Emerging Roles of Vitamin D-Induced Antimicrobial Peptides in Antiviral Innate Immunity.

Vitamin D deficiency, characterized by low circulating levels of calcifediol (25-hydroxyvitamin D, 25D) has been linked to increased risk of infections of bacterial and viral origin. Innate immune cells produce hormonal calcitriol (1,25-dihydroxyvitamin D, 1,25D) locally from circulating calcifediol in response to pathogen threat and an immune-specific cytokine network. Calcitriol regulates gene expression through its binding to the vitamin D receptor (VDR), a ligand-regulated transcription factor. The hormone-bound VDR induces the transcription of genes integral to innate immunity including pattern recognition receptors, cytokines, and most importantly antimicrobial peptides (AMPs). Transcription of the human AMP genes ß-defensin 2/defensin-ß4 (HBD2/DEFB4) and cathelicidin antimicrobial peptide (CAMP) is stimulated by the VDR bound to promoter-proximal vitamin D response elements. HDB2/DEFB4 and the active form of CAMP, the peptide LL-37, which form amphipathic secondary structures, were initially characterized for their antibacterial actively. Notably, calcitriol signaling induces secretion of antibacterial activity in vitro and in vivo, and low circulating levels of calcifediol are associated with diverse indications characterized by impaired antibacterial immunity such as dental caries and urinary tract infections. However, recent work has also provided evidence that the same AMPs are components of 1,25D-induced antiviral responses, including those against the etiological agent of the COVID-19 pandemic, the SARS-CoV2 coronavirus. This review surveys the evidence for 1,25D-induced antimicrobial activity in vitro and in vivo in humans and presents our current understanding of the potential mechanisms by which CAMP and HBD2/DEFB4 contribute to antiviral immunity.

9-cis Retinoic acid and 1.25-dihydroxyvitamin D3 drive differentiation into IgA+ secreting plasmablasts in human naïve B cells.

Calcitriol and 9-cis retinoic acid (9cRA) play a fundamental role in shaping the adaptive immune response by altering the Ig profile and the differentiation of B cells, controlled by their corresponding nuclear receptors, VDR and RAR. Herein, after the establishment of a plasmablast differentiation culture, we investigated how both ligands modulate human naïve B cell differentiation and to which extent VDR/RXR and RAR/RXR signaling interferes. Calcitriol and 9cRA mediated activation of purified naïve B cells resulted in a strong differentiation of CD27+ CD38+ plasmablasts and antibody secretion. The significant IgA response was preceded by a strong induction of α-germline transcription (GLT). Induction of αGLT and consecutively IgA secretion driven by calcitriol is a novel observation and we show by magnetic chromatin IP that this was mediated by recruitment of the VDR to the TGF-ß promoter thus inducing TGF-ß expression. Finally, as revealed by transcriptomic profiling calcitriol and 9cRA modulate several signals required for differentiation and isotype switching in a noncompeting but rather additive manner. Calcitriol and 9cRA participate in the control of the IgA response in human activated naïve B cells. The balance between both ligands may be an important factor in channeling humoral immune responses toward a protective direction.

Lack of interleukin-33 and its receptor does not prevent calcipotriol-induced atopic dermatitis-like inflammation in mice.

Current studies addressing the influence of interleukin-33 or its receptor (IL-33R/ST2) on development of atopic dermatitis-like inflammation in mice have reported conflicting results. We compared the response in single- and double-deficient IL-33-/-/ST2-/- C57BL/6J BomTac mice in the well-established calcipotriol-induced model of atopic dermatitis. All genotypes (groups of up to 14 mice) developed atopic dermatitis-like inflammation yet we observed no biologically relevant difference between groups in gross anatomy or ear thickness. Moreover, histological examination of skin revealed no differences in mononuclear leukocyte and granulocyte infiltration nor Th2 cytokine levels (IL-4 and IL-13). Finally, skin CD45+ cells and CD3+ cells were found at similar densities across all groups. Our findings indicate that lack of interleukin-33 and its receptor ST2 does not prevent the development of AD-like skin inflammation.

Immunomodulatory Effects of Calcitriol through DNA Methylation Alteration of FOXP3 in the CD4+ T Cells of Mice.

