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MASTOCYTE

Mastocytes are often found in the connective tissue proper. They differentiated from myeloid cells and contain many granules with substances such as histamine and heparin. Mastocytes are related to the immune system, more precisely with allergic and hypersensitivity responses. They are probably an evolutionary ancient cell lineage because they are found in all species with circulatory blood system. Masctocytes are rounded cells with metachromatic granules (show a different color from the color of the dye).

Mastocytes were first described by Paul Earlich at the end of 1800s as cells that could be stained with aniline dyes and showing metrachromatic granules in the cytoplasm. It named them "Mastzellen" (well-fed, in German), because he thought that the granules were food leftovers after phagocytosis and digestion. Food was incorporated from the surrounding tissue. Mastocytes have been found in every vertebrate species studied ever since, fishes included.

1. Morphology

At light microscopy, mastocytes are round or ovoid. In humans, they are 8-20 µm in size depending on the organ they are found. The nucleus is not lobulated and occupies a central position. The more salient features is the large amount of metachromatic granules in the cytoplasm. Metachromasia is clearly visible when they are stained with toluidin blue because granules show a reddish color (Figures 1 and 2). This is mostly caused by heparin, a sulfated glycosaminoglycan.

Mastocytes
Figure 1. Mastocytes in the pig dermis stained with toluidin blue. However, granules provides to the cytoplasm a purple-reddish color.
Mastocytes
Figure 2. Mastocytes stained with toluidin blue. Semithin section.

Microvilli and small folds are visualized at the cell surface with the electron microscope. Mastocytes do not have many mitochondria, endoplasmic reticulum profiles are short, but show many free ribosomes. The secretory granules are about 1.5 µm in diameter and the granule content aspect varies according to the stored substances and to the animal species. For example, in rodents, granule content looks like fine granulate, whereas in humans the granule content may be organized in thin and concentric sheets. At electron microscopy, different densities are observed in the granules of the same mastocyte, which means a different content in the same cell. The aspect of the granule content may sometimes be related with its function. For example, granules that contains chymase enzyme are crystalline in or homogeneous in humans.

Besides granules, there are structures non-bounded by membranes in the cytoplasm known as lipid bodies. They are more frequent in humans than in rodents, and are places for storing arachidonic acid.

Mastocytes of an individual do not constitute a homogeneous population. For example, electron microscopy studies show that different types of mastocytes contain specific set of granules. Two major types of mastocytes have been identified based on morphological and functional features: connective tissue mastocytes (Figures 3) are found in the connective tissue of the skin, peritoneum and serose layers of many organs, and mastocytes of mucosas are found in the intestinal and respiratory mucosas (Figure 4). Connective tissue mastocytes show red granules when stained with safranin, probably because the high concentration of heparin, whereas mucosa mastocytes lack this type of granules. However, detailed functional studies suggest more than two populations. For example, mastocytes in the same tissue, but located in different areas, show distinct sets of proteases in their granules. It seems that these features appear once the mastocytes arrive at the places where they have to perform their functions.

Kidney
Figure 3. Strongly stained mastocytes (arrows) after hematoxylin-eosin general staining in the kidney calix.
Mastocitos en el estomago
Figure 4. Mastocytes stained with Alcian blue (arrows) in the mucosa and serose (lower arrow) of the stomach.

An interesting classification of mastocytes is based on protease content because their functions rely on the proteases profile that mastocytes put at work. Mastocytes from at different locations have different protease profiles. Human mastocytes can be divided in those containing triptases (located in the respiratory and digestive mucosa, close to T lymphocytes), and those containing triptases and chimases, together with other enzymes (found in the epidermis, intestine and stomach submucosa, myocardium, lymphatic nodules, conjunctive and synovium). Later, another type of mastocytes was discovered containing chimase without triptase (found in the intestine and stomach submucosa). However, regarding other features like how they respond to T lymphocytes, more subtypes of mastocytes may be characterized. Altogether, it can be said that mastocytes form a heterogeneous population.

