Mast cell

What is a Mast Cell?
We still have a lot to leabout the origins of mast cells (or mastocyte), but it is generally accepted that they are the offspring of stem cells found in the bone marrow, and that mast cells start out life as mast cell 'precursor' cells.

Mast cell precursor cells migrate from bone barrow through the bloodstream to tissue and organ sites to eventually become mast cells. Mast cells are found abundantly in the skin, gastrointestinal and genitourinary (reproductive and urinary) tracts, but can also be found in clusters next to small blood vessels and in loose connective tissue.

Mast cells might behave in different ways depending on where they end up in the body, and the cells adapt to whatever situation they find themselves. In healthy individuals, mast cells also die off regularly (this is known as apoptosis) after a set amount of time, allowing new mast cells to replace them.

Mast cells are large, oval cells with coarse granules containing various substances densely packed into the cytoplasm, but can also be spindle-shaped. You might think of the mast cell like a very thin, sometimes leaky, water balloon, packed full of even smaller balloons that contain various potent substances.

On the surface (membrane) of the mast cell are receptors (called IgE-receptors), like tiny keyholes waiting for a Y-shaped key in order to unlock the cell. Mast cells sometimes have c-Kit receptors on their surface, for the stem cell factor (SCF, c-Kit ligand) and a bone marrow biopsy, if carried out correctly, can show if your mast cells have this receptor. This is interesting if you have Mastocytosis because it can suggest treatment options.

The major function of mast cells is to protect the body from intruders (including allergens and parasites) by way of immediate hypersensitive reaction (the allergic cascade) - when mast cells perceive a threat, the cell disintegrates like a tiny bomb of chemicals.

The chemicals released result in a near-instant chain reaction, which might mean an itchy nose if only a few cells disintegrate, to asthma or hives, right the way through to anaphylactic shock (anaphylaxis) if there is an over-reaction and mass disintegration of mast cells. Mast cells are what makes a wound itch as it is healing, and some people with Mastocytosis report that, at times, they heal extraordinarily quickly.

No-one with too few mast cells has been found, suggesting they are essential to life.

[|What is MS]

What chemicals are inside a Mast Cell?
Some of the chemicals released by mast cells when activated are:

• heparin proteoglycan (an anticoagulant)

• serotonin

• dopamine

• tryptase (mast cells located in mucosal areas have a higher level of tryptase than mast cells

• chymase

• histamine (a substance that causes vasodilation and increased permeability of capillaries)

• neutral proteases

• eosinophil chemotactic factor of anaphylaxis (ECF-A)

• phospholipases activation, which results in the secretion of

¤ prostoglandins and

¤ leukotrienes (also called slow reacting substance of anaphylaxis, SRS-A)

• Pro-inflammatory cytokines:

¤ IL-4, IL-5, IL-6, IL-13, IL-18, IFN-γ, TNF-α

• Chemokines:

¤ MCP-1, IL-8, RANTES, eotaxin, leukotriene

• Proteases:

¤ Tryptase, chymase, angiotensin converting enzyme (ACE), carboxypeptidase, cathepsin G, cysteinyl cathepsins

• Hematopoeitic factors:

¤ IL-3, GM-CSF

• Growth factors:

¤ bFGF, VEGF, TGF-beta, PDGF

• Chondroitin sulfate proteoglycan

(Activated mast cells also synthesize and secrete lipid-derived mediators (such as prostaglandins, leukotrienes, and platelet-activating factor) and cytokines (such as interleukin 1, interleukin 3, interleukin 4, interleukin 5, interleukin 6, interleukin 13, tumor necrosis factor-alpha, GM-CSF, and several chemokines.[26][27] These mediators contribute to inflammation by attracting other leukocytes.) histamine, proteoglycans, serine proteases, tryptase, prostoglandins, leukotrienes, cytokines, chemokines

How are Mast Cells activated?
We have learned, above, that the mast cell has an interior full of various substances, a thin membrane surface with tiny receptors waiting for the Y-shaped Antigen/IgE key in order to release the substances.

A mast cell is activated (or triggered) when an antigen binds and crosslinks IgE-receptor complexes on the plasma membrane. At that point a signaling cascade is initiated (like turning the key).



A mast cell (or mastocyte) is a resident cell of several types of tissues and contains many granules rich in histamine and heparin. Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being intimately involved in wound healing and defense against pathogens.

In tests, granules inside the mast cells stain dark purple with basic blue dyes and a lavender/pink color with other staining techniques (which is why you see them represented as purple in such branding as Mastopedia). Mast cells are not easily identified in routine staining because the granules are water-soluble and seldom preserved, which is why it is important, as a Masto patient, to ensure your doctor knows how to stain the slides correctly to get accurate results. Even when the granules are preserved, the mast cell plasma membrane is frequently ruptured in the staining process and granules may be seen in the surrounding tissue.

Origin and classification
Mast cells were first described by Paul Ehrlich in his 1878 doctoral thesis on the basis of their unique staining characteristics and large granules. These granules also led him to the mistaken belief that they existed to nourish the surrounding tissue, and he named them "Mastzellen" (from the Ancient Greek masto, "I feed"). They are now considered to be part of the immune system.

Mast cells are very close to basophil granulocytes (a class of white blood cells) in blood; the similarities between mast cells and basophils has led many to speculate that mast cells are basophils that have "homed in" on tissues. However, current evidence suggests that they are generated by different precursor cells in the bone marrow. Nevertheless, both mast cells and basophils are thought to originate from bone marrow precursors expressing the CD34 molecule. The basophil leaves the bone marrow already mature, whereas the mast cell circulates in an immature form, only maturing once in a tissue site. The tissue site an immature mast cell chooses to settle in probably determines its precise characteristics.

