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Vitamin D3 (VD3), the most physiologically relevant form of vitamin D can be synthesized in the skin from 7-dehydrocholesterol, a process which depends on sunlight or can be acquired in the diet or in vitamin supplements. VD3 is converted in the liver to 25-dihydroxyvitamin D3 (25(OH) VD3), which is the main circulating form of VD3, which is then metabolized in the kidneys to 1, 25(OH) 2VD3, the most physiologically active VD3 metabolite. The enzyme 24-hydroxylase, which is most abundant in the kidney and intestine, catabolizes 1, 25(OH)2 VD3 to its inactive metabolite, calcitroic acid, which is then excreted in the bile.
Activated T cells (and probably also B cells) can only perform the final step of converting 25(OH) VD3 to 1, 25(OH)2 VD3. Importantly, dendritic cells (DCs) and macrophages may be an important immune source of active 1, 25(OH)2D3 as they are able to generate 1,25(OH)2D3 due to their expression of the enzyme 25-hydroxyvitamin D3-1α-hydroxylase (CYP27b1). The ability of immune cells to produce its own 1, 25(OH) 2VD3 ensure that 1, 25(OH) 2VD3 is concentrated locally in lymphoid microenvironments that contain physiologically high concentrations of VD3, thereby increasing its specific action and also limiting potentially undesirable systemic effects of VD3, such as hypercalcaemia and increased bone resorption.
2-Immunomodulatory Role of Vitamin D
The insight of the role for vitamin D in the regulation of immune responses was triggered by the discovery of vitamin D receptor (VDR) expression in almost all immune cells, including activated CD4+ and CD8+ T cells, B cells, neutrophils, and antigen-presenting cells (APCs), such as macrophages and DCs 18 D.M. Provvedini, C.D. Tsoukas, L.J. Deftos and S.C. Manolagas, 1,25-dihydroxyvitamin D3 receptors in human leukocytes, Science 221 (1983), pp. 1181-1183. View Record in Scopus Cited By in Scopus (200). Importantly, VDR expression in some immune cells is controlled by immune signals. Naïve T cells only display very low VDR levels. However, this receptor is abundantly present upon T cell activation. In contrast, differentiation of monocytes either into macrophages or DCs is accompanied by a decrease in VDR-expression, making these cells less sensitive to 1, 25(OH)2 D3 when they mature. Thus, the high abundance of receptors for active vitamin D throughout the immune system and their regulation by immune signals argues for an important role for VD3 as a modulator of immune responses. With this finding, several studies were undertaken to elucidate the immunomodulatory actions of 1, 25(OH)2 D3, which has led to the appreciation of several VD3-mediated effects, which influence different cellular players within the immune system.
These studies found that VD3 metabolites, particularly 1, 25 (OH)2 VD3 have a strong influence on the innate and acquired immune systems. In vitro, 1, 25(OH) 2 VD3 exerts a marked inhibitory effect on adaptive immune cells. It inhibits T-cell proliferation, and the production of IL-2, and IFN-gamma in T cells, and CD8 T-cell-mediated cytotoxicity, i.e. suppression of cell mediated immunity/Type-1 immune responses. These inhibitory effects of 1,25(OH)2VD3 are most pronounced in the effector and memory T-cell compartment, which is concomitant with the higher expression of VDR in effector and memory T cells compared with naive T cells. On the other hand, 1, 25(OH)2VD3 enhances nonspecific T-cell suppressor activity, as measured by the ability of 1,25(OH)2VD3-treated T cells to suppress primary mixed-lymphocyte reactions and cytotoxic T-cell responses.
