Vitamin D and Autoimmune Disease
The development of non calcemic vitamin D analogues have created a possibility for their therapeutic applicability in immune modulation, induction of cell differentiation and the inhibition of cell proliferation (Bouillion et al 2003). Recent studies have enhanced our understanding of the mechanisms of vitamin D at the molecular or at the biological level. Until the beginning of the 198os, the role of vitamin D in the immune system was sketchy and evidentially unsupported. The function of vitamin D was only understood with regard to phosphorus, calcium and bone metabolism. It was widely accepted that it prevented rickets in children, in adults; it prevented osteomalacia and hypocalcemic tetany. Therefore, in the 1980s research was mainly concentrated in the elucidation of the mechanisms of mineral metabolism regulation.
However, based on the understanding that vitamin D was biologically inactive and must through some processes be metabolically activated before it achieved it functionary duties, the molecules were isolated, identified and the active forms characterized. What followed next was the elucidation of the biochemical progression of vitamin D metabolism in the liver. The initial by product of the metabolism of the molecule in the liver was demonstrated to be 25-hydroxyvitamin D3 (25-OH-D3 which is the predominant form of vitamin D circulating in the body. This form was biologically inactive and must be converted to an active product of the metabolic pathway; the 1 ,25-dihydroxyvitamin D3 (1,25-(OH)2D3). This last stage in the metabolic pathway occurred almost exclusively in the kidneys proximal convoluted tubules cells. The process eventually produces vitamin D, 1,25-(OH)2D3(Deluca & Cantorna 2001).
This final active product; 1,25-(OH)2D3 functions directly on the enterocyte hence significantly increasing calcium and phosphorus absorption from the intestinal lumen into the plasma compartment. Additionally, it also mobilizes calcium from the bone tissue when the parathyroid hormone is present. Vitamin D and parathyroid hormone when combined improves the absorption of calcium in the kidney. It is also in the kidney where the parathyroid hormone binds to the entire nephron length and osteoblasts. While in the kidney, hormone stimulates the secretion of1 -hydroxylase that produces the final form of vitamin D. Without this elucidation of the processes of metabolism, it would never have been possible to discover vitamin D receptor (VDR) and consequently its roles in immunomodulation and anti-inflammation (Deluca & Cantorna 2001; Holick 2004).
The bioactive form of Vitamin D; 1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], is a secosteroid hormone critical in bone and mineral homeostasis. It is essentially involved in the regulation of growth and differentiation of a variety of cell types. I also display anti-inflammatory and immunoregulatory properties. All the cells involved in adaptive and innate immune responses inclusive of dendritic cells, macrophages, B-cells and T-cells express Vitamin D receptor(VDR) (Adorini & Penna 2008; Luciano 2002). These cells have the capacity to produce and respond to 1,25-Dihydroxyvitamin D(3) (Deluca & Cantorna 2001). Thus, the net effect of Vitamin D on the immune response system is that it enhances innate immunity on one hand and on the other, essential in the regulation of adaptive immunity.
Current epidemiological evidence attests that there exists a significant association between 1,25-Dihydroxyvitamin D(3) deficiency and an elevation in the incidence of autoimmune diseases. Based on these demonstrations, the physiological roles of endogenous Vitamin D receptor agonists have been clarified and put to clinical use. Basically, synthetic VDR agonists are prodifferentiative, antiproliferative, anti-bacterial, anti-inflammatory and immunomodulatory(Adorini & Penna 2008). These properties lie behind their potentialities in the treatment of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythromatous, inflammatory bowel diseases, Type-I diabetes, psoriasis and autoimmune prostates(Luciano 2002; Adorini & Penna 2008).
Until recently, the non calcemic roles of Vitamin D were largely unknown, this includes its roles in the immune system such as T-cell mediated immunity(Deluca & Cantorna 2001). In addition to directly stimulating T-cell activation Vitamin D receptor ligands modulate in conjunction with various mechanisms the function and phenotype of antigen presenting cells(APCs) especially the dendritic cells. In vivo and in vitro studies, it has been demonstrated that VDR ligands induce dendritic cells to acquire teratogenic properties instrumental in the induction of regulatory effector T-cells(Luciano 2002).
Under the classification as a secosteroid, one of the rings is broken by ultraviolet B sunlight. The major source of Vitamin D in the body is the de novo synthesis in the integument. Even though the vitamin can be derived from food sources, the level of dietary intake is low and insufficient for physiological functions. Diet can only supply 20% of Vitamin D requirements in the body. Owing to its role in immunosuppression, vitamin D insufficiency has been correlated to the prevalence of autoimmune disease susceptibility and as well as severity(Cotulo 2009; Adams & Hewinson 2008). Therefore vitamin D is not only regulates calcium and bone metabolism but also exhibits immunomodulatory properties through the expression of nuclear VDR in APCs and activated T-cells or B-cells. This regulation is mediated by interfering with nuclear transcription factors(NTFs) like NF-AT or alternatively by directly interacting with vitamin D responsive elements found in the cytokine gene promoter regions.
