6. Mast Cells Flashcards
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