At the level of the APC such as DCs, 1,25(OH)2D3 inhibits DCs maturation by inhibition of the surface expression of MHC-II-complexed antigen and of co-stimulatory molecules (CD40, CD80, CD86). DCs maturation is critical pathway that is not only important for activation of innate immune cells such as NK and NKT cells, but also for activation of antigen specific T cells during infectious diseases, autoimmune diseases, cancer, and transplantation. In support of role of VD3 in DCs maturation, VDR-deficient mice have increased numbers of mature DCs in skin-draining lymph nodes. Furthermore, 1,25(OH)2D3 inhibits the production of the cytokines IL-12 and IL-23 by DCs; a Th1- and Th17- promoting cytokines, by dendritic cells, thereby indirectly shifting the polarization of T cells from a Th1 and Th17 (T regulatory cells involved in induction of autoimmune disease) phenotype towards a Th2 phenotype. Furthermore, 1,25(OH)2D3 directly affects T cell responses, by inhibiting the production of Th1 cytokines (IL-2 and IFN-γ), Th17 cytokines (IL-17 and IL-21), and by stimulating Th2 cytokine production such as IL-4 and IL-10 by T cells. Moreover, 1, 25(OH)2D3 favors Treg cell development via modulation of DCs (decreased IL-12 and enhanced IL-10 production) and by directly targeting T cells. Similar to its inhibitory effect on T cells, 1,25(OH)2VD3 decreases B-cell proliferation, plasma-cell differentiation and IgG secretion, which would down regulate humoral immune responses. 1, 25 (OH)2VD3 might also affect leukocyte migration by blocking chemokine synthesis at effector sites. For instance, 1,25(OH)2VD3 decreased the expression of CCL2, CCL3, CXCL10 and subsequent monocyte infiltration in experimental autoimmune encephalomyelitis(EAE). Similarly, a 1,25(OH)2VD3 analogue decreased the production of the chemokines CCL2, CCL5, CXCL10 and consequent TH1-cell infiltration in non-obese diabetic (NOD) mice, a model of type 1 diabetes.
Paradoxically, although 1, 25(OH)2VD3 primarily has inhibitory effects on the adaptive immune response, some of its effects on innate immune cells are stimulatory. For example, 1,25(OH)2VD3 can stimulate human monocyte proliferation in vitro and has been shown to increase the production of both IL-1 and the bactericidal peptide cathelicidin by monocytes and macrophages as will be described later. These contradictory observation raises several question that constitute important gaps in our knowledge such as: 1) What are the physiologic, pathologic, or immunological conditions that triggers the stimulatory or inhibitory functions of VD3?; 2) whether these paradoxical functions of VD3 on the immune system is determined by VD3 levels in the blood and/or in the tissues?; 3) what are the optimal level of VD3 intake that enhances the inhibitory function of VD3 (i.e modulation of immune responses from Th1 to Th2 or the immunosuppressive effect) or the stimulatory functions of VD3 on monocytes and macrophage?; and 4) whether differential functions of VD3 is controlled by ethnicity, age, sex, and health status and genetic makeup of the individual?. These questions or gaps in our knowledge need to be answered before implementation of vitamin D as a therapeutic or prophylactic approach in the treatment or prevention of particular health problem.
3-Vitamin D mediated modulation of innate immunity and host defense against infection
1,25(OH)2D3 has been recognized as an important mediator of innate immune responses during infection , enhancing the antimicrobial functions of immune cells such as monocytes and macrophages, mainly against infection with Mycobacterium tuberculosis. Addition of the1,25(OH)2D3 to M. tuberculosis infected human monocytes and macrophages in vitro, resulted in reduction of intracellular bacterial load. Analysis of the mechanism and signaling pathway that mediate VD3 effect revealed a unique cross-talk between VD3 and Toll like receptors (TLRs). TLRs are pathogen-associated molecular patterns (PAMPs) that are expressed on the surfaces of monocytes, macrophages, and dendritic cells. TLRs are thus crucial members of the innate immune compartment, which sense various infectious agents, and provide a first-line defense against several microbial pathogens. It has been shown that, in humans, the activation of TLR2/1 results in the induction of VDR and the 25-hydroxyvitamin D3-1α-hydroxylase (CYP27b1), which converts the vitamin D prohormone (25D) into the active form (1,25D) as mentioned above. Under conditions where levels of the pro-vitamin D (25D) is present at sufficient levels, bacteria-mediated TLR2/1 activation of monocytes results in production or up regulation of CYP27b1, which convert 25D into the active form. The active form of vitamin D then activates antimicrobicidal functions of macrophages and the expression of the antimicrobial peptide, cathelicidin, which exert direct microbicidal activity against intracellular M. tuberculosis. Inhibition of the VDR or siRNA inhibition of 1,25(OH)2D3 resulted in decreased cathilicidin production and abrogation of the TLR2/1-induced antimycobacterial activity, suggesting that VDR activation is a critical step in the host defense against M. tuberculosis . These findings potentially explain the association of 25D serum levels to the susceptibility to tuberculosis, where low levels of 25D cannot provide sufficient substrate for CYP27b1-mediated production of 1,25D to activate the VDR-dependent antimicrobial response.
