mast cells

Question 1

mast cells background

Answer 1

tissue resident granulocytes
involved in ige and allergic reaction
major source of histamine

found in most tissues around blood vessels and potential sites of damage
contain large nos of vesicles with preformed inflam mediators

Question 2

mast cell morphology

Answer 2

dense granules in cytoplasm
found in tissue near damage sites
develop from hematopoeitic stem cells in the bone marrow

Question 3

stem cell factor

Answer 3

drives proliferation of hsc and mast cells
c kit
- tyrosine receptor kinase
- expressed n hsc and cmp
- mast cells are only mature cells to express high levels of c kit receptor
up regulated / activated in some cancers
inhib of scf or c kit stop mast cells development

Question 4

il3

Answer 4

stimulates proliferation of myeloids including mast cells
promotes hsc differentiation into cmp or lymphoid progenitor
il3 ko doesnt affect mast cells in vivo

Question 5

heterogeneity of mast cells

Answer 5

final differentiation occurs in tissues
likely that mast cells retain plasticity and in vivo phenotype reflect local cytokines they are exposed to
mast cell subsets are best described by the proteases they express

Question 6

mouse mast cells

Answer 6

mucosal and connective tissues

Question 7

human mast cells

Answer 7

MCt - tryptase only
MCc - chymase only
MCtc - tryptase and chymase

Question 8

function of granules

Answer 8

secrete vesicles storing preformed inflam mediators
histamine
mast cells specific proteases
cytokines
lysosomal proteases
mast cells can also synthesise inflam mediators de novo following stimulation

Question 9

what are granules

Answer 9

specialised secretory vesicles
formed from the golgi network
clathrin coated vesicles bud from the golgi to form progranules
fusion of progranules to form immature granules hem mature granules

Question 10

components of granules

Answer 10

amines - histamine, serotonin, dopamine
proteases - mast cell specific proteases, lysosomal proteases
proteoglycnas - aid storafge of proteases
cytokines - tnf and il6

Question 11

histamine background

Answer 11

made from amino acid histidine
generated during the formation of granules and stored until release
mast cellsa re major source but histamine can also act as a neurotransmitter in the cns
stimulates cells via histamine receptors
- h1 receptor - widely expressed, drive vasodilation and bronchoconstriction
- h2 receptors - inhibs t and b cells actions and smooth muscle relaxation
- h3 receptor - mainly expressed on neurons, represses neurotransmitter release
- h4 receptor - stimulates mast cell chemotaxis

Question 12

mast cell specific proteases

Answer 12

trypase - serine protease - cleaves after arg/lys
chymase - serine protease - cleaves after aromatic residue
carboxypeptidase - metaloprotease

proteases found are depepndent on type of mast cell
synthesised as proenzymes, converted into active enzymes in granule via cleavage of pro-sequence

diverse functions

• cleavage of cytokines
• losening tight juncs between enothelial cells
• extracellular matrix remodelling
• cleavage of protein toxins

Question 13

stimulation of degranulation

Answer 13

mast cells express ige receptors
ige bind receptors of inactive mast cells
polyvalent antigens are able to being multiple ige resulting in receptor decluttering - required for efficient activation
receptor activation - activation of tyrosine kinase Jyk .
stimulates degranulation

Question 14

FcE receptor

Answer 14

ige
tetrameric
b chain contains itam motif and binds to the tyrosine kinase lyn
y chain has 2 copies and are bound by a disulphide bridge containing itams that recruit jyk

Question 15

FcE in the stimulation of degranulation

Answer 15

FcER activated by clustering
syk is the key kinase that allows activation of downstream signalling
pkc and calcium signalling drive degranulation

Question 16

other mast cell products

Answer 16

not preformed are synthesised on mast cell activation
cytokine spromote th2 function
chemokines are for immune cell recruitment

Question 17

mast cell functions

Answer 17

likely to play a role in immune response
activation is pro-inflam 
2 main forms of activation 
 1. degranulation 
 2. selective relase of cytokines 
activated mast cells pro-inflam effects
 - increased vascular permeability
 - vasodilation 
 - recruitment and activation of immune cells incl neutrophils

Question 18

type 1 hypersensitivity

Answer 18

mast cells express receptors for igE
mast cells bind igE from active b cells
challenge with the same antigen will activate the mast cell for degranulation
- polyvalent antigen is required
- receptor crosslinking or clustering is required for efficient activation

Question 19

drugs targeting mast cell actions

Answer 19

antihistamines - block receptors activated by histamine
leukotriene antagonists - block leukotriene receptors targeted by leukotrienes released from mast cells
mast cell stabilisers inhib degranulation

Question 20

enigma of mast cells

Answer 20

allergic disease and anaphylaxis after degranulation
proteases may degrade toxins
potential role in wound healing
may play roles in initial response to infection
not all mast cell activation is ige dependent
protective function of mast cells is not unique to mast cells

Question 21

mast cells and infection

Answer 21

located at skin/mucosal membranes
fast responding cell
proinflam

other innate cells are also present at these locations
they are not essential for immunity

Question 22

helminth infections

Answer 22

antiworm are th2 biased
cytokines secreted by mast cells promote th2
mast cell nos increase with worm infection
ckit muts showed delated response to t spiralis
mast cells protease 1 or 6 ko also have delayed expulsion

Question 23

bacterial infection

Answer 23

mast cells can be activated by bacterial pamps
pamps stimulate cytokine and chemokin secretion by mast cells leading to inflam and neutrophil recruitment but not degranulation

klebsiella pneumoniae

Question 24

immune receptors on mast cells

Answer 24

FcERI
- binds ige - activated by receptor clustering following binding of polyvalent antigens bound to ige
- promotes degranulation of cytokine release
complement receptos
TLRs
IL33
- both promote cytokine and prostoglandin release but not degranulation
combo of FcER TLR or IL33 has synergistic effect on mast cell activation

Question 25

Il-1/TLR

Answer 25

dimer
activation via monovalent ligands
signal via myd88
activates mapk and nfkb
stimulates cytokine and prostoglandin production

Question 26

FcER

Answer 26

tetramer and igE bound
multivalent ligand requires receptor clustering
signals via receptor associates tyrosine kinases
activates calcium PKC and MAPK
stimulates degranulation
cytokine and prostoglandin production

Question 27

il33

Answer 27

member of il1 cytokine fam
doesnt process signal peptide sequence
not processed by inflammasome
constitutive expression in epithelial and endothelial cells
released from necrotic cells acts as an alarmin
promotes th2 production
promotes granulocyte recruitment

Question 28

granulocytes

Answer 28

white blood cell characterised by the presence of granules and a labelled nucleus
neutrophils are the most common wbc
one of the first cells to be recruited to site of infection / inflam
proinflam/ pathogen killing cells
die during resolution - clearance of dead neutrophils by macrophages promotes antiinflam phenotype