Mast cells are immune cells derived from the myeloid lineage. After arising in the bone marrow, progenitor cells circulate and become home to various tissues. Under the influence of stem cell factors locally produced by many cells in the tissue, the progenitor differentiates into a mature mast cell. Mature mast cells are present only in tissue and are not found in circulation.
Mast cells are found in loose (areolar) connective tissue throughout the body, in virtually every organ. They play an important role in inducing the inflammatory cascade. Innate or adaptive immune mechanisms can induce the mast cell to degranulate, releasing inflammatory mediators into the extracellular space. Mast cells are associated with many pathologies, including type I hypersensitivity reactions, mastocytosis, mast cell activation syndrome, and urticaria.
Mast cells are mononuclear cells. Most characteristically, they contain many small secretory granules, ranging in size from 0.2 to 0.8 micrometers. The granules are often so dense as to obscure the nucleus. IgE receptors are found in the plasma membrane. These bind the Fc region of circulating IgE, and two crosslinks to induce cell degranulation.
Two major types of mast cell have been identified and are distinguished by the content of their secretory granules. MC(T) cells contain granules with mostly tryptase. The majority of MC(T) cells are found near mucosal tissue that is exposed to the outside world, i.e. gastrointestinal or respiratory mucosa. These cells act predominantly in the immune response. MC(TC) cells contain tryptase as well as chymase and carboxypeptidase in the secretory granules. The majority of MC(TC) cells are found in the submucosa and connective tissue adjacent to the conjunctiva and skin, often near blood and lymphatic vessels. These cells play a pivotal role in tissue repair.
The classic and most well-known function of mast cells involves the inflammatory cascade. The mast cell functions as part of the body’s innate immune system. When membrane-bound IgE binds a foreign substance and two Fc receptors crosslink, the mast cell immediately releases a large number of mediators into the nearby extracellular space via degranulation. Granules are contained within a lipid membrane which fuses with the plasma membrane. The most important cytokines released is histamine. Histamine induces white blood cell chemotaxis, airway smooth muscle constriction, and increased vascular permeability. Other mediators released from the granules include tryptase, chymase, and TNF-alpha.
Next, the mast cell synthesizes and releases lipid-based prostaglandins and leukotrienes, which have pro-inflammatory effects. Finally, cytokine production is increased due to an increase in gene transcription.
The inflammatory effect of the mast cell is used by the innate immune system as a first line of defense. MC(T) cells are the predominant cell type in the immune response. When a foreign protein is encountered, the pro-inflammatory effects exerted by the mast cell result in recruitment of circulating immune cells. Cytokines released also have direct effects on local tissue, such as increased mucus production or increased gut peristalsis to reduce pathogen invasion.
Mast cells also play a role in tissue repair and angiogenesis. Upon injury, MC(TC) release procoagulant cytokines, leukotrienes, and platelet-activating factor independent of IgE mechanisms. Later, heparin, tryptase, and t-PA from the cell modulate blood flow to increase nutrient and immune cell delivery. Inflammatory mediators promote the differentiation and growth of fibroblasts and endothelial cells. Mast cells also possess many angiogenic cytokines, such as VEGF and FGF 2. Finally, mast cells have been implicated in the wound contraction and the regeneration of nerve fibers.
No deficiency in mast cells has ever been noted, implying that the functions of the cell are vital for life.
Histochemistry and Cytochemistry
The presence of cytoplasmic granules characterizes mast cells. Owing to the high acidity of the heparin in these granules, alkaline dyes undergo a change in color. This property, known as metachromasia, is unique to mast cells and basophils. The alkaline dye toluidine blue will stain secretory granules red-violet. After granules are expelled from the cell, they lose their metachromatic properties and stain pink with toluidine blue.
Mast cells can usually be distinguished from basophils due to their mononuclear morphology, and any question can be resolved with special stains such as tryptase or monoclonal antibodies to the mast cell kit (CD117) receptor.
Hematoxylin and eosin staining reveals eosinophilic granules and does not allow the microscopist to reliably distinguish between mast cells and eosinophils.
Mast cells are oval or irregularly shaped cells. Under light microscopy, a dense granular cytoplasm is seen, often obscuring the nucleus and other organelles. When it can be visualized, the nucleus is central, and the cell is mononuclear.
Mast cells are found throughout the body in loose connective tissue. Some are randomly dispersed in the tissue. They tend to concentrate near blood vessels, where the cell is more elongated. In the skin, concentrates can also be found near follicles, sebaceous glands, and sweat glands.
There are three morphologies of mast cell noted by light microscopy;
- Intact Cells are found near blood vessels as well as deep in the dermis and subcutaneous tissue. Granules are packed very close, making it hard to make out other cellular structures. As noted above, these cells are spindle-shaped in appearance.
- Spreading Cells are found in the superficial connective tissue, near the upper dermis. There are still many granules but fewer than in the intact cell type. This allows a distinction between each granule to be drawn.
- Degranulated Cells are no longer metachromatic. They are pale staining, now appearing light pink with a blue nucleus.
Under scanning electron microscopy, mast cells are again characterized by the abundance of cytoplasmic granules, which may also be described as secondary lysosomes. These granules are surrounded by a lipid membrane. Under the proper conditions, deep invaginations of the cell membrane can be noted. When degranulating, the cell form channels with its plasma membrane, allowing granules deep within the cell to be exposed to the extracellular environment.
The cell has many small, finger-like pseudopods projecting out of the cell membrane. The centrally located nucleus is round with densely packed peripheral chromatin.
The type of cell determines granule ultrastructure.
- Intact Cells have granules with little discernible structure.
- Spreading Cells have a majority of granules composed of fine particulate matter. These granules also have lamellae in circular "scroll-like" patterns interspersed among the particulate matter.
Mast cell pathology is characterized by the signs and symptoms of mast cell degranulation. The most well known is the type I immediate hypersensitivity reaction IgE that bind harmless antigens, circulate throughout the body, and bind to the Fc receptor on mast cells. Upon encountering the specified antigen, IgE receptor crosslinking results in cell degranulation. The release of mediators can lead to a wide variety of effects, including edema, vasodilation, mucous secretion, and bronchoconstriction. Clinically, this can present as allergic rhinitis, asthma, urticaria, anaphylaxis, and angioedema.
Mastocytosis is the result of an abnormal polyclonal proliferation of mast cells due to an activating mutation of the KIT receptor. An increase in inflammatory mediators explains the symptoms of pruritus, hypotension, flushing, and gastrointestinal (GI) upset. Cutaneous mastocytosis (CM), which affects the skin only, is more commonly seen in children. In the skin, mastocytosis may present with a hyperpigmented macule due to the stimulation of melanocytes by the same stem cell factor that promotes mast cell proliferation. One type of CM is maculopapular cutaneous mastocytosis/urticaria pigmentosa. Other variants include diffuse cutaneous mastocytosis, cutaneous mastocytoma, and telangiectasia macularis eruptive perstans.
Systemic mastocytosis can affect nearly any organ in addition to possible skin involvement and is seen in more commonly in adults. The systemic involvement can be indolent or well differentiated. The indolent form is indolent systemic mastocytosis. The well-differentiated form is known as well-differentiated systemic mastocytosis. The skin, GI tract, and bone marrow are most commonly affected. Invasion of a specific organ can lead to organ dysfunction.
Mast cells and their mediators are common targets for pharmaceuticals. Antihistamines block histamine from interacting with its receptor and are widely used to treat type I hypersensitivity reactions. Cromolyn sodium is a mast cell stabilizer that is thought to act on both chloride channels and signaling proteins in the cell membrane to inhibit degranulation.