lecture 21: mast cells: friend and foe Flashcards
What is the peritoneal mast cell?
Who was paul ehrlich?
- mastzellen - well fed cells
- one of his many observations/advances in immunology
- nobel prize in 1908
What are mast cells best known for?
- their role in Allergic Diseases
- elevated allergen-specific immunoglobulin E (IgE) levels - atopy
- allergic rhinitis (hay fever)
- asthma
- allergic dermatitis/urticaria
- anaphylaxis
Where are mast cells located?
- everywhere!
- particularly prevalent at body sites in contact with the external environment: Skin/Gut/Lung
- commonly found close to blood vessels/nerves/glands
What are some of the stimuli that activate mast cells?
- antigen
- via immunoglobulin E (IgE)
- complement fragments
- neuropeptides
- cytokines/chemokines/growth factors
- bacterial components
- physical
What does cell activation produce in the Mast Cell?
- dramatic changes in mast cell surface topography
What is mast cell degranulation?
- compound degranulation (anaphylactic degranulation)
What are some mediators released by mast cells?
- granular
- histamine
- tryptase/chymase
- other protease
- (cytokines)
- de novo synthesized
- LTC4
- PGD2
- transcriptional regulation
- cytokines and chemokines
What are features to consider of the mighty mast cell?
- location
- reactivity
- armoury
- ideally suited to initiating/regulating
- pathophysiological and physiological (?) processes
- how is cell activation controlled?
- focus: IgE-dependent activation
What controls mast cell activation?
- Fc epsilon RI receptor
- ITAMS: Immuno receptor Tyrosine-based Activation MotifS (have a consensus sequence)
What is FceRI receptor signalling?
What is ITAM-mediated signalling?
- commonly found in the major immune regulating receptors (kinases involved will differ according to cell type)
- examples include:
- B-cell receptor
- T-cell receptor
- Fc receptors for other immunoglobulins
- also seen in several virally encoded proteins
- inhibitory version also exists in some receptors - immunoreceptor tyrosine-based inhibitory motif - ITIM
How has the role of mast cell been examined?
- disodium cromoglycate (DSCG) - mast cell ‘stabilising’ drug
- mast cell deficient mice
- mutation in stem cell factor system: ligand, receptor, gene promoter
- also newer transgenics - deletion strategies through gene targeting of mast cells
How may stem cell factor be important to many cells?
- reconstitution of animals with mast cell grown in culture (bone marrow-derived mast cells)
- look for reversal of phenotype
- mast cells from KO/transgenic animals can also be used)
In what ways is mast cell a foe?
- allergic disease
- cardiovascular disease
- kidney disease
- rheumatoid arthritis
- obesity
- mast cells increased in human white adipose tissue from obese donors
- enhanced serum levels of tryptase
- mast cell deficient animals, or those treated with DSCG, gain less weight on Western diet
- CNS - multiple sclerosis
- cancer (not just mastocytosis)
- infectious diseases
- (still a work in progress)
- asthma
- mast cells uniquely elevated in asthmatic airways cw eosinophilic bronchitis
- found in close proximity to airway smooth muscle cells
How could we get rid of mast cells?
- IgE-Fc portion - binds to FceRI
- fused with pseudomonas exotoxin A (PE40)
- this toxin causes cell death
- means targeting and selectively eliminating mast cells
What is parasite-derived mast cell inhibitor?
- ES-62
- a glycoprotein secreted by filarial nematodes
What is mast cell protection against bacterial infection?
- cecal ligation and puncture (CLP) model of sepsis
- W/Wv - another mast cell deficient mouse
What is envenomation?
What are ways of utilising mast cells?
- enhance mast cell activation in immunity as a vaccine adjuvant
- compound 48/80