2. Origin and distribution

Since mastocytes show similar functions and morphology than some leucocytes, it was initially thought that mastocytes differentiate from leucocytes or from a common myeloid progenitor. In 1977, it was observed that mastocytes develop from a hematopoietic precursor cell located in the bone marrow. In addition, and unlike basophils, mastocytes abandon the bone marrow as undifferentiated agranular cells and are transported through the blood stream as undifferenciated cell (morphologicaly, they are agranular leucocytes). Therefore, there is a circulating population of progenitor cells in the blood, and they are found in the lymphatic ganglia as well. After a while, undifferentiated mastocytes exit blood vessels and populate connective tissues to complete differentiation and become mature functional cells. This last process is induced by tissue local signals, mostly coming from fibroblasts, endothelial cells and reticular cells. Not all mastocytes differentiate after leaving the blood stream but some of them remain as pool of undifferentiated cells.

The ability of mastocytes to populate, move and interact with the extracellular matrix of different tissues relies on their adhesion capabilities. Adhesion mostly relies on integrins, and in extracellular matrix proteins such as laminins, fibronectins and vitronectins. In humans, α4-β1 integrin is important. Other integrins are also relevant and those mastocytes expressing the β7 sununit are frequently found in the mucosa. Mastocytes can also be adhered to other cells like epithelial cells, fibroblasts and lymphocytes. However, these cell-cell adhesions seem to be related to cell communication. The number of mastocytes in a tissue is relatively constant.

Mastocytes are ubiquitous and can be found in almost any tissue. Unlike other cells with hematopoietic origin, mature differentiated mastocytes populate non-pathological tissues. Mastocytes can move and are concentrated around small blood and lymphatic vessels, and nerve fascicles. They are more abundant in the dermis, urinary tracts, and in the respiratory and digestive ducts (in the connective tissue of mucosa and submucosa). It means that mastocytes are frequently found in those structures where the external and internal environment are close, and are potential entry pathways for pathogens. Mastocytes also live in vulnerable regions like joints and peritoneum. They are not present in the bone matrix, cartilage, nor in the cornea, all of them non-vascularized tissues. In the human skin, mastocytes are concentrated close to the epidermis and are more abundant in the skin of the nose and cheeks than in the abdominal skin. In humans, there is mastocyte reservoirs in the connective tissue surrounding the hair follicles. The uterus is another organ with many mastocytes, but the number and granule content is regulated by reproductive hormones. Many mastocyte progenitors are found in the adipose tissue. In the nervous tissue, mastocytes are mostly associated with the leptomeninge, but they can also be found in the hypothalamus, thalamus and spinal cord duramadre meninge. Since there is a constant incoming of new mastocytes into the tissues, it is thought that the total number is regulated by apoptosis induced by signal coming from the surrounding tissue. In humans, it has been estimated that the total population of mastocytes might form an organ similar in size to the spleen.

3. Functions

Mastocytes need to be activated to perform their functions. This may be done by activating the Fc-IR plasma membrane receptor, which recognizes the constant domain of E immunoglobulins. This receptor is also found in basophils, Langerhans cells and monocytes. Other non-immune molecules can also activate mastocytes, such as neuropeptides, certain basic substances, some drugs like opioids, and some others. Masctocytes harbor a broad variety of receptors in the plasma membrane that allows them to respond to a great amount of diverse stimuli.

Once activated, mastocytes release the granule content by a mechanism known as degranulation. Mastocytes are probably among the first cells to be activated during inflammation. There are two types of degranulation: explosive (anaphylactic or mixed exocytosis) and slow. During explosive degranulation, the membranes of nearby granules fuse to one another and then fuse with the plasma membrane, resulting in a massive and instant release. The fusion between granules form channels that allow the release of the content of the inner granules as well. Explosive degranulation is triggered by the concentration of FCεRI receptors after the binding and crosslinking of IgE immunoglobulins with di- or trivalent antigens. Granules swell and decrease in density. Large compartments known as secretory channels are formed in the peripheral regions of the cytoplasm. This mechanism allows for secretion of large amount of substances in a very short period of time. It has been observed that the secretory channels are already present 3 minutes after the stimulation. Strikingly, it is very rare to observe these compartments in vivo and most descriptions of this type of degranulation come from cell culture. Slow degranulation releases small amounts of granule content for a longer time. This mechanism is more frequent, and it happens in infiltrated tumor and inflamed tissues. Explosive degranulation is observed during allergic responses. Slow release was proposed after the observation of mastocytes with cytoplasmic regions containing empty granules not connected with the plasma membrane. These mastocytes also contain more endoplasmic reticulum and more abundant vesicles, which were sometimes fused with granules. This activated morphology is frequent in tissue regions with chronic inflammation. The cellular mechanism for the release of granule content depends on the vesicular trafficking. Actually, portions of granule content is included in small vesicles that pinch of from the granules themselves. Then, they are moved toward the plasma membrane and are exocyted. A similar amount of endocytosis vesicles fuse with granules to keep the granule membrane constant. Explosive degranulation is massive, non-accommodating and non-selective regarding the granule type and granule content. Slow degranulation is long-lasting, may change the release flow intensity, and may select the granule type and granule content to be released.

