Mast cells synthesis

Synthesis. Histamine [51-45-6] 2-(4-imidazolyl)ethylarnine (1) is formed by decarboxylation of histidine by the enzyme L-histidine decarboxylase (Fig. 1). Most histamine is stored preformed in cytoplasmic granules of mast cells and basophils. In humans mast cells are found in the loose connective tissue of all organs, especially around blood and lymphatic vessels and nerves. These cells are most abundant in the organs expressing allergic diseases the skin, respiratory tract, and gastrointestinal tract. 

Although mast cells and basophils probably account for >90% of stored histamine in the body, histamine is also present in platelets, enterochromaffin-like cells, endothelial cells, and neurons. Histamine can act as a neurotransmitter in the brain. Histaminergic nerves have their cell bodies within a very small area of the brain (the magnocellular nuclei of the posterior hypothalamus) but have axons in most areas of the forebrain. There is also evidence for axons projecting into the spinal (Fig. 1) cord. Finally, there is evidence that histamine synthesis can be induced in tissues undergoing rapid tissue growth and repair. In certain neonatal tissues (e.g. liver), the rate of synthesis of this unstored diffusable histamine (termed nascent histamine) is profound and may point to a role for histamine is cell proliferation. 

Type I allergic reactions are inappropriate immune responses to an allergen with preferential synthesis of immunoglobulin E (IgE), a special antibody class, which binds to mast cells and basophilic granulocytes via Fee receptors. Binding of the allergen to the cell-bound IgE initiates the rapid release of allergic mediators, most prominently histamine, and the de novo synthesis of arachidonic acid metabolites and cytokines, which are responsible for the clinical symptoms. 

Zsebo KM, Metcalfe DD. Geissler EN. Galli SJ Induction of mast cell proliferation, maturation, and heparin synthesis by the rat c-kit ligand, stem dS cell factor. Proc Natl Acad Sci USA 1991 88 6382. 

Histamine is synthesised by decarboxylation of histidine, its amino-acid precursor, by the specific enzyme histidine decarboxylase, which like glutaminic acid decarboxylase requires pyridoxal phosphate as co-factor. Histidine is a poor substrate for the L-amino-acid decarboxylase responsible for DA and NA synthesis. The synthesis of histamine in the brain can be increased by the administration of histidine, so its decarboxylase is presumably not saturated normally, but it can be inhibited by a fluoromethylhistidine. No high-affinity neuronal uptake has been demonstrated for histamine although after initial metabolism by histamine A-methyl transferase to 3-methylhistamine, it is deaminated by intraneuronal MAOb to 3-methylimidazole acetic acid (Fig. 13.4). A Ca +-dependent KCl-induced release of histamine has been demonstrated by microdialysis in the rat hypothalamus (Russell et al. 1990) but its overflow in some areas, such as the striatum, is neither increased by KCl nor reduced by tetradotoxin and probably comes from mast cells. 

There are two distinct pools of HA in the brain (1) the neuronal pool and (2) the non-neuronal pool, mainly contributed by the mast cells. The turnover of HA in mast cells is slower than in neurons it is believed that the HA contribution from the mast cells is limited and that almost all brain histaminergic actions are the result of HA released by neurons (Haas Panula, 2003). The blood-brain barrier is impermeable to HA. HA in the brain is formed from L-histidine, an essential amino acid. HA synthesis occurs in two steps (1) neuronal uptake of L-histidine by L-amino acid transporters and (2) subsequent decarboxylation of l-histidine by a specific enzyme, L-histidine decarboxylase (E.C. 4.1.1.22). It appears that the availability of L-histidine is the rate-limiting step for the synthesis of HA. The enzyme HDC is selective for L-histidine and its activity displays circadian fluctuations (Orr Quay, 1975). HA synthesis can be reduced by inhibition of the enzyme HDC. a-Fluoromethylhistidine (a-FMH) is an irreversible and a highly selective inhibitor of HDC a single systemic injection of a-FMH (10-50 mg/kg) can produce up to 90% inhibition of HDC activity within 60-120 min (Monti, 1993). Once synthesized, HA is taken up into vesicles by the vesicular monoamine transporter and is stored until released. 

In other studies, mast cells have been shown to be abundant in the marrow of osteoporotic patients, and heparin, which is contained within the secretory granules of connective tissue (peritoneal)-type mast cells, has been shown to enhance bone resorption and to inhibit bone-cell replication and collagen synthesis in vitro [130]. Moreover, heparin is known to bind growth factors such as fibroblast growth factor and may therefore be important in limiting their availability [134], Taken together, these various studies suggest a possible involvement of mast cells in the homeostasis of bone, but much more work is needed before any definitive conclusions can be drawn. 

Figure 4.8. Hypothesis for the local generation of mast-cell-stimulating peptides by the action of neutrophil-derived enzymes on albumin. Initial stimulation of the mast cell by any of a variety of agents causes the release of preformed histamine (H) neutrophil and eosinophil chemotactic factors (NCF, ECF) and enzymes and the de novo synthesis of prostaglandins (PG) and leukotrienes (LT). These agents increase vascular permeability and vessel diameter. As a result, albumin and later neutrophils (PMN) enter the tissue space where the latter undergo phagocytosis and the secretion of proteolytic enzymes to the extracellular space where they act on albumin to generate NRP (neurotensin-related peptide) and HRP (histamine-releasing peptide). These newly formed peptides then act as a second stimulus to the mast cell. In addition NRP and HRP may affect other immunocompetent celt such as monocytes, macrophages or eosinophils.

PAF synthesis can be demonstrated upon the appropriate stimulation of a diverse range of cells, including rat and mouse peritoneal macrophages [22], mouse bone marrow-derived mast cells [23, 24], rat kidney cells [25], human cultured lymphoid cell lines [26] and endothelial cells [27-29], human and... 

The classical cellular sources of histamine are mast cells and basophils, gastric enterochromaffin-like cells, platelets and histaminergic neurons. Interestingly the cells in the immune system, which do not store histamine, show high HDC activity and are capable of production of high amounts of histamine, which is secreted immediately after synthesis [20]. These cells include platelets, monocytes/macrophages, DCs, neutrophils, and T and B lymphocytes. 

Tanaka S. Takasu Y, Mikura S, Satoh N, Ichikawa A Antigen-independent induction of histamine synthesis by immunoglobulin E in mouse bone marrow-derived mast cells. J Exp Med 2002 196 229-235. 

Initial observations on khellin (32), a furochromone-type compound from Ammi visnaga L., showed a mast-cell stabilizing effect. This led to the synthesis of many derivatives of this lead for the potential treatment of allergy and asthma, most notably the approved preventive antiasthma drug, cromolyn sodium (33). The precise molecular mechanism of this class of drugs is not yet clearly imderstood. ... 

Histamine is synthesized from the amino acid histidine by an action of the enzyme histidine decarboxylase (Fig. 38.1). Following synthesis, histamine is either rapidly inactivated or stored in the secretory granules of mast cells and basophils as an inactive complex with proteases and heparin sulfate or chondroitin sulfate. 

Corticosteroids and cromolyn are also useful in asthma. Corticosteroids inhibit eicosanoid synthesis and thus limit the amounts of eicosanoid mediator available for release. Cromolyn appears to inhibit the release of eicosanoids and other mediators such as histamine and platelet-activating factor from mast cells. 

Synthesis. Histamine, 2-(4-imidazolyl)ethylamine, is formed by decarboxylation of histidine by the enzyme l.-histidinc decarhoxylase. Most histamine is stored preformed in cytoplasmic granules of mast cells and basophils. 

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