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      The Vitamin D Receptor and T Cell Function

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          Abstract

          The vitamin D receptor (VDR) is a nuclear, ligand-dependent transcription factor that in complex with hormonally active vitamin D, 1,25(OH) 2D 3, regulates the expression of more than 900 genes involved in a wide array of physiological functions. The impact of 1,25(OH) 2D 3-VDR signaling on immune function has been the focus of many recent studies as a link between 1,25(OH) 2D 3 and susceptibility to various infections and to development of a variety of inflammatory diseases has been suggested. It is also becoming increasingly clear that microbes slow down immune reactivity by dysregulating the VDR ultimately to increase their chance of survival. Immune modulatory therapies that enhance VDR expression and activity are therefore considered in the clinic today to a greater extent. As T cells are of great importance for both protective immunity and development of inflammatory diseases a variety of studies have been engaged investigating the impact of VDR expression in T cells and found that VDR expression and activity plays an important role in both T cell development, differentiation and effector function. In this review we will analyze current knowledge of VDR regulation and function in T cells and discuss its importance for immune activity.

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          Most cited references101

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          A decade of molecular biology of retinoic acid receptors.

          P Chambon (1996)
          Retinoids play an important role in development, differentiation, and homeostasis. The discovery of retinoid receptors belonging to the superfamily of nuclear ligand-activated transcriptional regulators has revolutionized our molecular understanding as to how these structurally simple molecules exert their pleiotropic effects. Diversity in the control of gene expression by retinoid signals is generated through complexity at different levels of the signaling pathway. A major source of diversity originates from the existence of two families of retinoid acid (RA) receptors (R), the RAR isotypes (alpha, beta, and gamma) and the three RXR isotypes (alpha, beta, and gamma), and their numerous isoforms, which bind as RXR/RAR heterodimers to the polymorphic cis-acting response elements of RA target genes. The possibility of cross-modulation (cross-talk) with cell-surface receptors signaling pathways, as well as the finding that RARs and RXRs interact with multiple putative coactivators and/or corepressors, generates additional levels of complexity for the array of combinatorial effects that underlie the pleiotropic effects of retinoids. This review focuses on recent developments, particularly in the area of structure-function relationships.
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            Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis.

            To explore the association between low serum vitamin D and risk of active tuberculosis in humans. Systematic review and meta-analysis. Observational studies published between 1980 and July 2006 (identified through Medline) that examined the association between low serum vitamin D and risk of active tuberculosis. For the review, seven papers were eligible from 151 identified in the search. The pooled effect size in random effects meta-analysis was 0.68 with 95% CI 0.43-0.93. This 'medium to large' effect represents a probability of 70% that a healthy individual would have higher serum vitamin D level than an individual with tuberculosis if both were chosen at random from a population. There was little heterogeneity between the studies. Low serum vitamin D levels are associated with higher risk of active tuberculosis. Although more prospectively designed studies are needed to firmly establish the direction of this association, it is more likely that low body vitamin D levels increase the risk of active tuberculosis. In view of this, the potential role of vitamin D supplementation in people with tuberculosis and hypovitaminosis D-associated conditions like chronic kidney disease should be evaluated.
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              Noncalcemic actions of vitamin D receptor ligands.

              1alpha,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], the active metabolite of vitamin D(3), is known for the maintenance of mineral homeostasis and normal skeletal architecture. However, apart from these traditional calcium-related actions, 1,25-(OH)(2)D(3) and its synthetic analogs are being increasingly recognized for their potent antiproliferative, prodifferentiative, and immunomodulatory activities. These actions of 1,25-(OH)(2)D(3) are mediated through vitamin D receptor (VDR), which belongs to the superfamily of steroid/thyroid hormone nuclear receptors. Physiological and pharmacological actions of 1,25-(OH)(2)D(3) in various systems, along with the detection of VDR in target cells, have indicated potential therapeutic applications of VDR ligands in inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological indications (psoriasis, actinic keratosis, seborrheic dermatitis, photoaging), osteoporosis (postmenopausal and steroid-induced osteoporosis), cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), secondary hyperparathyroidism, and autoimmune diseases (systemic lupus erythematosus, type I diabetes, multiple sclerosis, and organ transplantation). As a result, VDR ligands have been developed for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. Furthermore, encouraging results have been obtained with VDR ligands in clinical trials of prostate cancer and hepatocellular carcinoma. This review deals with the molecular aspects of noncalcemic actions of vitamin D analogs that account for the efficacy of VDR ligands in the above-mentioned indications.
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                Author and article information

                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                18 June 2013
                2013
                : 4
                : 148
                Affiliations
                [1] 1Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark
                Author notes

                Edited by: Karsten Sauer, The Scripps Research Institute, USA

                Reviewed by: Christopher E. Rudd, University of Cambridge, UK; Gottfried Baier, Medical University of Innsbruck, Austria; Amnon Altman, La Jolla Institute for Allergy and Immunology, USA

                *Correspondence: Marina Rode von Essen, Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3C, DK-2200 Copenhagen, Denmark e-mail: messen@ 123456sund.ku.dk

                This article was submitted to Frontiers in T Cell Biology, a specialty of Frontiers in Immunology.

                Article
                10.3389/fimmu.2013.00148
                3684798
                23785369
                a2365c0b-754a-46ba-ab19-1dd528e46c6d
                Copyright © 2013 Kongsbak, Levring, Geisler and von Essen.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                History
                : 25 March 2013
                : 29 May 2013
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 115, Pages: 10, Words: 10159
                Categories
                Immunology
                Review Article

                Immunology
                vitamin d receptor,t cell function,vitamin d,signaling,expression,activity
                Immunology
                vitamin d receptor, t cell function, vitamin d, signaling, expression, activity

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