Vitamin D plays a variety of physiological functions, such as regulating mineral homeostasis. More recently, it has emerged as an immunomodulator player, affecting several types of immune cells, such as regulatory T (Treg) cells. It has been reported that vitamin D exerts some mediatory effects through an epigenetic mechanism. In this study, the impacts of calcitriol, the active form of vitamin D, on the methylation of the conserved non-coding sequence 2 (CNS2) region of the forkhead box P3 (Foxp3) gene promoter, were evaluated. Fourteen C57BL/6 mice were recruited in this study and divided into two intervention and control groups. The CD4+ T cells were isolated from mice splenocytes. The expression of Foxp3, IL-10, and transforming growth factor-beta (TGF-ß1) genes were relatively quantified by real-time PCR technique, and the DNA methylation percentage of every CpG site in the CNS2 region was measured individually by bisulfite-sequencing PCR. Vitamin D Intervention significantly (p<0.05) could increase the expression of Foxp3, IL-10, and TGF-ß1 gene in the CD4+ T cells of mice comparing with the control group. Meanwhile, methylation of the CNS2 region of Foxp3 promoter was significantly decreased in three of ten CpG sites in the vitamin D group compared to the control group. The results of this study showed that vitamin D can engage the methylation process to induce Foxp3 gene expression and probably Treg cytokines profile. Further researches are needed to discover the precise epigenetic mechanisms by which vitamin D modulates the immune system.

Immune Dysfunction and Risk of Infection in Chronic Kidney Disease.

Cardiovascular disease and infections are directly or indirectly associated with an altered immune response, which leads to a high incidence of morbidity and mortality, and together, they account for up to 70% of all deaths among patients with chronic kidney dysfunction. Impairment of the normal reaction of the innate and adaptive immune systems in chronic kidney disease predisposes patients to an increased risk of infections, virus-associated cancers, and a diminished vaccine response. On the other hand, an abnormal, exaggerated reaction of the immune systems can also occur in this group of patients, resulting in increased production and decreased clearance of proinflammatory cytokines, which can lead to inflammation and its sequelae (eg, atherosclerotic cardiovascular disease). Epigenetically, modifications in hematopoietic stem cells involving a shift from lymphoid to myeloid cell lineage may underlie uremia-associated immunological senescence, which is not reversed by renal replacement therapy, including kidney transplantation. Measures aimed at attenuating the immune abnormalities in chronic kidney disease/end-stage renal disease should be an area of focused research as this could potentially lead to a better understanding and, thus, development of therapies that could reduce the disastrously high death rate in this patient population. The aim of the present article is to review the characteristics, causes, and mechanisms of the immune dysfunction related to chronic kidney disease.

Vitamin D controls the capacity of human dendritic cells to induce functional regulatory T cells by regulation of glucose metabolism.

Tolerogenic dendritic cells (tolDCs) instruct regulatory T cells (Tregs) to dampen autoimmunity. Active vitamin D3 (1α,25-dihydroxyvitamin D3; 1α,25(OH)2D3) imprints human monocyte-derived DCs with tolerogenic properties by reprogramming their glucose metabolism. Here we identify the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) as a critical checkpoint and direct transcriptional target of 1α,25(OH)2D3 in determining the tolDC profile. Using tracer metabolomics, we show that PFKFB4 activity is essential for glucose metabolism, especially for glucose oxidation, which is elevated upon 1α,25(OH)2D3 exposure. Pharmacological inhibition of PFKFB4 reversed the 1α,25(OH)2D3-mediated shift in metabolism, DC profile and function, as determined by expression of inhibitory surface markers and secretion of regulatory cytokines and factors. Moreover, PFKFB4 inhibition in 1α,25(OH)2D3-treated DCs blocked their hallmark capacity to induce suppressive Tregs. This work demonstrates that alterations in the bioenergetic metabolism of immune cells are central to the immunomodulatory effects induced by 1α,25(OH)2D3.

A tryptophan metabolite of the skin microbiota attenuates inflammation in patients with atopic dermatitis through the aryl hydrocarbon receptor.