The requirement of adequate 25D for the induction of host defense mechanisms via TLR could explain why black people who have low serum level of 25D are more susceptible to virulent tuberculosis infections. As mentioned above, the biosynthesis pathway of 25D in humans involves the absorption of UV in the skin which converts 7-dehydrocholesterol into a pre-vitamin D3 precursor. The high melanin content in pigmented skin will thus absorb UV rays, which will prevent this reaction to occur. Interestingly, when monocytes cultured in African American sera were stimulated with a TLR2/1 ligand, there was no upregulation of cathelicidin mRNA, whereas monocytes cultured in sera from Caucasians did. Supplementation of the sera from African American individual with exogenous 25D3 restored the induction of cathelicidin mRNA. This implies that the level of 25D in any individual may influence their ability to fight infection, and that supplementation with vitamin D analogues could potentially restore their protective immunity and host defense mechanism.
Besides Calithicidin, the gene encoding the antimicrobial peptide, defensin β2, was also identified as direct a target for 1,25(OH)2D3 Exposure to 1,25(OH)2D3 results in a strong induction of these peptides, directly leading to enhanced antimicrobial activity in various cell types, including myeloid cells, keratinocytes, neutrophils, and bronchial epithelial cells.
Recently, it has been demonstrated that 1,25(OH)2D3 is a direct and robust inducer of expression of the gene encoding pattern recognition receptor (PRR) called NOD2/CARD15/IBD1 in monocytes and epithelial cells. This PRR detects muramyl dipeptide (MDP), a lysosomal breakdown product of bacterial peptidoglycan common to Gram-negative and Gram-positive bacteria. MDP-induced NOD2 activation stimulates the transcription factor NF-κB, which induces expression of the defensin β2 gene as well as several cytokines and chemokines that enhances the functions of the innate and acquired immune responses against these pathogens. Other signaling pathways have also been proposed to participate in the anti-mycobacterial activities of 1,25(OH)2D3. For example, phosphatidylinositol 3-kinase was found to regulate the anti-mycobacterial activity of 1,25(OH)2D3 by enhancing the generation of reactive oxygen species (ROS) in monocytes and macrophages. Importantly, it has been recently demonstrated that vitamin D is able to induce autophagy and to mediate co localization of Mycobacterium tuberculosis and antimicrobial peptides within autophagolysosomes, facilitating the destruction of these bacteria.
Paradoxically, while 1,25(OH)2D3 promotes the antimicrobial activities of phagocytic cells, VD3 also inhibits TLR2 expression and TLR4 expression on monocytes, thus inducing a state of hyporesponsiveness to PAMPS. This effect, which is most prominent after 72 h, was suggested to take place as negative feedback mechanism, preventing excessive TLR activation and inflammation at a later stage of infection. Interestingly, 1, 25(OH)2 D3 was also reported to induce secretion of IL-10, which suppress the antimicrobial host defense against M. tuberculosis mediated by T cells and macrophages. These findings represent a a paradoxical immunomodulatory effect for 1, 25(OH)2 D3 in Mycobacterium tuberculosis infection and require further investigation. However, it is possible that VD3-mediated Il-10 production is taking place as a regulatory mechanism that prevents excessive stimulation of Th1, cell mediated responses, which causes necrosis of the tuberculous granulomas and progression of disease. Thus, it appears that VD3 play a dual role in host defense against infection, an early stimulatory of anti-microbial responses by phagocytic cells and late regulatory role that prevent the development of immune mediated pathology.
4-Effect of impaired vitamin D signaling on human health and disease:
As mentioned above, it is clearly evident that an adequate vitamin D levels is required to maintain not only bone health, but also to ensure optimal immune function. With this knowledge, the increasing incidence of insufficient vitamin D levels in many populations across the world is obviously considered as a major health problem.
Consistent with vitamin D mediated antimicrobial effect, several studies have reported a correlation between vitamin D deficiency and susceptibility to respiratory infections, especially in the context of infection by mycobacteria and Gram-negative bacteria. Also, the fact that 1,25(OH)2VD3 has a physiological protective role in dampening or limiting potentially pathogenic immune responses at the cellular level, one might predict that interfering with vitamin D effects could predispose to hypersensitivity or autoimmunity. Consistent with this idea, levels of serum 1,25(OH)2VD3 are often decreased in patients with systemic lupus erythematosis (SLE), and 1,25(OH)2VD3 levels are inversely correlated with disease activity in patients with rheumatoid arthritis. VD3 deficiency might also predispose to type I diabetes. This is clearly evident in children with rickets who have a higher incidence of diabetes than VD3-sufficient children, but they are also more susceptible to infection, which is consistent with the anti-microbial role of vitamin D. In non-obese diabetic (NOD) mice (a mouse model spontaneously developing type-1 diabetes (T1D) with a pathogenesis similar to human disease), vitamin D deficiency during early life resulted in more aggressive disease manifestation and a higher incidence. Mechanistically, at the T cell level, vitamin D deficient NOD mice displayed reduced numbers of CD4+CD62L+ Treg cells in the thymus and in the periphery compared to wild type-vitamin D sufficient mice, suggesting a defect in the maintenance of T cell tolerance to self antigens.
