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      Vitamin D as an Immunomodulator: Risks with Deficiencies and Benefits of Supplementation

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          Abstract

          Vitamin D refers to a class of fat-soluble secosteroids often associated with their role in absorption and metabolism of minerals such as calcium and phosphate. In recent years, our understanding of vitamin D has expanded to include its role in modulating the immune system. Of particular focus are the effects of vitamin D deficiency and supplementation on patients suffering from disorders due to dysregulation of the immune system. In patients with multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease, deficiencies in vitamin D have been associated with an increased risk of disease activity. In this review, we will look at the current state of research in regards to the relationship between vitamin D and immune-dysregulation. We will focus on both the risks associated with vitamin D deficiency as well as the benefits of vitamin D supplementation.

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          Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression.

          Tian-Tian Wang, Frederick Nestel, Véronique Bourdeau … (2004)
          The hormonal form of vitamin D(3), 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), is an immune system modulator and induces expression of the TLR coreceptor CD14. 1,25(OH)(2)D(3) signals through the vitamin D receptor, a ligand-stimulated transcription factor that recognizes specific DNA sequences called vitamin D response elements. In this study, we show that 1,25(OH)(2)D(3) is a direct regulator of antimicrobial innate immune responses. The promoters of the human cathelicidin antimicrobial peptide (camp) and defensin beta2 (defB2) genes contain consensus vitamin D response elements that mediate 1,25(OH)(2)D(3)-dependent gene expression. 1,25(OH)(2)D(3) induces antimicrobial peptide gene expression in isolated human keratinocytes, monocytes and neutrophils, and human cell lines, and 1,25(OH)(2)D(3) along with LPS synergistically induce camp expression in neutrophils. Moreover, 1,25(OH)(2)D(3) induces corresponding increases in antimicrobial proteins and secretion of antimicrobial activity against pathogens including Pseudomonas aeruginosa. 1,25(OH)(2)D(3) thus directly regulates antimicrobial peptide gene expression, revealing the potential of its analogues in treatment of opportunistic infections.
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            Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation.

            Sheng Chen, Gary P. Sims, Xiao Chen … (2007)
            1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) can modulate immune responses, but whether it directly affects B cell function is unknown. Patients with systemic lupus erythematosus, especially those with antinuclear Abs and increased disease activity, had decreased 1,25(OH)(2)D(3) levels, suggesting that vitamin D might play a role in regulating autoantibody production. To address this, we examined the effects of 1,25(OH)(2)D(3) on B cell responses and found that it inhibited the ongoing proliferation of activated B cells and induced their apoptosis, whereas initial cell division was unimpeded. The generation of plasma cells and postswitch memory B cells was significantly inhibited by 1,25(OH)(2)D(3), although the up-regulation of genetic programs involved in B cell differentiation was only modestly affected. B cells expressed mRNAs for proteins involved in vitamin D activity, including 1 alpha-hydroxylase, 24-hydroxylase, and the vitamin D receptor, each of which was regulated by 1,25(OH)(2)D(3) and/or activation. Importantly, 1,25(OH)(2)D(3) up-regulated the expression of p27, but not of p18 and p21, which may be important in regulating the proliferation of activated B cells and their subsequent differentiation. These results indicate that 1,25(OH)(2)D(3) may play an important role in the maintenance of B cell homeostasis and that the correction of vitamin D deficiency may be useful in the treatment of B cell-mediated autoimmune disorders.
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              1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells.

              A. Boonstra, F. J. Barrat, C Crain … (2001)
              1alpha,25-Dihydroxyvitamin D3 (vitD3) is an immunoregulatory hormone with beneficial effects on Th1 mediated autoimmune diseases. Although the inhibitory effects of vitD3 on macrophages and dendritic cells are well documented, any direct effects of vitD3 on Th cell development are not clearly defined. Using CD4(+)Mel14(+) T cells derived from mice on a BALB/c and a C57BL/6 genetic background we examined the effect of vitD3 on Th cell development. We demonstrated that vitD3 affects Th cell polarization by inhibiting Th1 (IFN-gamma production) and augmenting Th2 cell development (IL-4, IL-5, and IL-10 production). These effects were observed in cultures driven with splenic APC and Ag, as well as with anti-CD3 and anti-CD28 alone, indicating that CD4(+) cells can also be direct targets for vitD3. The enhanced Th2 development by vitD3 was found in both BALB/c and C57BL/6 mice. An increased expression of the Th2-specific transcription factors GATA-3 and c-maf correlated with the increased production of Th2 cytokines after vitD3 treatment. The vitD3-induced effects were largely mediated via IL-4, because neutralization of IL-4 almost completely abrogated the augmented Th2 cell development after vitD3 treatment. These findings suggest that vitD3 acts directly on Th cells and can, in the absence of APC, enhance the development of a Th2 phenotype and augment the expression of the transcription factors c-maf and GATA-3. Our findings suggest that the beneficial effects of vitD3 in autoimmune diseases and transplantation operate through prevention of strong Th1 responses via the action on the APC, while simultaneously directly acting on the T cell to enhance Th2 cell development.
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                Author and article information

                Contributors
                Samir Samman: Role: Academic Editor
                Ian Darnton-Hill: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Healthcare (Basel)
                Journal ID (iso-abbrev): Healthcare (Basel)
                Journal ID (publisher-id): healthcare
                Title: Healthcare
                Publisher: MDPI
                ISSN (Electronic): 2227-9032
                Publication date (Electronic): 14 April 2015
                Publication date Collection: June 2015
                Volume: 3
                Issue: 2
                Pages: 219-232
                Affiliations
                Department of Internal Medicine, University of Michigan, 3116G Taubman Center, SPC 5368, Ann Arbor, MI 48109, USA; E-Mail: goldsmja@ 123456med.umich.edu
                Article
                Publisher ID: healthcare-03-00219
                DOI: 10.3390/healthcare3020219
                PMC ID: 4939543
                PubMed ID: 27417758
                SO-VID: 5f56fa4b-dafa-4f75-8840-b3c9634b92f8
                Copyright © © 2015 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 15 March 2015
                Date accepted : 08 April 2015
                Categories
                Subject: Review

                Keywords: vitamin d,immune function,immunomodulator,inflammatory bowel diseases,multiple sclerosis,rheumatoid arthritis,treg
                Data availability:
                Keywords: vitamin d, immune function, immunomodulator, inflammatory bowel diseases, multiple sclerosis, rheumatoid arthritis, treg

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