L11.1 Mast cells and allergy Flashcards Preview

Pharmacology > L11.1 Mast cells and allergy > Flashcards

Flashcards in L11.1 Mast cells and allergy Deck (27):
1

Location of Mast cells

  • Everywhere, but particularly at sites in contact with external env (lungs/skin/gut)
  • Commonly found close to BV/N/glands

2

Relation of mast cells with IgE

  • ↑ IgE
  • Associated with: hay fever, asthma…

3

Stimuli for mast cells

  • Antigens via IgE
  • Complement fragments (result of innate immunity)
  • Neuropeptides (mast cells found localised around neurons)
  • Cytokines/chemokines
  • Bacterial components
  • Physical trauma

4

Mast cell degranulation

  • Degranulation occurs upon activation
    • Release anaphylactic agents 
  • Granules fuse with plasma membrane and release contents 

5

Degranulation via granule fusion

  • Granules can fuse with other granules (already docked at plasma membrane) → prod large granule with common exit point
    • Compound degranulation (anaphylactic degranulation)

6

Mediators released by mast cells: Granular

  • Histamine
  • Tryptase → used for activating precursor cytokines
  • Preformed mediated (e.g. TNFα)

7

De Mediators released by mast cells: De novo

  • LTC4 → bronchoconstrictor
  • PGD2 → bronchoconstrictor and regulatory roles

8

Mediators released by mast cells: transcriptional regulation

  • ↑ Cytokines/chemokines (Few hours later)

9

Mediators released by mast cells

  • Exosomes (Membrane enclosed mini granules)
    • Have variety of protein on surface that can transfer them to specific sites → have specific site actions
    • Contain mRNA and miRNA → alter transcriptional processes

10

Features of the 3 subunits of FceR1

  • α → binds IgE
    • Glycosylation of subunits → keeps α-subunits from bind with each other → prevent initiating allergen independent activation(pineapples)
  • Β → spans membrane 4 times
    • Interacts with α
    • Attractant at the tail
    • Have motif to recruit kinases/adaptor molecules
  • γ → Have motif at tail to signal downstream molecules

11

ITAMS

 

  • Motifs at β and γ tails = ITAMS (immunoreceptor tyrosine-based activation motifs - have common sequence)
  • Motifs have tyrosine (Y) residues and are able to be phosphorylated (Y-P)

12

Mechanism of antigen/IgE cross-linking

  1. Antigens exposure → cross-links the FceR1 α R
  2. Lyn kinase recruited → phosphorylates ITAMS of γ subunit
    • Lyn has Y-P motifs in the ITAMs
  3. Syk brought in and is phosphorylated by Lyn → downstream signallings
  4. Downstream pathways:
    • Ras
    • PLC
    • MAPK

13

ITAM mediated signalling

  • Commonly found in major immune regulating R
    • B-cell R/T-cell R
    • Also in virally encoded proteins

14

Dampening IgG pathway

  • Allows auto-regulation of immune pathways
  • ITIM (immunoreceptor tyrosine-based inhibtory motifs)
    • e.g. IgG R (FcγR11b)
  • Draw in phosphatases → remove phosphate groups → dampen ITAM signalling pathways
  • IgG upregulated when you already have high AB against that antigen
    • When antigens bind → also binds FcγR11b → dampens downstream signalling for clonal proliferation

15

Lipid Rafts/microdomains

  • Sub-structures within cellular membrane
  • Cross-linking of α R → might enable R to enter these microdomains to allow signalling (instead of recruiting Lyn)

16

Histamine Receptors

  • Mediates activity through H1,2,3,4
    • H4 selectively in immune cells
  • All are GPCRs

17

Triple response from histamine

  • Redding - Vasodilatation at initial site
  • Wheal - ↑ vascular permeability
  • Flare - broader reddening from spreading of sensory neurons

18

Anti-allergic therapies

  • Selective H1 antagonist - preventing action of histamine on H1 R
  • May also block mast cell actions
  • Hayfever/dermatitis…
  • NOT in colds/asthma

 

19

Sedative H1 antagonist 

  • Chloropheniramine, promethazine
  • Causes Drowsiness 
  • Crosses BBB therefore sedative

20

Non-sedative H1 antagonists

  • Terfenadine, astemizole
  • Lack anti-Mus activity
  • Does not cross BBB
  • Withdrawn due to Ventricular arrhythmia

21

Newer non-sedative H1 antagonists

  • cetirizine, loratidine
  • less cardiac adverse effects

22

Omalizumab

  • Humanised anti-IgE AB
    • Very specific binding to FceR1 α R (stabilises cell surface due to loss of IgE)
  • Manage moderate/severe asthma
  • Prevents initial antigen presentation (interacting with dendritic cells)

23

Targeting mast cells: Disodium cromoglycate

  • Prevents degranulation of mast cells
  • Agonist at GPR35

24

Targeting mast cells: Syk kinase inhibitors

  • Impairs eisonophil levels in the airways

25

Targeting mast cells: Immunotherapy

  • Give small and increasing dose of substance allergic to → Desensitise IgE dependent activation pathway (develop a tolerance)
    • Skewing towards a IgG response → neutralise IgE response

26

Problems with immunotherapy

  • Adverse reaction → may exacerbate anaphylatic (allergic) rxn

27

Rushed immunotherapy

  • speedy densitisation → ↑allergen over short time
  • Danger → suffer from ↑A.E
  • Pre-treat with omlizumab → ↓IgE levels first → better compliance (dampen allergen specific effects of IgE)