6. Mast Cells Flashcards
(23 cards)
Mast Cells:
- Tissue resident granulocytes
- Involved in IgE and allergic responses
- Found in most tissues, but especially around blood vessels and sites of potential damage such as skin and lungs
- Contain a large number of vesicles with preformed inflammatory mediators (High levels of histamine, mast cell-specific proteases, cytokines (e.g. IL-6, TNF))
IL-3 stimulates the proliferation of myeloid cells, including mast cells
TRUE OR FALSE
TRUE
IL-3 suppresses HSC differentiation into CMPs
FALSE
L-3 promotes HSC differentiation into CMPs
IL-3 suppresses HSC differentiation into CMPs
FALSE
IL-3 promotes HSC differentiation into CMPs
IL-3 -> IL-3R -> JAK-STAT signalling
Stem Cell Factor (SCF) drives proliferation of BLANK and BLANK
Stem Cell Factor (SCF) drives proliferation of HSCs and Mast Cells
SCF binds to a receptor called “C-kit” (A Tyrosine Kinase Receptor), inducing MAPK, PI3K, and PLC signalling
Mast cells are the only mature immune cell to express high levels of C-kit
Mast Cell Heterogeneity:
Mast Cell subsets are best characterised by the proteases they express:
Humans:
MCt : Tryptase Only
MCc: Chymase Only
MCtc: Tryptase AND Chymase
Mice:
MMC (Mucosal Mast Cell): Mcpt-1, -2
CTMC (Connective Tissue Mast Cell): Mcpt-4, -5, -6
Mast Cell Granules:
Specialised Secretory Vesicles
Formed from Golgi network
- Progranules derived from Golgi
- Progranules fuse in cytoplasm to form an immature granule
- Immature granule grows into mature granule
As the granules grow, acidification increases
Granule Components:
Biological Amines:
-Histamine, serotonin, dopamine
Proteases:
-Mast cell-specific proteases, lysosomal proteases
Proteoglycans (Aid storage of proteases):
Cytokines:
-TNF, IL-6
Histamine:
Generated from histidine by action of histadine decarboxylase
Generated in cytoplasm -> Transferred into granules and stored until release
Stimulates cells via Histamine receptors (GPCRs)
- H1 receptor: Widely expressed, drives vasodilation and bronchoconstriction
- H2 receptor: inhibits T and B cell action, relaxes smooth muscles
- H3 receptor: Mainly expressed in neurons, represses neurotransmitter release
- H4 receptor: Stimulates mast cell chemotaxis
Mast cell-specific proteases:
Tryptase: Cleaves after Arg or Lys
Chymase: Cleaves after aromatic residues
Carboxypeptidase
All synthesised as pro-enzymes, converted to active enzymes in the granule via cleavage of the pro-sequence
Diverse functions:
- Cleavage of cytokines
- Cleavage of protein toxins
- Loosening of tight junctions between endothelial cells
- Extracellular matrix remodelling
Stimulation of degranulation:
- Mast cells express receptors for IgE (FcεR)
- IgE binds the receptors on inactivated mast cells
- Monovalent antigens recognised by IgE = Not potent stimulators of mast cell activation
- Polyvalent antigens bind multiple IgEs = Receptor clustering = Efficient mast cell activation
- Receptor activation -> activation of the Tyr kinase “Syk” -> stimulates degranulation
FcεR:
- Tetramer
- Binds IgE
- Alpha-chain: Binds IgE
- Beta-chain: Contains ITAM motif, binds the Src family Tyr Kinase “Lyn”
- Gamma-chain: 2 copies bound by disulphide bridge, contains ITAMs that recruit “Syk”
2 main effects of mast cell activation:
- Degranulation
2. De novo synthesis of inflammatory mediators
Activated mast cells have predominantly PRO/ANTI-inflammatory effects
Activated mast cells have predominantly pro-inflammatory effects
Activated mast cells have predominantly PRO/ANTI-inflammatory effects
Activated mast cells have predominantly pro-inflammatory effects
Increased vascular permeability
Vasodilation
Recruitment and activation of immune cells, including neutrophils
Not all mast cell activation is IgE dependent
TRUE OR FALSE
TRUE
Mast cells are located at skin and mucosal membranes, which are sites of pathogen entry, therefore mast cells are fast responding
TRUE OR FALSE
TRUE
Mast cells express multiple immune receptors:
FcεRI
TLRs
Complement Receptors
IL-33 Receptor
TLR agonists and IL-33 promote cytokine and prostaglandin release without mast cell degranulation
TRUE OR FALSE
TRUE
IL-33/TLRs vs FcεR:
IL-33/TLRs:
- Dimer
- Monovalent ligands
- Signals via MyD88
- Activates MAPK and NFκB
- Stimulates cytokine and prostaglandin production
FcεR:
- Tetramer
- Polyvalent ligands -. receptor clustering
- Signals via Syk
- Activates Ca2+, PKC, and MAPK
- Stimulates degranulation and cytokine and prostaglandin production
IL-33 is constitutively expressed in epithelial and endothelial cells
TRUE OR FALSE
TRUE
IL-33 is released from necrotic cells and acts as an alarmin
TRUE
TRUE
IL-33 induces production of Th2 cytokines (IL-5, IL-13) by mast cells
TRUE OR FALSE
TRUE