Mastocyte function is varied and sometimes similar to those of other immune cells, such as basophils, monocytes and neutrophils. Mastocytes are able to do phagocytosis, antigen processing, release of cytokines and vasoactive substances. Allergic responses largely relies on mastocytes.

In the 1950s, studies had already been demostrated a positive correlation between the amount of histamine and the number of mastocytes. Histamine were related to allergic and anaphylactic processes, so that mastocytes had to contain histamine and be involved in these processes. Later, it was observed that basophil also contain histamine and therefore they would be involved in these functions as well.

Cytoplasmic granules, besides enzymes, contain molecules known as mediators, which influence the activity of other cells. Mediators can be divided in preformed mediators (primary mediators) and precursors (secondary mediators). Primary mediators are histamine, heparin, and chemotactic molecules for eosinophils and neutrophils. Secondary mediators are derived from lipids, from arachidonic acid, such as prostaglandins and leukotrienes, and those derived from other molecules like interleukins (3, 4, 5, and 6), together with other factors, such as platelets activator and necrosis activator.

Allergy. Although many cells are involved in allergy responses, mastocytes are the cells that trigger the process (Figure 4). It begins when the receptors Fc-IR bind immunoglobulin E (IgE)-antigen complexes. IgE is released by other cells after the antigen (allergen) is recognized. The first mastocyte response is the fast degranulation that release the granule content with pro-inflammatory molecules. In many allergic responses there is a second phase starting about 2 to 4 hours later, which consists in releasing cytokines and chemokines. The effect of the allergic response depends on the tissue where it is taking place.

Allergy
Figure 4. Mastocytes influence allergic responses (Adapted from Bischoff 2007).

Allergic reactions may be local, as in nasal mucosa during rhinitis and as in lungs during asthma, or may be general when an anaphylactic shock is going on. Generally, the release of histamine and other lipidic mediators increase the permeability of blood vessel walls, facilitating the exit of plasma molecules to the surrounding tissues, which ends up as edemas. Leukotrienes induce the contraction of the smooth muscle layer in the respiratory ducts. In addition, mastocytes release chemotactic factors to attract eosinophils and neutrophils, which partially counteract the reaction by releasing anti-histamine by eosinophils and defense activity of neutrophils. The symptoms of allergic reactions are pruritus, skin edemas, cutaneous erythema (redness of the skin), swelling of the nasal mucosa and aqueous nasal secretion, spams and increase of the mucous secretion by respiratory ducts.

The strategic position of mastocytes around blood capillaries and nerves, and the high amount of chemical substances in their granules, may suggest that they are also involved in inflammatory and immune responses. Many receptors have been found in the plasma membrane of mastocytes and many chemical mediators in their granules. Mastocytes may participate in the response mechanisms to more than 20 non-allergic pathologies, such as arteriosclerosis, atopic dermatitis, cystitis, migraines, osteoporosis, psoriasis, and several tumors.

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Bibliography

Bischoff SC. 2007. Role of mast cells in allergic and non-allergic immune responses: comparison of human and murine data.. Nature reviews in inmunology 7: 93-104.

Metcalfe DD, Baram D, Mekori YA. 1997. Mast cells. Physiological reviews 77:1033-1079. Abstract

Molderings GJ. 2010. Mast cell function in physiology and pathophysiology. Biotrend reviews 5:1-12. Read the article

Sobota W. 2008. Histología (2ª ED.) Ed. Panamericana. ISBN: 9788498351781.

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