Vitamin C was first isolated (1928) by C.G. King and W.A. Waugh at the University of Pittsburgh and Albert Szent-Gyorgyi in Hungary, from orange and cabbage juices, and adrenal glands. In 1933 Haworth determined its structure and in 1971 Linus Pauling published the beneficial effects of vitamin C in the common cold. Vitamin C occurs in two forms, namely reduced ascorbic (meaning “without scurvy”) acid (AA), and oxidized dehydroascorbic acid where only the L isomer of AA has activity.

Vitamin C deficiency causes scurvy, a potentially fatal condition described before Christ, and with historical evidence of its existence in Rome, Greece, and Egypt, which is characterized by muscle and collagenous structure weakness, lethargy, bleeding gums, tooth loss, joint pains, bone and connective tissue disorders, poor wound healing, fatigue, and bleeding under the skin provoking tiny pinpoint bruises [1].

In the 1700s, British physician James Lind found that the men who ate citrus fruit were not affected by scurvy and those who were suffering from this disease rapidly improved.

Vitamin C is specifically for anti-scorbutic activity and is very susceptible to destruction through oxidation [2]. Low intake of vitamin C can compromise many body functions such as the ability to rid the body of cholesterol and fight off infections and other diseases such as cardiovascular and allergic diseases [3]. Ten mg of vitamin C is needed daily to prevent scurvy, a disease that rarely appears today, except in infants who do not get enough vitamin C. Supplements of AA are used to acidify the urine during certain bladder or kidney diseases, or are given to people who will be undergoing surgery to ensure a sufficient supply of vitamin C to promote healing [4]. Therefore this vitamin, a water-soluble antioxidant as well as a reducing agent, is absorbed in a manner similar to monosaccharide, and in its metabolism AA is first converted to dehydroascorbate by a number of enzyme or nonenzymatic processes and is then reduced in cell [5].

Absorbed vitamin C is excreted in sweat, feces, and urine after concentration in blood plasma [6].

High levels of vitamin C are found in pituitary and adrenal gland, pancreas, liver, spleen and brain, and tend to localize around healing wounds [7]. Here we report the concentration of vitamin C in human tissues (Table 1).

Table 1: Concentration (mg/100 g) of vitamin C in human tissue.

It is widely accepted that vitamin C, which has also psychological effects, has been recommended for cold prevention and for the treatment of schizophrenia, senility, cancer, inflammation and other pathological conditions [8]. Administration of high doses of vitamin C in cancer patient have not been found to be toxic but show no effect on symptoms nor does it affect the survival [9]. However, in some individuals, the administration of high doses of vitamin C can cause blood in the stool, and may lead to the development of calcium oxalate kidney stone. Moreover, it increases excretion of uric acid, decreases the amount of copper, breaks down red blood cells in individuals with an inherited disease (sickle cell anemia) and diarrhea, an effect mediated by intestinal mast cell [10]. It is well known that the immune system is involved in cancer, infection, and allergy, as well as autoimmune and neurodegenerative diseases. Dietary supplementation with vitamin C, enhances a number of aspects of lymphocyte, macrophages and mast cell functions, exerts antiinflammatory effects in man and animals, and is an indicator of the degree of oxidative stress taking place in the plasma [11]. Moreover, high administration of vitamin C in experimental animals results in better outcome in sepsis, oxidative stress and inflammation [12].

Vitamin C functions as an antioxidant that reacts with free radicals deactivating them before they cause damage to proteins or lipids, acts as a hydrogen donor involved in reversible oxidation and reduction, and it plays an important role in many biochemical reactions including incorporation of oxygen into the substrate [13]. In addition, vitamin C contributes towards synthesis, maturation, and secretion of collagen which can be degraded by MCs, along with various components of pericellular and extracellular matrices [14].

In 1878 a Nobel-Prize winner, immunologist Paul Ehrlich discovered small cells (6-12 mm in diameter) named mast cells (MCs). MCs derive from CD34+/CD117+ pluripotent progenitor cells, reside in the tissues, and they are mediators of allergic, inflammatory and autoimmune diseases [15,16]. They can be activated through IgE binding high-affinity surface receptor FceRI and other receptors such as TrkA, complement component receptors, Toll-like receptors, and cytokine receptors [17,18]. It is well known that MCs produce a plethora of mediators (such as arachidonic acid products, cytokines, phospholipases, tryptase, chymase, and cholinesterase) and participate in innate and adaptive immune systems [19,20]. They are distributed in virtually all organs and vascularized tissues, reside in the CNS where they are sensor and effectors, interacting with microglia and astrocytes through the release of neuroactive stored mediators and newly synthesized compounds such us arachidonic acid products [leukotrienes, prostaglandins and lipoxins] and cytokines/chemokines [21,22]. These compounds allow MCs to communicate with immune, vascular and nervous systems where they contribute to emotion and cognition [23].