BACKGROUND: Previous studies have revealed significant alterations in the skin microbiota of patients with atopic dermatitis (AD) not only in diversity and composition but also in function, and the tryptophan (Trp) metabolic pathway is attenuated in the skin microbiota of patients with AD. OBJECTIVE: We sought to assess Trp metabolites on the skin surfaces of patients with AD and to explore the function of the microbial Trp metabolites in skin inflammation in patients with AD. METHODS: A gel-patch method was developed to collect metabolites on the skin surface, which were then assessed by using liquid chromatography-tandem mass spectrometry. A mouse model of calcipotriol (MC903)-induced AD-like dermatitis was used to evaluate the effects of microbial metabolites on AD, and aryl hydrocarbon receptor (AhR)-null mice and keratinocyte cultures were used to investigate the mechanism. RESULTS: Major microbial metabolites of Trp were detected on the skin surfaces of healthy subjects, and the level of indole-3-aldehyde (IAId), an indole derivative of Trp catabolism, was significantly lower in lesional and nonlesional skin of patients with AD than that of healthy subjects. IAId significantly attenuated skin inflammation in mice with MC903-induced AD-like dermatitis, and this effect was blocked by an AhR antagonist and abolished in AhR-null mice. Furthermore, IAId was found to inhibit the MC903-induced expression of thymic stromal lymphopoietin in keratinocytes in vivo and in vitro, which was mediated by binding of AhR to the thymic stromal lymphopoietin promoter. CONCLUSION: IAId, a skin microbiota-derived Trp metabolite, negatively regulated skin inflammation in patients with AD, revealing that skin microbiota play a significant functional role in the pathogenesis of AD.

Vitamin D: Immunomodulatory Aspects.

Vitamin D is a group of liposoluble prohormones consisting of 5 different vitamins, the most important forms being vitamin D2 and vitamin D3. The ergocalciferol (vitamin D2) is less efficacious and derives from irradiated fungi, while colecalciferol (vitamin D3), derived from cholesterol, is synthesized via ultraviolet B rays in animal organisms. Only the ultraviolet B rays (290 to 315 nm) portion of the solar ray photolyzes 7-dehydrocholesterol in the skin to previtamin D3, which is converted subsequently to vitamin D3. Moreover, the skin makes little vitamin D from the sun at latitudes above 37 degrees north or below 37 degrees south of the equator. Calcidiol [25(OH)D] is the more stable metabolite of vitamin D in serum and the best indicator of the vitamin D status. Optimal values range are >30 ng/mL. Calcitriol [1,25(OH)2D] is the active hormone form of vitamin D. The 1,25(OH)2D binds to its nuclear receptor (vitamin D receptor), expressed in many tissues, regulating the expression of genes involved in calcium metabolism, cell differentiation, apoptosis, and immunity. About immunity, calcitriol stimulates innate immune responses by enhancing the chemotactic and phagocytotic responses of macrophages as well as the production of antimicrobial peptides. 1,25(OH)2D strongly enhances production of interleukine-10 by stimulating T regulatory cells and inhibiting Th1 and Th17 cell differentiation. Furthermore, several studies suggest that lower 25(OH)D serum levels are associated with an increased risk of respiratory infection at all ages in a dose-response manner.

A preliminary study on topical ozonated oil in the therapeutic management of atopic dermatitis in murine.

OBJECTIVE: To explore whether ozonated oil recovery atopic dermatitis (AD) via immunoregulation. METHODS: Mice were repeatedly challenged with the triplex allergens of staphylococcal enterotoxin B, ovalbumin and calcipotriol ointment on the back to develop AD lesions, and were treated with ozonated oil. The lesional skins were scanned by reflectance confocal microscopy to measure the thickness of epidermis. The skin tissues were stained. Th1-type and Th2-type cytokines in serum and in tissues were detected by ELISA and real-time PCR, respectively. RESULTS: Ozonated oil significantly inhibited inflammation and healed the lesions in 7 d. Ozonated oil inhibited NGF expression as compared to the groups treated with vehicle or PBS (p < .01).The serum proteins and lesional transcripts of Th2 cytokines including IL-4 and IL-31 were lower in the ozonated oil treated group than the groups treated with vehicle or PBS (p < .05). The IL-10 level was increased with treatment of ozonated oil (p < .01). On the other hand, the expressions of Th1 cytokines including IL-2, TNF-α, and IFN-γ in the serum were not regulated by ozonated oil. CONCLUSIONS: Our results showed that ozonated oil could suppress inflammation in an AD murine via decreasing Th2-dominant cytokines response and increasing IL-10 expression. These suggest that ozonated oil may be a potential remedy for AD.

