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mast cells

From this article in CELLS alive!:

1.3.1 Mast cells and basophils

Mast cells and basophils play a central role in inflammatory and immediate allergic reactions. They
are able to release potent inflammatory mediators, such as histamine, proteases, chemotactic
factors, cytokines and metabolites of arachidonic acid that act on the vasculature, smooth muscle,
connective tissue, mucous glands and inflammatory cells.

Mast cells settle in connective tissues and usually do not circulate in the blood stream.

Basophils are the smallest circulating granulocytes with relatively the least known function. They
arise in the bone marrow, and following maturation and differentiation, are released into the blood
circulation. If they are adequately stimulated they may settle in the tissues.

Both mast cells and basophils contain special cytoplasmic granules which store mediators of
inflammation. The extracellular release of the mediators is known as degranulation and may be
induced by:

(a) physical destruction, such as high temperature, mechanical trauma, ionising irradiation, etc.;

(b) chemical substances, such as toxins, venoms, proteases;

(c) endogenous mediators, including tissue proteases, cationic proteins derived from eosinophils
          and neutrophils;

(d) immune mechanisms which may be IgE-dependent or IgE-independent. The former is elicited
          by aggregation of IgE bound to high-afinity receptors (FcRI) on the surface of these cells.
          Specific antigen (allergen) is responsible for the IgE aggregation. In the IgE-independent way,
          the anafylatoxins C5a, C3a and C4a are formed during activation of complement. Then, the
          degranulation is triggered through C5a-receptors on the surface of mast cells and basophils.

There are two categories of inflammatory (anaphylactic) mediators in mast cells and basophils.
Preformed mediators, stored in secretory granules and secreted upon cell activation, include a
biogenic amine, typically histamine, proteoglycans, either heparin, over-sulphate chondroitin
sulphates or both, and a spectrum of neutral proteases. Released histamine acts at H1, H2 and H3
receptors on cells and tissues, and is rapidly metabolized extracellularly. The proteoglycan, which
imparts the metachromatic staining characteristic of mast cells when exposed to certain basic dyes
such as toluidine blue, has two functions: it may package histamine and basic proteins into
secretory granules, and in human mast cells it appears to regulate the stability of the protease
called tryptase. Neutral proteases, which account for the vast majority of the granule protein, serve
as markers of mast cells and of different types of mast cells.

Newly generated mediators, often absent in the resting mast cells, are typically produced during
IgE-mediated activation, and consist of arachidonic acid metabolites, principally leukotriene C
(LTC) and prostaglandin D (PGD) and cytokines. Of particular interest in humans is the production
of tumour necrosis factor (TNF-), IL-4, IL-5 and IL-6. In the cytoplasma of both mastocytes and
macrophages are special organelles -- lipid bodies -- where metabolism of arachidonic acid occur
and where their products, including leukotrienes, may be stored.

Mast cells are heterogeneous -- two types of them, mucosal and connective tissue, were reported
in rodent tissue back in the 1960's on the basis of histochemical and fixation characteristics that
reflect, in part, whether heparin proteoglycan was present in secretory granules. Neutral proteases
better reflect the heterogeneity or plasticity of mast cells in vivo and in vitro, particularly in humans
where histochemical heterogeneity is less apparent (Table 1.2).
 

Table 1.2:  Predominant granule mediators of mast cells

In murine mast cells, five chymases ( mouse mast cell protease -- MMCP-1,-2,-3,-4 and-5), one
mast cell carboxypeptidase and two tryptases (MMCP-6 and -7) have been reported.

In human mast cells, genes encoding two chymotryptic enzymes (chymase and cathepsin G-like
protease) and one mast cell carboxypeptidase enzyme, and at least two genes encoding tryptase
peptides have been detected. The gene encoding chymase resides on chromosome 14, closely
linked to the gene encoding cathepsin G, an enzyme apparently expressed in mast cells and various
myelomonocytic cells, and to the genes encoding granzymes, which are expressed in cytotoxic T
lymphocytes and natural killer cells. Two types of mast cells have been found by
immunohistochemical analyses. The MCtype contains tryptase, chymase, cathepsin G like
protease and mast-cell carboxypeptidase, and predominates in normal skin and intestinal
submucosa, whereas the MCtype contain only tryptase, and predominates in normal intestinal
mucosa and lung alveolar wall. Nearly equivalent concentrations of each type are found in nasal
mucosa. In MC cells, tryptase, chymase and mast-cell carboxypeptidase reside in macromolecular
complexes with proteoglycan, but interestingly, tryptase reside in a separate complex from that in
which chymase and mast-cell carboxypeptidase are found.