In contrast to the effects of vitamin D deficiency, abrogation of VDR in mice has resulted in inconsistent results in different autoimmune disease models. In models of inflammatory bowl disease (IBD), absence of the VDR results in an exacerbation of the disease, whereas VDR deficient mice on a high calcium diet are less susceptible to develop experimental autoimmune encephalomyelitis (EAE).
5-Vitamin D Supplementation as Therapeutic Approach
Local vitamin D metabolism allows immune cells to modulate immune responses autonomously, but optimal functioning of vitamin D depends on the availability of circulating 1,25(OH)D3. The exact levels of circulating 1,25(OH)D3 that is necessary to achieve a sufficient level of vitamin D are still a matter of debate, especially in the light of the non-classical effects of vitamin D. Nevertheless, it is generally accepted that vitamin D deficiency are highly prevalent in many populations across the globe. Therefore, vitamin D supplementation represents an attractive strategy to ensure sufficient 25(OH)D3 levels for adequate immune function, thus eliminating one of the risk factors that may underlie disorders such as chronic infections and autoimmunity.
A recent randomized control trial concluded that administration of vitamin D supplements is associated with a decrease in overall mortality rates. The use of vitamin D supplements was found to improve tuberculosis outcome in Indonesian pulmonary tuberculosis patients. In contrast, a more recent study reported that vitamin D supplementation did not improve the clinical outcome among tuberculosis-patients, although it is possible that the dose used was not sufficient or the time at which vitamin D was administered during the course of the disease was not optimal to show maximal effect of vitamin D supplementation.
Supplementation studies have also been conducted in the context of autoimmune diseases. With regard to T1D, distinct studies have found that supplementation with regular vitamin D in early life is associated with a lower risk of disease onset. Similarly, other study found that the risk of T1D development was significantly reduced when high doses of vitamin D supplementation (up to 2000 IU/d) were given during infancy. Overall, these studies suggest that vitamin D-mediated protection against diabetes may be dose-dependent, with individuals receiving higher amounts of vitamin D having a lower risk of developing T1D. Other studies have concluded that vitamin D supplementation in children and infants is not effective in preventing autoimmune diseases. The discrepancy in the results between those clinical trials could be accounted by small sample sizes, short follow-up duration, lack of control groups, applying different doses of vitamin D, and the initial vitamin D status or vitamin D level of the individuals. Thus, despite the promising results that were obtained in these clinical trials, there is still a lack of large-cohort- well controlled studies that can examine the effect of vitamin D supplementation on immune function.
It has been proposed that 1,25(OH)2VD3 could also be used as an adjuvant in immunomodulatory therapy in transplantation. 1,25(OH)2VD3 and a 1,25(OH)2VD3 analogue prolonged the survival of mouse cardiac allografts, and decreased the rates of allograft rejection and increased survival in a rat model of liver transplantation and in fully mismatched mouse pancreatic islet transplants. Interestingly, polymorphisms in VDR are associated with a higher incidence of GVHD in patients who undergo bone-marrow transplantation, which further suggests that 1,25(OH)2VD3 might have a role in suppressing alloreactive immune responses in humans. Consistent with this possibility, 1,25(OH)2VD3 supplementation has been shown to have a beneficial effect by improving allograft function of human renal transplants. This is especially relevant if one consider that renal insufficiency is associated with decreased 1,25(OH)2VD3 synthesis. However, it would be important to determine if vitamin D supplementation in transplantation interfere with protective immune responses against pathogens. Few studies have shown that this is not the case and suggested that there is an immunomodulatory threshold induced by vitamin D that apparently does not exert further immunosuppression. Another side effect that need to be considered when use vitamin D for therapy is the possible development of hypercalcaemia and bone resorption. Therefore, multiple drug development efforts are aimed at finding 1, 25(OH)2VD3 analogues that exert immunomodulation without causing significant hypercalcaemia.