Inhibiting mast cell activation (omalizumab), inhibiting mediator production (glucocorticoids), inhibiting mediator actions (antihistamines and leukotriene receptor antagonists)