6. Mast Cells

Question 1

Mast Cells:

Answer 1

• 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))

Question 2

IL-3 stimulates the proliferation of myeloid cells, including mast cells
TRUE OR FALSE

Answer 2

TRUE

Question 3

IL-3 suppresses HSC differentiation into CMPs

Answer 3

FALSE

L-3 promotes HSC differentiation into CMPs

Question 4

IL-3 suppresses HSC differentiation into CMPs

Answer 4

FALSE
IL-3 promotes HSC differentiation into CMPs
IL-3 -> IL-3R -> JAK-STAT signalling

Question 5

Stem Cell Factor (SCF) drives proliferation of BLANK and BLANK

Answer 5

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

Question 6

Mast Cell Heterogeneity:

Answer 6

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

Question 7

Mast Cell Granules:

Answer 7

Specialised Secretory Vesicles
Formed from Golgi network

1. Progranules derived from Golgi
2. Progranules fuse in cytoplasm to form an immature granule
3. Immature granule grows into mature granule

As the granules grow, acidification increases

Question 8

Granule Components:

Answer 8

Biological Amines:
-Histamine, serotonin, dopamine

Proteases:
-Mast cell-specific proteases, lysosomal proteases

Proteoglycans (Aid storage of proteases):

Cytokines:
-TNF, IL-6

Question 9

Histamine:

Answer 9

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

Question 10

Mast cell-specific proteases:

Answer 10

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

Question 11

Stimulation of degranulation:

Answer 11

• 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

Question 12

FcεR:

Answer 12

• 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”

Question 13

2 main effects of mast cell activation:

Answer 13

1. Degranulation

2. De novo synthesis of inflammatory mediators

Question 14

Activated mast cells have predominantly PRO/ANTI-inflammatory effects

Answer 14

Activated mast cells have predominantly pro-inflammatory effects

Question 15

Activated mast cells have predominantly PRO/ANTI-inflammatory effects

Answer 15

Activated mast cells have predominantly pro-inflammatory effects

Increased vascular permeability
Vasodilation
Recruitment and activation of immune cells, including neutrophils

Question 16

Not all mast cell activation is IgE dependent

TRUE OR FALSE

Answer 16

TRUE

Question 17

Mast cells are located at skin and mucosal membranes, which are sites of pathogen entry, therefore mast cells are fast responding
TRUE OR FALSE

Answer 17

TRUE

Question 18

Mast cells express multiple immune receptors:

Answer 18

FcεRI
TLRs
Complement Receptors
IL-33 Receptor

Question 19

TLR agonists and IL-33 promote cytokine and prostaglandin release without mast cell degranulation
TRUE OR FALSE

Answer 19

TRUE

Question 20

IL-33/TLRs vs FcεR:

Answer 20

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

Question 21

IL-33 is constitutively expressed in epithelial and endothelial cells
TRUE OR FALSE

Answer 21

TRUE

Question 22

IL-33 is released from necrotic cells and acts as an alarmin

TRUE

Answer 22

TRUE

Question 23

IL-33 induces production of Th2 cytokines (IL-5, IL-13) by mast cells
TRUE OR FALSE

Answer 23

TRUE