mast cells Flashcards
mast cells background
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
mast cell morphology
dense granules in cytoplasm
found in tissue near damage sites
develop from hematopoeitic stem cells in the bone marrow
stem cell factor
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
il3
stimulates proliferation of myeloids including mast cells
promotes hsc differentiation into cmp or lymphoid progenitor
il3 ko doesnt affect mast cells in vivo
heterogeneity of mast cells
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
mouse mast cells
mucosal and connective tissues
human mast cells
MCt - tryptase only
MCc - chymase only
MCtc - tryptase and chymase
function of granules
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
what are granules
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
components of granules
amines - histamine, serotonin, dopamine
proteases - mast cell specific proteases, lysosomal proteases
proteoglycnas - aid storafge of proteases
cytokines - tnf and il6
histamine background
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
mast cell specific proteases
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
stimulation of degranulation
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
FcE receptor
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
FcE in the stimulation of degranulation
FcER activated by clustering
syk is the key kinase that allows activation of downstream signalling
pkc and calcium signalling drive degranulation
other mast cell products
not preformed are synthesised on mast cell activation
cytokine spromote th2 function
chemokines are for immune cell recruitment
mast cell functions
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
type 1 hypersensitivity
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
drugs targeting mast cell actions
antihistamines - block receptors activated by histamine
leukotriene antagonists - block leukotriene receptors targeted by leukotrienes released from mast cells
mast cell stabilisers inhib degranulation
enigma of mast cells
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
mast cells and infection
located at skin/mucosal membranes
fast responding cell
proinflam
other innate cells are also present at these locations
they are not essential for immunity
helminth infections
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
bacterial infection
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
immune receptors on mast cells
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
Il-1/TLR
dimer activation via monovalent ligands signal via myd88 activates mapk and nfkb stimulates cytokine and prostoglandin production
FcER
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
il33
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
granulocytes
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
