Mast cell

A mast cell (or mastocyte) is a resident cell of connective tissue that 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.

Origin and classification

Mast cells were first described by Paul Ehrlich in 1878 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," meaning "feeding-cells." Nowadays, they are considered part of the immune system. Mast cells are very similar 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 while 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 recognised, 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 express a high-affinity receptor (FcεRI) for Immunoglobulin E (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, in turn, synthesized by B-cells (the antibody-producing cells of the immune system). IgE molecules, like all antibodies, are specific to one particular epitope.

In allergic reactions, mast cells remain inactive until an allergen binds to IgE already in association with the cell (see above). Allergens are generally proteins or polysaccharides. The allergen binds to the Fab part of the IgE molecules on the mast cell surface. It appears that binding of two or more IgE molecules (this is called crosslinking) is required to activate the mast cell; the steric changes lead to a slight disturbance to the cell membrane structure, causing a complex sequence of reactions inside the cell that lead to activation of the cell. 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).

When activated, a mast cell rapidly releases its characteristic granules and various hormonal mediators into the interstitium. Other forms of activation besides IgE (such as by the complement system) have been described.

The molecules thus released into the intercellular environment include:

preformed mediators (from the granules):
- histamine (2-5 pg/cell)
- proteoglycans, mainly heparin (active as anticoagulant)
- serine proteases
newly formed lipid mediators (eicosanoids)
- prostaglandin D2
- leukotriene C4
cytokines

Histamine dilates blood vessels, makes them leaky, and activates the endothelium. 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). Cuteanous 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. These cytokines and other mediators clearly also come into play during injury and wound healing.

Role in disease

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. Cromoglycate-based drugs (sodium cromoglycate, 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, 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.

Immunity

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 cells are also integral to the innate immune response and are important for clearance of bacteria and viruses.

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. A mastocytoma is a mast cell tumor, often seen in dogs and cats.

Sources

Prussin C, Metcalfe DD. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 2003;111(2 Suppl):S486-94. PMID 12592295.

Granulocytes

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