Mechanisms of Action
The mechanism of the bioactive form of vitamin D; 1,25(OH)2D is akin to the mechanism of action of other steroid hormones and it is basically mediated by the binding of its VDR. VDR is classified as a member of a super family consisting of nuclear hormone receptors that include the retinoic acid receptors, steroid and thyroid hormones receptors. Vitamin D receptors function as a heterodimer with retinoid X receptor in regulating the target genes for vitamin D. These heterodimeric complexes specifically interact with DNA sequences [for instance, vitamin D response elements(VDREs)] which are located within the promoter region of the target genes. The interaction results in the activation or repression of gene transcription. The vitamin D response elements can at times be thousands of nucleotides away from the start site of transcription(Bickle 2008). For the transcription process to be successfully controlled, coregulators have to be recruited in the process
In activating the target genes, two promoter complexes are required. The first complex is the steroid receptor activator complex (SRC). This complex is composed of the p160 family of the SRC1 family, SRC2 family and the SRC3 coactivator family complexes and lastly the vitamin D receptor interacting protein complex(DRIP) or in other cases a mediator complex. All these co-activator complexes with AF-2 (C-terminal) domain of the Vitamin D receptor following ligand binding and the recruitment of cAMP response element binding(CREB) protein to protein binding, methyltransferases and histone acyl transferases(HATS) resulting into a multi-subunit complex. Methyltransferase and histone acyl transferase activity inside the SRC complex destabilizes DNA and histone core interaction hence stimulating the process of transcription. Since the DRIP component of the complex possesses no HAT activity, it is enlisted in recruiting RNA polymerase II critical for the beginning of transcription(Bickle 2008).
Co-repressors function in blocking the VDR mediated transcriptional activity. Nuclear co-repressor(NCoR) and silencing mediator of retinoic acid and thyroid receptor(SMRT) are the most understood co-repressors. Co-repressors bind to the VDR in the physiological absence of 1,25(OH)2D resulting in their displacement when 1,25(OH)2D binding eventually recruits co-activators to the VDR.
In the regulation of immune function, vitamin D and its bioactive metabolite; 1,25(OH)2D play a very important function. These roles are in both adaptive an innate immunity. Usually adaptive immunity involves the ability of B and T lymphocytes to produce immunoglobins and cytokines to specifically combat the antigen sources from the antigens presented to them by dendritic cells and macrophages. In adaptive immunity vitamin D exerts an inhibitory action. The active metabolite 1,25(OH)2D causes the suppression of the proliferation and the production of immunoglobin as well as the retardation of the differentiation of the B cells from immaturity to mature functional cells(Bickle 2008).
Dendritic cells are the primary targets for the expression of the immunomodulatory potential of 1,25(OH)2D3. This has been indicated by the inhibition of the differentiation and maturation of dendritic cells, resulting in the down regulation of the expression of MCH-II costimulatory molecules(CD 80, CD40 and CD86) coupled to the decrease in the production of IL-2. Additionally, Vitamin D 3 enhances Interleukin 10 production and promotes apoptosis of dendritic cells. In collaboration, these effects lead to the inhibition of dendritic cell dependent T-cell activation. Particularly, the active synthesis of vitamin D have been demonstrated to exert and autoregulatory function through the inhibiting monocyte precursors to differentiate into immature dendritic cells and eventually the ability of these immature cells to undergo terminal differentiation under the stimulation of a maturation stimuli(Adams & Hewinson 2008).
1,25(OH)2D3 succeeds in inhibiting T cell proliferation especially the T helper 1 cells which have the capacity to produce IL-2, IFN- and activating macrophages. By inhibiting T helper1 cells, 1,25(OH)2D prevents any further presentation and recruitment of T lymphocytes. Recruitment of these T lymphocytes is the responsibility of IFN- . The prevention of presentation is the role of IL-2. In contrast to the inhibition of IL-2, and IFN- which are behind T helper cell 1 importance, the production of IL-4, 5 and 10 can be increased hence shifting the balance to a T helper 2(Th2) phenotype. 1,25(OH)2D3 also increases the production of CD4+/CD25+ regulatory T cells (Treg cells) which can be shown by increase in IL-10 production and FoxP3 expression. The increased production of IL-10 causes the Treg mediated blocking of Th1 development. When the effects of all these actions are combined, they reduce the antigen presenting capability of dendritic cells(Bickle 2008).