It is well known that mast cells mostly reside on abluminal of the brain where there is a cross-talk between them and astrocytes, microglia, neurons and other resident cells [24]. Activated MCs generate numerous vasoactive, neuroactive, and immunoactive cellular and molecular response. Microglia and astrocytes respond to proinflammatory cytokines released by immune cells; on the other hand there are several biological compounds that enhance and regulate the interaction between mast cells and receptor brain cells [24]. MCs are also found in the hypothalamus, in connective tissues, as well as between the ganglion cells and nerve fibers. MCs are activated through cross-linking of their surface receptors for IgE, leading to degranulation, and release vasoactive, pro-inflammatory and nociceptive mediators that include histamine, serotonin, proinflammatory and anti-inflammatory cytokines/chemokines and proteolytic enzymes [25]. MCs are found preferentially in intraepithelial locations, and around blood vessels, and perform important beneficial roles in host defence [26].

Vitamin C is an important enzymatic cofactor involved in MCs, epithelial and endothelial barriers of the skin and plays an important function in maintaining tissue integrity [27]. It influences both cellular and humoral immune responses and orchestrates the function of innate and adaptive immune systems. Vitamin C has beneficial effects on systemic mast cell inflammation, therefore, since it is well known that its deficiency is associated with impaired cell-mediated immunity, it is possible that it may improve this interaction and be used as an adjuvant therapeutic compound in several inflammatory and allergic diseases [28]. Vitamin C deficiency provokes a decrease in appetite, growth, immunity, heart resistence, and skeletal muscle, and an increase in vascular capillary fragility, hemorrhage and nerve tenderness. In fact, it has been reported that deficiency of vitamin C suppresses T cytotoxic responses, natural killer (NK) cell activity, and antibacterial response and plays a role in delayed type hypersensitivity [29].

Vitamin C is involved in host resistance to tumor where it probably has a selective cytotoxic effect [30]. As an adjuvant this candidates it among the therapeutic compounds for the treatment of cancer. In addition to the classic therapies, vitamin C is involved in NK cell activation and differentiation of Th0 subset into Th1 characterized by interferon gamma generation and it is implicated with the synthesis of proinflammatory cytokines/chemokines, and the expression of adhesion molecules [31,32].

Because anti-tumor NK cells are activated by IL-2 and vitamin C may be an adjuvant in immunotherapy with IL-2, it may be pertinent to use vitamin C in immunotherapy in combination with IL-2 against certain cancers [33]. The addition of vitamin C in this immunotherapy, not only increases the effects of IL-2, but also reduces the production of TNF, a cytokine produced by several immune cells, including MCs, which has strong inflammatory properties, induces endothelial cell apoptosis and plays a relevant role in MC mediating asthma [34]. Moreover, vitamin C reduces endothelial cell expression of the adhesion molecule ICAM-1 in response to TNF-alpha in human umbilical vein endothelial and suppresses systemic neutrophil extravasation during bacterial infections; demonstrating its antiinflammatory properties [35]. Therefore, vitamin C has significant impact on endothelial cells, including the inhibition of p38 MAPK pathway and endothelial NF-kappa B activity, and the suppression of endothelial permeability and vascular leakage; effects due to the inflammatory cytokines such as IL-1, TNF, IL-6 and IL-33 generated by MCs [36].

In addition, through the enzyme cholesterol 7-alphamonooxygenase, vitamin C is involved in the metabolism of cholesterol to bile acids and may be of benefit in cardiovascular disease and atherosclerosis, a disease where MCs are also involved [37]. Vitamin C is an antioxidant which protects the immune cells against intracellular reactive oxygen species (ROS) generated in the allergic inflammatory response and it is a reducing compound which enhances the hydroxylation of carcinogens due to the hepatic cytochrome P450 [38]. Supplementation of vitamin C and other vitamins opposes free radicals produced by antigen activated immune cells and in this way maintains efficient the immune functions. Therefore, when the immune system is not efficient, it would be good to recommend patients to take vitamin C [39].

Administration of vitamin C decreases bronchial hypersensitivity caused by the common cold [40], an effect also mediated by mast cells. In addition it shortens the duration of colds, prevents pneumonia, and decreases the incidence of sneezing, runny nose, cough and other symptoms, all effects related to MC activation.

It has been reported that vitamin C inhibits excessive activation of the immune system and its administration seems beneficial to asthma patients, in fact, MC-mediated bronchial hypersensitivity, which is a characteristic feature of asthma is alleviated by vitamin C. Patients treated with AA administration express decreased bronchial hypersensitivity to histamine and bronchoconstriction in asthma, effects mediated by MCs.

In the light of these studies, we found that vitamin C relieves most of the symptoms of diseases that involve activation of MCs and we can conclude that further research on the role of vitamin C and MCs is needed.