Neutralization of IL-17C Reduces Skin Inflammation in Mouse Models of Psoriasis and Atopic Dermatitis.

IL-17C is a functionally distinct member of the IL-17 family that was believed to play a role in the pathogenesis of psoriasis. Here we confirmed that IL-17C is involved in psoriasis and explored potential roles for IL-17C in atopic dermatitis (AD). An anti-IL-17C antibody, MOR106, was generated that potently and selectively binds to human and mouse IL-17C, thereby inhibiting the binding of IL-17C to its IL-17RE receptor. The antibody inhibited cutaneous inflammation in an IL-23-induced psoriatic-like skin inflammation model. In lesional skin of patients with AD, IL-17C expression levels were increased and localized to keratinocytes and infiltrating immune cells. To determine the contribution of IL-17C to AD pathogenesis, MOR106 was tested in two distinct in vivo models. In the calcipotriol-induced AD model, ear skin inflammation, TSLP, and IL-33 protein production in ears was suppressed by MOR106. Consistently, in the flaky tail strain mouse model, spontaneous development of AD-like skin inflammation was reduced by MOR106. Moreover, serum IgE levels, number of mast cells in skin and T helper type 2-related cytokines IL-4 and CCL17 in serum were all reduced. Overall, our results indicate that IL-17C is a central mediator of skin inflammation beyond psoriasis and is relevant in particular in AD.

Endogenous Calcitriol Synthesis Controls the Humoral IgE Response in Mice.

The vitamin D receptor participates in the control of IgE class-switch recombination in B cells. The physiologic vitamin D receptor agonist, 1,25(OH)2D3 (calcitriol), is synthesized by the essential enzyme 25-hydroxyvitamin D3-1α-hydroxylase (CYP27B1), which can be expressed by activated immune cells. The role of endogenous calcitriol synthesis for the regulation of IgE has not been proven. In this study, we investigated IgE-responses in Cyp27b1-knockout (KO) mice following sensitization to OVA or intestinal infection with Heligmosomoides polygyrus Specific Igs and plasmablasts were determined by ELISA and ELISpot, Cyp27b1 expression was measured by quantitative PCR. The data show elevated specific IgE and IgG1 concentrations in the blood of OVA-sensitized Cyp27b1-KO mice compared with wild-type littermates (+898 and +219%). Accordingly, more OVA-specific IgG1-secreting cells are present in spleen and fewer in the bone marrow of Cyp27b1-KO mice. Ag-specific mechanisms are suggested as the leucopoiesis is in general unchanged and activated murine B and T lymphocytes express Cyp27b1 Accordingly, elevated specific IgE concentrations in the blood of sensitized T cell-specific Cyp27b1-KO mice support a lymphocyte-driven mechanism. In an independent IgE-inducing model, i.e., intestinal infection with H. polygyrus, we validated the increase of total and specific IgE concentrations of Cyp27b1-KO compared with wild-type mice, but not those of IgG1 or IgA. We conclude that endogenous calcitriol has an impact on the regulation of IgE in vivo. Our data provide genetic evidence supporting previous preclinical and clinical findings and suggest that vitamin D deficiency not only promotes bone diseases but also type I sensitization.

Low utility of serum 25-hydroxyvitamin D3 and 1, 25-dihydroxyvitamin D3 in predicting peripheral Treg and Th17 cell counts in ESRD and renal transplant patients.