When tolerogenic dendritic cells are briefly induced with 1,25(OH)2D3 or vitamin D analogues, they can cause the induction of CD4+CD25+ T regulatory (Treg) cells. These cells subsequently mediate the transplantation of tolerance before arresting the development of immunity. However, tolerogenic dendritic cells are not always involved in the process of generating Treg cells by vitamin D receptor agonists but when combined with dexamethasone and 1,25(OH)2D3 they induce naïve CD4+ T cells (Th0) to undergo in vivo differentiation into IL-10 producing Treg cells even when antigen presenting cells are absent. Vitamin D agonists favor the induction of CD4+CD25+ Treg cells and the enhancement of their suppressive activity. In addition, it may also be recruited at inflammatory sites. Natural killer T- cell functions in vivo and in vitro can also be induced by 1,25(OH)2D3 treatments(Cotulo 2009).
Given that NK cells cause the alteration of the autoimmunity outcome, its induction coupled to the induction of Treg cells and the direct inhibition Th1 cells by 1,25(OH)2D3, form the basis of the mechanisms of the suppression of autoimmunity by vitamin D. Vitamin D receptor agonists also inhibit the production of IL-17 by T cells. IL-17 is a pro-inflammatory and its production by pathogenic T cells, specifically the Th17 typifies its basic anti-inflammatory action. Incidentally, the production of IL-17 is sustained by IL-23 which is a member of IL-12 family. As such it consists of the p19 and p40 chains. VDR agonists strongly inhibit the p40 chains (Cotulo 2009).
Recent research has established that treatment with 1,25(OH)2D3 induces a significantly inhibits normal lymphoid cell progenitor growth of B lineage as well as T lineage and also the malignant growth of B cell lineage lymphoid progenitors. These inductions occur without the induction of a cytotoxic effect. On B cell responses, 1,25(OH)2D3 inhibits only the ongoing proliferation and subsequent induction of apoptosis without impeding initial cell divisions(Chen et al 2007). Moreover, 1,25(OH)2D3 is also involved in the inhibition of post switch memory of B cells and the generation of plasma cells, although the process of up-regulating the genetic programmes that are involved in the differentiation of B cells was modestly affected in comparison with the generation of plasma cells. B cells express mRNAs involved in 1,25(OH)2D3 activity inclusive of , 24-hydroxylase, 1 -hydroxylase and the VDR. Each of these are regulated and or activated by 1,25(OH)2D3. Interestingly, though vitamin D up regulates the expression of p27 but not the expression of p18 or p21. The latter two are more instrumental in the regulation of the activation of B cell proliferation and the subsequently their differentiation in plasma cells(Chen et al 2007).
More recent discoveries include the effects of vitamin D on the development and function of Th17. Many of the effects of 1,25(OH)2D3 on Th1 have also been demonstrated in TH17. It is through these processes that vitamin D suppresses the adaptive immune system hence acting as a potential intervention for the treatment of a number of immune system diseases where the immune response is directed at the self. In a number of experimental models it has been established that vitamin D could be beneficial in the treatment of autoimmune diabetes, inflammatory arthritis and inflammatory bowel disease.
In innate immunity, vitamin D has been found to be useful in activating toll like receptors(TLRs) in monocytes, polynuclear cells(PMNs) and macrophages. Innate immunity also involves the activation of a number of epithelial cells in the intestine, gingival, epidermis, lungs, vagina and bladder. Toll like receptors are transmembrane receptors that recognize pathogens that interact with the specific infectious agents secreted by the pathogen and which trigger the hosts’ innate immune response. When TLRs are activated, reactive oxygen species and antimicrobial peptides are induced hence killing the organism. Cathelicidin is one of the most common antibacterial peptides. The expression of cathelicidin occurs when it is induced vitamin D active metabolite in epithelial and myeloid cells. They have the capacity to respond to 1,25(OH)2D because they possess VDR and CYP27B1. Increased expression of CYP27B1 occurs when TLR2 is stimulated by antimicrobial peptides found in macrophages or when TLR2 is stimulated in keratinocytes in cases of physical injuries. When the increase in the expression of CYP27B1 occurs when the substrate 250HD is present, the expression of cathelicidin is stimulated. Lack of VDR, CYP27B1 and abundant substrate blunts the ability of cells to respond with regard to the cathelicidin production.