Two types of mast cells are recognized, those from connective tissue and a distinct set of mucosal mast cells. The activities of the latter are dependent on T-cells.

Mast cells are present in most tissues in the vicinity of blood vessels, and are especially prominent near the boundaries between the outside world and the internal milieu, such as the skin, mucosa of the lungs and digestive tract, as well as in the mouth, conjunctiva and nose.

Physiology
Mast cells play a key role in the inflammatory process. When activated, a mast cell rapidly releases its characteristic granules and various hormonal mediators into the interstitium. Mast cells can be stimulated to degranulate by direct injury (e.g. physical or chemical), cross-linking of Immunoglobulin E (IgE) receptors, or by activated complement proteins.

Mast cells express a high-affinity receptor (FcεRI) for the Fc region of IgE, the least-abundant member of the antibodies. This receptor is of such high affinity that binding of IgE molecules is essentially irreversible. As a result, mast cells are coated with IgE. IgE is produced by B-cells (the antibody-producing cells of the immune system). IgE molecules, like all antibodies, are specific to one particular antigen. In allergic reactions, mast cells remain inactive until an allergen binds to IgE already in association with the cell (see above). Other membrane activation events can either prime mast cells for subsequent degranulation or can act in synergy with FceRI signal transduction. Allergens are generally proteins or polysaccharides. The allergen binds to the antigen-binding sites, which are situated on the variable regions of the IgE molecules bound to the mast cell surface. It appears that binding of two or more IgE molecules (cross-linking) is required to activate the mast cell. The clustering of the intracellular domains of the cell-bound Fc receptors, which are associated with the cross-linked IgE molecules, causes a complex sequence of reactions inside the mast cell that lead to its activation. Although this reaction is most well understood in terms of allergy, it appears to have evolved as a defense system against intestinal worm infestations (tapeworms, etc).

The molecules thus released into the extracellular environment include:
 * preformed mediators (from the granules):
 * histamine (2-5 pg/cell)
 * serotonin
 * proteoglycans, mainly heparin (active as anticoagulant)
 * serine proteases
 * newly formed lipid mediators (eicosanoids):
 * prostaglandin D2
 * leukotriene C4
 * cytokines
 * Eosinophil chemotactic factor

Histamine dilates post capillary venules, activates the endothelium, and increases blood vessel permeability. This leads to local edema (swelling), warmth, redness, and the attraction of other inflammatory cells to the site of release. It also irritates nerve endings (leading to itching or pain). Cutaneous signs of histamine release are the "flare and wheal"-reaction. The bump and redness immediately following a mosquito bite are a good example of this reaction, which occurs seconds after challenge of the mast cell by an allergen.

The other physiologic activities of mast cells are much less well-understood. Several lines of evidence suggest that mast cells may have a fairly fundamental role in innate immunity – they are capable of elaborating a vast array of important cytokines and other inflammatory mediators, they express multiple "pattern recognition receptors" thought to be involved in recognizing broad classes of pathogens, and mice without mast cells seem to be much more susceptible to a variety of infections.

Mast cell granules carry a variety of bioactive chemicals. These granules have been found to be transferred to adjacent cells of the immune system and neurons via transgranulation via their pseudopodia.

Allergic disease
Many forms of cutaneous and mucosal allergy are mediated for a large part by mast cells; they play a central role in asthma, eczema, itch (from various causes) and allergic rhinitis and allergic conjunctivitis.

Antihistamine drugs act by blocking the action of histamine on nerve endings. Cromoglicate-based drugs (sodium cromoglicate, nedocromil) block a calcium channel essential for mast cell degranulation, stabilizing the cell and preventing release of histamine and related mediators. Leukotriene antagonists (such as montelukast and zafirlukast) block the action of leukotriene mediators, IgE antibody (omalizumab) also inhibits the binding of free IgE to the high-affinity IgE receptor (FcεRI) on the surface of mast cells and basophils, and are being used increasingly in allergic diseases.

Anaphylaxis In anaphylaxis (a severe systemic reaction to allergens, such as nuts, bee stings or drugs), body-wide degranulation of mast cells leads to vasodilation and, if severe, symptoms of life-threatening shock.

Autoimmunity Mast cells are implicated in the pathology associated with the autoimmune disorders rheumatoid arthritis, bullous pemphigoid, and multiple sclerosis. They have been shown to be involved in the recruitment of inflammatory cells to the joints (e.g. rheumatoid arthritis) and skin (e.g. bullous pemphigoid) and this activity is dependent on antibodies and complement components.

Mast cell disorders Mastocytosis is a rare condition featuring proliferation of mast cells. It exists in a cutaneous and systemic form, with the former being limited to the skin and the latter involving multiple organs.

References:
Text & Image courtesy Barbara Vertel PhD. Histology "Connective Tissue 2 - Cells & Types of CT" Link: http://acad.rosalindfranklin.edu/cms/anatomy/histohome/lectures/ct2/ct_2_lecture_with_figures.html http://www.ncbi.nlm.nih.gov/pubmed/9495641 http://www.pnas.org/content/102/32/11129.full http://www.healthsystem.virginia.edu/internet/hematology/HessEDD/BenignHematologicDisorders/normal-hematopoietic-cells/mast-cell.cfm http://www.abcam.com/index.html?pageconfig=resource&rid=12011&pid=10694

See also http://www.nature.com/nri/journal/v4/n10/fig_tab/nri1460_F1.html