Vitamin D is a lypidic vitamin (such as vitamins A,E, K) and its role in calcium and phosphate metabolism is well known.
The two major forms are vitamin D2 and vitamin D3: vitamin D2 (_ergocalciferol_) is largely human-made and added to foods, whereas vitamin D3 is synthesized in the skin of humans from 7-dehydrocholesterol and is also consumed in the diet via the intake of animal-based foods.
The activation steps involved in converting vitamin D from the diet and cutaneous synthesis are illustrated in Figure 1. Vitamin D, in either the D2 or D3 form, is considered biologically inactive until it undergoes two enzymatic hydroxylation reactions:
- The first takes place in the liver, mediated by the 25-hydroxylase (most likely cytochrome P450 2R1 CYP2R1) which forms 25-hydroxyvitamin D(25OHD).
- The second reaction takes place in the kidney, mediated by 1α-hydroxylase (CYP27B1), which converts 25OHD to the biologically active hormone, calcitriol (1,25-dihydroxyvitamin D).
The classical actions of vitamin D, which by itself is inactive, are due to the functions of the active metabolite, calcitriol. These actions take the form of the regulation of serum calcium and phosphate homeostasis and, in turn, the development and maintenance of bone health. On the contrary, the role of vitamin D in the immunitary system is often underestimated.
The intention of this work is to focus on the importance of this vitamin in defence mechanisms, expecially as regards activation of monocites and macrophages, which are essential in first-line defense against infections such as tuberculosis.
Vitamin D and cell-mediated immunity
Many studies demonstrate the relationship between Vitamin D and immunity. In this research, macrophage defense mechanism against intracellular bacteria, 2015, they show that Vitamin D2 have been linked to induction autophagy as an anti-microbial effector mechanism .
Several lines of evidence indicated that vitamin D metabolism plays an important role in human macrophage host responses to infection with mycobacteria. The active form of vitamin D 1,25-dihydroxyvitamin D3 exerts its activity upon binding to a specific vitamin D receptor (VDR).
The expression of this latter receptor as well as the vitamin D converting hydroxylases, mainly vitamin D-1 hydroxylase CYP27b1, is induced after TLR2 activation of human monocytes/macrophages. This results in increased expression of target genes containing vitamin D response elements within their promoter regions, such as the anti-microbial peptide cathelicidin (LL37).
Part of the anti-mycobacterial activity of cathelicidin can be traced back to augmentation of NOX2-mediated ROS formation and modulation of cytokine expression as well as to induction of autophagy. Of note, recent evidence suggests that vitamin D impacts M.tuberculosis infection also by modulating lipid composition within the mycobacterial phagosome. By inhibiting peroxisome proliferator-activated receptor γ (PPARγ), vitamin D prevented M.tuberculosis-induced lipid droplet accumulation, which is essential for mycobacterial multiplication .
That points to the importance of modulating the availability of nutrients to pathogens as part of the host response . Glucose and lipids are essential for M.tuberculosis, and MΦs aim at restricting the microbial access to this source.
Another research, Immunomodulation by vitamin D: implications for TB, 2011 shows that Mtb-sensing by the Toll-like receptor 2/1 (TLR2/1) complex increases expression of VDR and CYP27B1 in monocytes.
The resulting intracrine synthesis of 1,25D promoted VDR-mediated trans-activation of the antimicrobial peptide, cathelicidin (LL37), and killing of Mtb in monocytes provided that sufficient 25D was available for CYP27B1.
Recently, the potential power of this kind of intracrine activation by CYP27B1 in innate immune response to infection was confirmed in vivo when cells isolated from bacterially infected bovine mammary tissue showed a substantial increase in CYP27B1 when compared with cells isolated from mock infection.
The antibacterial effects of vitamin D are not restricted to induction of antibacterial proteins.
Recent studies have demonstrated a role for vitamin D in promoting the environment associated with antibacterial activity. Autophagy is the cellular process of degrading cytosolic components including decaying organelles and nonfunctional proteins, and has also been linked to immune processes and TB disease. It is therefore interesting to note studies showing that 1,25D promotes autophagy in monocytes, with inhibitors of autophagosome formation suppressing antibacterial activity . Other innate antibacterial mechanisms that may be targeted by vitamin D include the generation of reactive oxygen species (ROS), and monocytes treated with combined Mtb and 1,25D showed increased ROS generation. Another ROS, nitric oxide (NO) is known to play a key role in the killing of bacteria in mice, and a similar mechanism may also be present in humans.
- 1,25-dihydroxyvitamin D3, expecially when it is bound to VDR, increased expression of the anti-microbial peptide cathelicidin (LL37), which is important in ROS formation (including NO), cytokine expression and autophagy induction, defense mechanisms against M. tuberculosis.
- Vitamin D inhibits PPARγ, and prevents lipids accumulation, which are effential for M.tuberculosis moltiplication.