BACKGROUND: Vitamin D has shown an immune-modulatory effect in different studies. Vitamin D stimulates Tregs and inhibits Th17 cells. The immune-modulatory role of vitamin D in chronic kidney disease (CKD) and renal transplant patients is unclear. We measured whether different serum levels of vitamin D were associated with an increased or decreased presence of lymphocyte subsets including Treg and Th17 cells in end-stage renal disease (ESRD) and renal transplant recipients. METHODS: Eighty-seven renal transplant recipients and 53 end-stage renal disease (ESRD) patients were enrolled in this study. The absolute counts of CD4+ and CD8+ T, CD16+ CD56+ NK, CD19+ B, CD4+ CD25+ CD127- Foxp3+ (Tregs), Helios+ Tregs, CD38+ Tregs, and CD4+ CD17+ (Th17) cells were analyzed in peripheral blood in both patient groups. In addition, serum 25 (OH) D3, 1, 25 (OH)2 D3, IL-6, IL-17, IL-23, and TGF-ß1 were measured. The association between lymphocyte subset counts and 1, 25 (OH)2 D3 or 25 (OH) D3 was studied, as was the association between serum IL-6, IL-17, IL-23, or TGF-ß1 and 1,25 (OH)2 D3 or 25 (OH) D3. RESULTS: Serum 25 (OH) D3 and 1,25 (OH)2 D3 levels were not independently associated with peripheral CD4+ T, CD19+ B, CD16+ CD56+ NK, Treg, or Th17 cell counts. In contrast to serum 25 (OH) D3, serum1, 25 (OH)2 D3 was positively associated with CD8+ T cells counts in renal transplant recipients. CONCLUSION: Our findings indicate low utility of serum 25 (OH) D3 and 1, 25 (OH)2 D3 levels in predicting a change in lymphocyte subset counts in ESRD and renal transplant patients.

1,25(OH)2D3/VDR attenuates high glucose­induced epithelial­mesenchymal transition in human peritoneal mesothelial cells via the TGFß/Smad3 pathway.

Epithelial-mesenchymal transition (EMT) has been recognized to accelerate peritoneal membrane dysfunction. 1,25(OH)2D3/vitamin D receptor (VDR) is important for preventing various types of EMT in vivo. However, its function on EMT and inflammation of human peritoneal mesothelial cells (HPMCs) remains to be elucidated. Therefore, the present study investigated the effects of 1,25(OH)2D3/VDR on high glucose (HG)­induced EMT and inflammation in HPMCs and the underlying molecular mechanism. It was determined that HG reduced VDR expression, increased inflammatory cytokine expression, including transforming growth factor ß (TGFß) and interleukin­6 (IL­6) and phosphorylated­SMAD family member 3 (p­Smad3) expression. EMT was promoted as the expression level of the epithelial marker E­cadherin was reduced, whereas expression levels of the mesenchymal markers α­SMA and FN were increased. 1,25(OH)2D3 pretreatment inhibited the expression of inflammatory cytokines in HPMCs and attenuated HG­induced EMT, possibly through inhibition of the TGFß/Smad pathway by binding to its receptor VDR.

Immunomodulatory and Immunosuppressive Roles of 1α,25(OH)2D3 in Autoimmune Diseases.

Autoimmune diseases are pathological conditions characterized by abnormal responses, accompanied by autoantibodies to self-molecules. The role of vitamin D in autoimmune diseases has increased significantly in the recent past from its functions in calcium and phosphate homoeostasis, and it is now involved in the regulations and proliferations of Th1 and Th17 lymphocyte. 1α,25(OH)2D3 is very important in ameliorations of inflammatory disorders arising from autoimmune diseases, but the mechanism by which this is performed is still a bone of contentions. This review aimed to highlight the existing facts about the roles of Vitamin D in the treatment and management of autoimmune diseases. An extensive online literature search was conducted using PubMed, MEDLINE and Scopus. Accumulated bodies of research evidence are available which demonstrates that Vitamin D has a very important part to play in the regulation of immune responses in autoimmune diseases. Some of the authors suggested that Vitamin D3 carry-out its immunosuppressive and immune modulatory action, through its actions on antigen-presenting cells and activated T and B cells with the help of Vitamin D receptors present on the each of these cells. Vitamin D supplementation assists in autoimmune disorders by making qualitative and quantitative changes in the immune system (downregulation of Th1 and upregulations of Th2 cells). This resulted in the body to be more tolerant of self and less likely to mount autoimmune responses.

Anti-Inflammatory Effects of Vitamin D on Human Immune Cells in the Context of Bacterial Infection.

