Reviewer: S. Randhawa, M.D., Allergist/Immunologist
Role of mast cells in allergy had remained undetermined until the discovery of IgE in 1966. Then, IgE purified from many Liters of plasma, which had been donated from a patient with fatal myeloma, was distributed to researchers all over the world (http://buff.ly/12sD3cO).
Mast cells and basophils are the major cells in the early phases of immediate hypersensitivity reactions. Mast cells are fixed in the tissues while basophils circulate in the blood. Both are derived from CD34+ bone marrow progenitor cells.
CD differentiation (captions in German). Image source: Wikipedia.
Blood cell lineage. Image source: Wikipedia.
Mast cells (mind map).
Mast cells are derived from Kit+ (CD117), CD34+ stem cells in the bone marrow.
Mast cells are fixed in tissues and are bigger than basophils. They are 10 μm in size and have round nuclei. Mast cells have many more granules (1000 per cell) than basophils (80 granules) but their granules are 6 times smaller (0.2 µm vs. 1.2 µm).
Mast cells are subdivided into 2 types based on proteinase content:
TC mast cells - Tryptase and Chymase in granules, Kit+/CD88+
T mast cells - Tryptase only granules, Kit+/CD88-
TC
Tryptase/Chymase, Kit+/CD88+
T
Tryptase only, Kit+/CD88-
D
Dermis
Dual granules - Tryptase/Chymase
Dual surface markers - Kit+/CD88+
M
Mast cells
Major cell (10 µm) -- 2 times bigger than basophils (5 µm)
Minute granules (0.2 µm)
More granules (1000) than basophils (80)
Monophorm (round) nucleus
B
Basophils
Blood circulation
Bigger granules (1.2 µm)
Bilobar nucleus
Mast-Cell Signaling and Degranulation
Mast cells have FcεRI receptors which bind specific IgE. When a multivalent allergen binds to IgE, this leads to crosslinking of FcεRI receptors. Crosslinking, via signaling, leads to mast cell degranulation and production of cytokines, chemokines, and other mediators.
Role of IgE and mast cells in allergy. Image source: Wikipedia.
Mast Cell Mediators
The mediators fall into 3 groups remembered by the mnemonic ONC.
ONC:
Old
New
Cytokines
Old (pre-formed) Mediators in Granules of Mast Cells
Histamine is the classic example of a granule-associated mediator. Serine proteases (Tryptase/Chymase) are also pre-formed mediators in the granules of mast cells. The participate in airway remodelling in asthma.
Histamine structure. Image source: Wikipedia.
The seminal work on histamine was published in 1910, but histamine was not identified as a mediator of anaphylactic reactions until 1932. Histamine is a major mediator responsible for the symptoms of allergic rhinitis, with its activities mediated through 4 G protein-coupled receptors. Most of histamine's effects are exerted through the H₁ receptor, but some effects are through the H₂ and H₃ receptors, and possibly also through the H₄ receptor (source: The basics of histamine biology. Lieberman P. Ann Allergy Asthma Immunol. 2011 Feb;106(2 Suppl):S2-5. Epub 2010 Sep 16.)
Structure of trypsin, a typical serine protease. Image source: Wikipedia.
Hereditary angioedema (HAE) is an autosomal dominant condition associated with episodic attacks of nonpitting edema. Patients with HAE have low levels of C1 inhibitor (a serine protease inhibitor).
Mast cells quickly generate different mediators from the metabolism of arachidonic acid: leukotrienes and prostaglandins (LTC4, LTB4, PGD2). These substances are produced within minutes of IgE-receptor crosslinking on the surface of mast cells.
Eicosanoids are signaling molecules made by oxygenation of 20-carbon essential fatty acids. There are 4 families of eicosanoids (PP-LT): prostaglandins (PG), prostacyclins (PGI), leukotrienes (LT) and thromboxanes (TX).
Arachidonic acid. Image source: Wikipedia.
LTC4 is a cysteinyl leukotriene, as are D4 and E4. Image source: Wikipedia.
LTB4. Note the four double bonds, three of them conjugated. This is a common property of A4, B4, C4, D4, and E4. Image source: Wikipedia.
Prostaglandin D2. Image source: Wikipedia.
Leukotriene receptors mnemonic
Leukotriene
B4
BLT 1, 2 receptors
Leukotriene
C4, D4, E4
CysLT 1, 2 receptors
Cytokines
Different cytokines are produced by mast cells including interleukins, TNF, FGF, GM-CSF.
Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine that has been implicated in the airway pathology in asthma. TNF-α may play an important role in severe refractory asthma unresponsive to inhaled CS.
Etanercept (Enbrel) is a recombinant human TNF-α receptor fusion protein (anti-TNF-α). Its therapeutic potential is based on the fact that TNF-alpha is the "master regulator" of the inflammatory response in many organ systems.
Mediators released from mast cells
Preformed mediators (from the granules):
- serine proteases, such as tryptase
- histamine (2-5 pg/cell)
- serotonin
- proteoglycans, mainly heparin (active as anticoagulant)
- TNF
Mature tryptase (β-tryptase)
Both α- and β-tryptase are elevated in mastocytosis.
Only β-tryptase (mature tryptase) is elevated in anaphylaxis.
Newly formed mediators:
- prostaglandin D2 (PGD2, eicosanoid)
- leukotriene C4 (LTC4, eicosanoid)
- platelet-activating factor (PAF)
- cytokines, e.g. IL-4
- eosinophil chemotactic factor
Mast cells, described in 1878, play a multifunctional role in the immune system, including in male infertility. Antihistamines may be used to treat male infertility due to the suspected role of mast cells (Medscape, 2011).
References
Allergy and Immunology MKSAP, 3rd edition.
Targeting TNF-α: A novel therapeutic approach for asthma. JACI, Volume 121, Issue 1, Pages 5-10 (January 2008)
Related Reading
FIT Corner Q & A from 5th edition of Cellular and Molecular Immunology, edited by Abul K. Abbas and Andrew H. Lichtman. ACAAI, 2004.
Mast Cell Disorders (presentation on Google drive):
Published: 12/13/2010
Updated: 11/12/2012
1 comment:
Fantastic review of mast cells and comparisons with basophils. Has been very useful for my pre-reading on mast cells. Keep it up!
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