Type I diabetes usually abbreviated as TID is characterized by infiltration of leucocytes into the pancreatic islets. Recent studies have demonstrated that when infected adult mice are treated with vitamin D analogues, the progression of insulitis is arrested; the pancreatic infiltration of Th1 cells and the marked reduction of TID development are achieved. These impacts suggest that vitamin D analogues possess the ability to inhibit the production of chemokines by the islet cells. TLRs are expressed by both mice and human islet cells and are they are actively engaged by pathogen derived ligands in the enhancement of pro-inflammatory production of chemokine. On the other hand, vitamin D analogues down regulates both the in vitro and in vivo pro-inflammatory chemokine production, inhibits T cell recruitment into the islets of the pancreas and consequently the development of TID. It should also be noted that by inhibiting chemokine production in vivo, re-stimulation with TLR receptors persists. This persistence has been associated with up-regulating I B transcription which inhibits NF- B. All these processes coupled to the arrest of NF- Bp65 nuclear translocation represents a novel mechanism in which VDR ligands have become increasingly relevant in the treatment of autoimmune Type 1 diabetes (Giarratana et al 2004)
Some researchers have been able to connect the serum levels of vitamin D3 and prolonged darkness. Low levels of vitamin D among other factors like genetic background( for instance, vitamin D receptor polymorphism) and a set of nutritional factors can be used to offer an explanation on the prevalence of autoimmune diseases in relation to the latitudes in which people live(Cutulo et al 2007; Cotulo & Otsa 2008). The prevalence of diseases such as RA and SLE are latitude related. In SLE where patients present concomitant insults on tissues like bones, treatment of vitamin D deficiency using 1,25(OH)2D3 or its analogs may help these patients owing to the immunomodulatory effects of 1,25(OH)2D3. VDR agonists inhibit dendritic cell differentiation and pathogenic pro-inflammatory T cells like Th17 and Th1. Under maximum condition, this inhibition leads to a reversal to the Th2 pathway. These processes have been demonstrated to be significantly efficient in RA patients especially when they are therapeutically supported with 1,25(OH)2D3 administrations. In addition to these, vitamin D also plays a role in maintaining B cell homeostasis, correct vitamin D deficiency and consequently promote the therapeutic management of SLE; a B cell mediated autoimmune rheumatic disorder.
In the treatment of cancer, 1,25(OH)2D have been repeatedly evaluated so as to determine its anti-cancer activities both in cell and animal studies. VDR is expressed by a multitude of malignant cell types. This expression has been the major driving force behind the promise that 1,25(OH)2D may hold great potentials for the prevention and treatment of a variety of malignancy diseases inclusive of the prodifferentiating and the antiproliferative effects on most cells. Specifically, 1,25(OH)2D is involved in the stimulation of the expression of two particular cell cycle inhibitors; p21 and p27. They are also involved in the expression of E-catherin: a cell adhesion molecule. 1,25(OH)2D also inhibits the transcriptional activity of another molecule; β-catenin. In the keratinocytes, vitamin D promotes the repair of DNA damage induced by ultra violet radiation, increase the survival of the repaired DNA after UVR, reduce apoptosis and increase the levels of p53(Bickle 2008).
Several epidemiological evidences attest to the potential of 1,25(OH)2D in preventing of even treating so many cancers especially breast cancer, prostate cancer and colon cancer. However, clinical trials this potentiality has been more disappointing. In a study that was carried out to test the efficacy of 1,25(OH)2D or its analogs in cancer treatment, patients(seven in number) were given administered with 2.5 µg of 1,25(OH)2D for a period of six to fifteen months. Six patients out of the seven showed a marked decrease in the elevation of prostate specific antigen which is clinically used as a marker for tumor progression. The remaining patient showed a decline, but in all the patients hypercalciuria was not only common but limiting to the therapeutic intervention. In the end it was reported that with regard to the dosage levels, the effects of these 1,25(OH)2D analogs was non-significant. Thus, the potential of vitamin D in cancer treatment has largely been unsuccessful(Bickle 2008). However, more research and development of other analogs may yield an analog that is efficacious and non hypercalcemic.
Conclusion
The net effect of vitamin D, its bioactive form 1,25(OH)2D3, or its analogs is that it enhances innate immunity and in regulates adaptive immunity. A number of studies have satisfactorily affirmed that there exists a relationship between the incidence of autoimmune diseases and vitamin D deficiency. This connection clarifies the physiological roles that endogenous VDR agonists play in regulating autoimmune responses. These clarifications serve as a research incentive to the development of pharmacological VDR agonists for clinical use. In a nutshell, the properties in under such studies include; the pro-differentiative properties, the anti-proliferative properties, the anti-inflammatory properties and the immunomodulatory properties of synthesized VDR agonists. Based on these properties, vitamin D possesses the potential of treating a variety of autoimmune diseases. More research needs to be done for the full potentialities of vitamin D to be realized.
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