Vitamin D induces a diverse range of biological effects, including important functions in bone health, calcium homeostasis and, more recently, on immune function. The role of vitamin D during infection is of particular interest given data from epidemiological studies suggesting that vitamin D deficiency is associated with an increased risk of infection. Vitamin D has diverse immunomodulatory functions, although its role during bacterial infection remains unclear. In this study, we examined the effects of 1,25(OH)2D3, the active metabolite of vitamin D, on peripheral blood mononuclear cells (PBMCs) and purified immune cell subsets isolated from healthy adults following stimulation with the bacterial ligands heat-killed pneumococcal serotype 19F (HK19F) and lipopolysaccharide (LPS). We found that 1,25(OH)2D3 significantly reduced pro-inflammatory cytokines TNF-α, IFN-γ, and IL-1ß as well as the chemokine IL-8 for both ligands (three- to 53-fold), while anti-inflammatory IL-10 was increased (two-fold, p = 0.016) in HK19F-stimulated monocytes. Levels of HK19F-specific IFN-γ were significantly higher (11.7-fold, p = 0.038) in vitamin D-insufficient adults (<50 nmol/L) compared to sufficient adults (>50 nmol/L). Vitamin D also shifted the pro-inflammatory/anti-inflammatory balance towards an anti-inflammatory phenotype and increased the CD14 expression on monocytes (p = 0.008) in response to LPS but not HK19F stimulation. These results suggest that 1,25(OH)2D3 may be an important regulator of the inflammatory response and supports further in vivo and clinical studies to confirm the potential benefits of vitamin D in this context.

1,25D3 prevents CD8(+)Tc2 skewing and asthma development through VDR binding changes to the Cyp11a1 promoter.

Effector CD8(+) T cells convert from IFN-γ(+) (Tc1) to IL-13(+) (Tc2) cells in the presence of IL-4. Underlying regulatory mechanisms are not fully defined. Here, we show that addition of 1,25D3, the active form of vitamin D3, during CD8(+) T-cell differentiation prevents IL-4-induced conversion to IL-13-producers. Transfer of 1,25D3-treated CD8(+) T cells into sensitized and challenged CD8(+)-deficient recipients fails to restore development of lung allergic responses. 1,25D3 alters vitamin D receptor (VDR) recruitment to the Cyp11a1 promoter in vitro and in vivo in the presence of IL-4. As a result, protein levels and enzymatic activity of CYP11A1, a steroidogenic enzyme regulating CD8(+) T-cell conversion, are decreased. An epistatic effect between CYP11A1 and VDR polymorphisms may contribute to the predisposition to childhood asthma. These data identify a role for 1,25D3 in the molecular programming of CD8(+) T-cell conversion to an IL-13-secreting phenotype through regulation of steroidogenesis, potentially governing asthma susceptibility.

The phenotype and function of murine bone marrow-derived dendritic cells is not affected by the absence of VDR or its ability to bind 1α,25-dihydroxyvitamin D3.

The nuclear vitamin D receptor (VDR) is generally recognized as a ligand-dependent transcription factor that mediates the actions of its natural ligand, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) on multiple target genes involved in mineral homeostasis, bone development, as well as immune reactivity. As the VDR is widely distributed in nearly all cells of the body, it implies that the vitamin D endocrine system may regulate many cell types and functions. Experiments in VDR null mice established that the VDR has intrinsically critical roles in skin and keratinocyte biology but not in immune responses. Oppositely, absence of the VDR ligand is linked to susceptibility to autoimmunity, illustrating a potential role for the unliganded VDR in the immune system. This discrepancy stimulated us to further investigate the impact of the VDR on the phenotype and function of myeloid dendritic cells (DCs) generated ex vivo from bone marrow precursors of VDR null (with a truncated VDR) and VDR ΔAF2 mice (with a mutated C-terminal activation factor 2 domain thus rendering ligand-induced gene transcription impossible). Absent or unliganded VDR did not affect bone marrow-derived myeloid DC generation. DCs obtained from VDR null and VDR ΔAF2 bone marrow cells had comparable MHC-II, and costimulatory molecule CD86, CD80 and CD40 expression than DCs from wild-type bone marrow cells. Additionally, an unliganded VDR did not affect the cytokine production nor the antigen-specific T cell stimulatory capacity of bone marrow-derived DCs. In conclusion, we showed that although clear effects of 1α,25-dihydroxyvitamin D3 are described on DC generation, absence of VDR or presence of an unliganded VDR does not affect the profile and function of ex vivo generated bone marrow-derived DCs.