Vitamin D in Therapy
Many studies reported the efficacy of Vitamin D supplementation in Tuberculosis therapy. In this research, a single dose of Vitamin D enhances immunity to Micobacteria, a double-blind randomized controlled trial was conducted in 192 healthy adult TB contacts in London.
Participants were randomized to receive a single oral dose of 2.5 mg vitamin D or placebo and followed up at 6 weeks. The primary outcome measure was assessed with a functional whole blood assay (_BCG-lux_ assay), which measures the ability of whole blood to restrict luminescence, and thus growth, of recombinant reporter mycobacteria in vitro; the readout is expressed as a luminescence ratio (luminescence postinfection/baseline luminescence). IFN-γ responses to the Mycobacterium tuberculosis antigens early secretory antigenic target-6 and culture filtrate protein 10 were determined with a second whole blood assay. Vitamin D supplementation significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro compared with placebo (mean luminescence ratio at follow-up, 0.57, vs. 0.71, respectively; 95% confidence interval for difference, 0.01–0.25; p = 0.03) but did not affect antigen-stimulated IFN-γ secretion.
In conclusion, a single oral dose of 2.5 mg vitamin D significantly enhanced the ability of participants whole blood to restrict BCG-lux luminescence in vitro without affecting antigen-stimulated IFN-γ responses.
In another research, Vitamin D accelerates clinical recovery from tuberculosis: results of the SUCCINCT Study [Supplementary Cholecalciferol in recovery from tuberculosis]. A randomized, placebo-controlled, clinical trial of vitamin D supplementation in patients with pulmonary tuberculosis they focus on the security of Vitamin D Therapy, showing that vitamin D supplementation in patients with tuberculosis does not appear to be associated with hypercalcemia.
In preliminary safety data from one study, 11 patients with tuberculosis were administered a single dose of 100,000 IU ergocalciferol (vitamin D2).3 At eight weeks, there was a significant rise in serum vitamin D2 levels and no episodes of hypercalcemia.
In a randomized trial of 100,000 IU cholecalciferol (vitamin D3) in patients with tuberculosis in Guinea there was no difference in hypercalcemia symptoms or detection of biochemical hypercalcemia in those randomized to the treatment arm; however, patients in the treatment arm did not attain higher serum vitamin D levels than those randomized to placebo, suggesting that the vitamin D formulation used (an injectable preparation given orally) may have been poorly absorbed.
Other studies have also reported safe administration of vitamin D in patients with tuberculosis. Given the evidence of the potential benefits of vitamin D3 in the immune response toMycobacterium tuberculosis, optimizing vitamin D levels (while monitoring calcium levels) should not be considered contraindicated in patients with tuberculosis. Results from trials of vitamin D adjunctive therapy that are currently underway will provide further clarification of the benefit, if any, of vitamin D supplementation in patients with tuberculosis.
Finally, in this study made for the Italian superior Health institute, The potential role of vitamin D for prevention and treatment of tuberculosis and infectious diseases they summarize data from many researches, to demonstrate the efficacy of vitamin D in this therapy.
Vitamin D has been attributed a significant role in host immune defence against M. tuberculosis as observational studies have found evidence of an association with Vitamin D Deficiency and active tuberculosis. Clinical evidence using vitamin D in TB treatment was reported in several studies. The addition of vitamin D in the therapy of moderately advanced Tuberculosis had been proven to show a significant difference in sputum conversion compared with placebo.
In a research carried out in Jakarta The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion the group treated with vitamin D had higher sputum conversion and radiological improvement (100%) as compared to the placebo group (76.7%).
A black American woman with hypovitaminosis D and refractory drug-susceptible pulmonary TB was treated with antituberculous therapy and the correction of vitamin D deficiency. The patient demonstrated a significant radiographic improvement with negative sputum cultures at 13-month of total therapy. Vitamin D as Adjunctive Therapy in Refractory Pulmonary Tuberculosis: A Case Report
In an Egyptian study Vitamin D administration to tuberculous children and its value vitamin D was administered to children with tuberculosis, showing that clinical improvement was more evident in patients taking vitamin D as compared to those who received treatment alone. The study concluded that vitamin D therapy may be very effective in addition to antituberculous drugs in the treatment of TB children.
Vitamin D has been suggested as prophylaxis in TB household contacts, being a low-cost intervention that is also easy to administer in resource-poor settings. Serum 25-hydroxyvitamin D in a West African population of tuberculosis patients and unmatched healthy controls1-3.
All these studies reported that vitamin D ca be used as a supplementation during tuberculosis therapy: it increases activity of cell-mediated immunity (monocites/macrophages), reduces bacterial growth and it is safe, because there is no risk of Hypercalcemia. Moreover, some studies propose supplementation not only for therapy, but also for prophylaxis for relatives of tbc patients.