The biological function of mast cell neutral proteases, like mast cells themselves, remain to be fully
clarified. In serum, elevated levels of tryptase are detected in systemic mast-cell disorders, such as
anaphylaxis and mastocytosis. Ongoing mast-cell activation in asthma appear to be a charakteristic
of this chronic inflammatory disease. It is detected by elevated levels of tryptase and PGD in
bronchoalveolar lavage fluid, higher spontaneous release of histamine by mast cell obtained from
the bronchoalveolar lavage fluid of asthmatics than non asthmatics, and ultrastructural analysis of
mast cell in pulmonary tissue.

The number of basophils and mast cells increase at sites of inflammation. To reach these areas,
basophils must migrate from the blood into tissue sites. A crucial step in this process is the
adherence of cells to the endothelium. Cell adherence is mediated by several families of adhesion
molecules and adhesion receptors in the surface of basophils and mast cells that can mediate
binding to other cell and to the extracellular matrix (ECM) glycoproteins. Upon stimulation,
basophils and mast cells release cytokines, including TNF- and IL-4, that can modulate adhesion
molecules on endothelial cells. Activated endothelial cells express the intercellular adhesion
molecule (ICAM-1), endothelial-leukocyte adhesion molecule (ELAM-1) and vascular cell adhesion
molecule (VCAM-1) on their cell surface. Human basophils express integrins as receptors for these
molecules.

Until recently, the effects of adherence on cell function were believed to result only from changes
in cell shape and cytoskeletal organization. However, in addition to cell spreading, aggregated
adhesion receptors transduce a variety of intracellular signals that regulate cell function. These
signals include protein tyrosine phosphorylation, phosphoinositide hydrolysis, changes in
intracellular pH or calcium concentration and the expression of several genes. The adhesion
properties of basophils and mast cells regulate their migration, localization, proliferation and
phenotype.

Different mechanisms could contribute to the increase in the number of mast cells at sites of tissue
injury: mast cells or their progenitors could migrate to these sites; or resident mast-cell precursors
could proliferate. Adhesion receptors and their ligands also play a role in the localization and
migration of mast cells in normal tissues. ECM proteins that are the ligands for adhesion receptors
are chemotactics for mast cells. Adherence of mast cells to fibroblasts, other cells or to ECM
proteins can transduce signals that affect cell growth and differentiation.

The increase in the number of mast cells and basophils, and the enhanced secretion at sites of
inflammation, can accelerate the elimination of the cause of tissue injury or, paradoxically, may lead
to a chronic inflammatory response. Thus, manipulating mast-cell and basophil adhesion may be an
important strategy for controlling the outcome of allergic and inflammatory responses.

Mast Cell

            Cell (type: Leukocyte )

            Mast cells contain metachromatic granules which store a variety of inflammatory mediators. These include:
              Histamine and serotonin
              Proteolytic enzymes that can destroy tissue or cleave complement components
              Heparin or chondroitin sulfate, which are anticoagulants
              Chemotactic factors, such as eosinophil chemotactic factor of anaphylaxis that is an important regulator of
            eosinophil function, and neutrophil chemotactic factor.

              Mast Cell Stabilizers
              Basophil

            Normally, mast cells are not found in the circulation.

Mast Cells and Red Bumps
 

                                               Just under our skin are capillaries
                                               carrying blood with its circulating red
                                               cells () and a variety of white
                                               blood cell types. Just outside of the
                                               capillaries, in the tissue of the
                                               dermis, lurk specialized immune
                                               cells called MAST CELLS.

                                               When we get itchy red bumps on our
                                               skin from contact with an "allergen",
                                               it is due to how our mast cells
                                               respond to the allergen.

                                               Mast cells are covered with
                                               molecules of Immunoglobulin E
                                               antibody (IgE, ).
 
 
 
 
 

There are antigens () in dust mites, in their droppings () and shed exoskeletons.
Once these antigens get under the skin of an allergic host, the antigens cause mast cells to
go berserk.
 
 

           Antigens stick to the mast
           cell IgE antibodies, causing
           granules () in the mast cell
           to fire their contents into the
           surrounding tissue.

           This releases a host of
           inflammatory materials -
           leukotrienes, tumor necrosis
           factor, interleukin-4 and
           other cytokines that turn on
           other inflammatory cells.

           These materials cause fluid
           to leak from the capillaries
           and white cells ()
           including neutrophils, T cells
           and eosinophils to leave the
           circulation. The end result is
           a "local inflammatory
           response", a red, itchy welt.
 

Mast cell links:
Mast cells and basophils
Diagram depicting the multiple roles of mast cells
HON Allergy Glossary Mast Cell
Mast cells : Molecular and cell biology


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