The Active Metabolite of Vitamin D3 as a Potential Immunomodulator.

In the past, vitamin D was known for its classical, skeletal action as a regulator of calcium and bone homoeostasis. Currently, vitamin D was found to have a role in numerous physiological processes in the human body; thus, vitamin D has pleiotropic activity. The studies carried out in the past two decades showed the role of vitamin D in the regulation of immune system functions. Basically, these effects may be mediated not only via endocrine mechanism of circulating calcitriol but also via paracrine one (based on cell-cell communication that leads to production of signal inducing the changes in nearby/adjacent cells and modulating their differentiation or behaviour) and intracrine mechanism (the action of vitamin D inside a cell) of 1,25-dihydroxycholecalciferol (1,25(OH)2 D3 ) synthetized from its precursor 25-hydroxyvitamin D3 (25(OH)D3 ). Both vitamin D receptor (VDR) and 25-hydroxyvitamin D3 1-α-hydroxylase (CYP27B1) are expressed in several types of immune cells (i.e. antigen presenting cells, T and B cells), and thus, they are able to synthetize the bioactive form of vitamin D that modulates both the innate and adaptive immune system. This review discusses the role of vitamin D as regulator of immune system, and our understanding of how vitamin D regulates both adaptive and innate immunity as well as inflammatory cascade on the cellular level.

Regulation of Dendritic Cell Function by Vitamin D.

Studies over the last two decades have revealed profound immunomodulatory aspects of vitamin D on various aspects of the immune system. This review will provide an overview of Vitamin D metabolism, a description of dendritic cell subsets, and highlight recent advances on the effects of vitamin D on dendritic cell function, maturation, cytokine production and antigen presentation. The active form of vitamin D, 1,25(OH)2D3, has important immunoregulatory and anti-inflammatory effects. Specifically, the 1,25(OH)2D3-Vitamin D3 complex can affect the maturation and migration of many dendritic cell subsets, conferring a special immunoregulatory role as well as tolerogenic properties affecting cytokine and chemokine production. Furthermore, there have been many recent studies demonstrating the effects of Vitamin D on allergic disease and autoimmunity. A clear understanding of the effects of the various forms of Vitamin D will provide new opportunities to improve human health.

Vitamin D Antibodies in Systemic Sclerosis Patients: Findings and Clinical Correlations.

BACKGROUND: Vitamin D is a pivotal factor in calcium homeostasis and exerts immunomodulatory effects. Hypovitamin D has been demonstrated in systemic sclerosis (SSc) patients and may be related to more severe disease of longer duration and with extensive skin involvement. OBJECTIVES: To seek anti-vitamin D antibodies in SSc patients, as found by previous research in patients with systemic lupus erythematosus (SLE). METHODS: The study included 54 SSc patients and 41 volunteers. Immunoglobulin (Ig) G and IgM autoantibody levels against 25(OH)D and 1,25(OH)D were obtained from patients and controls and were compared. SSc patients were assessed for autoantibody profile and disease severity. RESULTS: Vitamin D antibodies were present in 87% of SSc patients and 42% of controls. Higher levels of anti-25(OH)D IgM antibodies were detected in SSc patients compared to controls (0.48 ± 0.22 vs. 0.29 ± 0.29, respectively, P = 0.002); however, IgG levels were lower in the SSc patients. No such discriminative. effect was found regarding anti-1,25(OH)D antibodies between SSc and controls. No correlation was found between,vitamin D antibodies and other autoantibodies, disease severity, or target organ damage. CONCLUSIONS: To the best of our knowledge; this is the first study of these novel, anti-vitamin D antibodies in SSc patients and the first time a correlation between IgM 25(OH) vitamin D antibodies and scleroderma has been identified. Further research on the pathophysiological significance and therapeutic potential of vitamin D is required.