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Special Issue "Immune Regulation by Vitamin D"

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A special issue of Nutrients (ISSN 2072-6643).

Deadline for manuscript submissions: closed (31 March 2015)

Special Issue Editors

Guest Editor
Prof. Dr. Antonio Ferrante

Department of Immunology, SA Pathology, Womens and Children’s Hospital Campus, Children’s Research Centre, University of Adelaide, North Adelaide, South Australia 5006, Australia
E-Mail
Phone: 61 8 81617216
Fax: +61 8 81616046
Interests: cellular immunology, cytokines and inflammation; intracellular signalling and leukocyte function; immunomodulation by fatty acids, their metabolites and other bioactive nutrients
Guest Editor
Prof. Dr. Margherita T. Cantorna

Center of Molecular Immunology and Infectious Disease, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, 115 Henning Building, University Park, PA 16802-3500, USA
E-Mail
Phone: 8148632819
Fax: +814 863 6140
Interests: T cells, autoimmunity, infection, gastrointestinal tract

Special Issue Information

Dear Colleagues,

An entirely new facet of vitamin D effects, distinct from its action on homeostasis and bone metabolism, is increasingly being appreciated. These non-classical effects of vitamin D have now been acknowledged as important components of vitamin D physiology. The fact that the active form of vitamin D, 1,25-dihydroxyvitamin D3, is a regulator of immune responses has been recently discovered. The effects of vitamin D on both the innate and adaptive immune responses has reached a new horizon with the realisation that the intracrine metabolism of vitamin D in immune cells may be a control point in immunity to infection and in chronic inflammatory disease. Because such non-classical effects of vitamin D have now been accepted, coupled with the fact that vitamin D insufficiency is presently a global health issue even in developed countries, new interest has been raised concerning disease development. In addition, present research efforts will provide the molecular rationale for intervention studies designed to test vitamin D as a chemo-preventative strategy for clinical management of autoimmune diseases.

Prof. Dr. Antonio Ferrante
Prof. Dr. Margherita T. Cantorna
Guest Editors

Submission

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Keywords

  • vitamin D and 1,25D3
  • infection and immunity
  • autoimmunity, inflammation
  • macrophages
  • dendritic cells
  • T cells
  • vitamin D
  • innate immunity
  • adaptive immunity
  • metabolism
  • deficiency

Published Papers (11 papers)

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Review

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Open AccessReview Mechanisms Underlying the Regulation of Innate and Adaptive Immunity by Vitamin D
Nutrients 2015, 7(10), 8251-8260; doi:10.3390/nu7105392
Received: 25 June 2015 / Revised: 11 September 2015 / Accepted: 15 September 2015 / Published: 24 September 2015
Cited by 10 | PDF Full-text (1519 KB) | HTML Full-text | XML Full-text
Abstract
Non-classical actions of vitamin D were first suggested over 30 years ago when receptors for the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), were detected in various tissues and cells that are not associated with the regulation
[...] Read more.
Non-classical actions of vitamin D were first suggested over 30 years ago when receptors for the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), were detected in various tissues and cells that are not associated with the regulation of calcium homeostasis, including activated human inflammatory cells. The question that remained was the biological significance of the presence of vitamin D receptors in the different tissues and cells and, with regard to the immune system, whether or not vitamin D plays a role in the normal immune response and in modifying immune mediated diseases. In this article findings indicating that vitamin D is a key factor regulating both innate and adaptive immunity are reviewed with a focus on the molecular mechanisms involved. In addition, the physiological significance of vitamin D action, as suggested by in vivo studies in mouse models is discussed. Together, the findings indicate the importance of 1,25(OH)2D3 as a regulator of key components of the immune system. An understanding of the mechanisms involved will lead to potential therapeutic applications for the treatment of immune mediated diseases. Full article
(This article belongs to the Special Issue Immune Regulation by Vitamin D)
Open AccessReview Regulation of Dendritic Cell Function by Vitamin D
Nutrients 2015, 7(9), 8127-8151; doi:10.3390/nu7095383
Received: 29 July 2015 / Revised: 4 September 2015 / Accepted: 10 September 2015 / Published: 21 September 2015
Cited by 7 | PDF Full-text (942 KB) | HTML Full-text | XML Full-text
Abstract
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
[...] Read more.
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. Full article
(This article belongs to the Special Issue Immune Regulation by Vitamin D)
Open AccessReview Vitamin D and Inflammatory Cytokines in Healthy and Preeclamptic Pregnancies
Nutrients 2015, 7(8), 6465-6490; doi:10.3390/nu7085293
Received: 28 April 2015 / Revised: 28 April 2015 / Accepted: 29 July 2015 / Published: 4 August 2015
Cited by 5 | PDF Full-text (737 KB) | HTML Full-text | XML Full-text
Abstract
Preeclampsia is a pregnancy disease characterized by hypertension and proteinuria. Among several disorders, the imbalance of inflammatory cytokines and the alteration of vitamin D metabolism have been reported in preeclampsia. The effects of calcitriol upon inflammatory cytokines has been demonstrated. In healthy pregnant
[...] Read more.
Preeclampsia is a pregnancy disease characterized by hypertension and proteinuria. Among several disorders, the imbalance of inflammatory cytokines and the alteration of vitamin D metabolism have been reported in preeclampsia. The effects of calcitriol upon inflammatory cytokines has been demonstrated. In healthy pregnant women there is a shift toward a Th2 cytokine profile, which is necessary for an adequate pregnancy outcome. As compared with normal pregnancy, high pro-inflammatory and low anti-inflammatory cytokine levels have been observed in preeclamptic women. Preeclampsia has been associated with low calcitriol levels and vitamin D deficiency is correlated with a higher risk of the development of this disease. It has been demonstrated that placenta is a source as well as the target of calcitriol and cytokines and placental dysfunction has been associated with preeclampsia. Therefore, the present manuscript includes a review about serum calcitriol levels in non-pregnant, pregnant, and preeclamptic women as well as a review on the fetoplacental vitamin D metabolism in healthy and preeclamptic pregnancies. In addition, circulating and fetoplacental inflammatory cytokines in healthy and preeclamptic pregnancies are reviewed. Finally, the effects of calcitriol upon placental pro-inflammatory cytokines are also explored. In conclusion, maternal and placental calcitriol levels are low in preeclampsia which may explain, at least in part, high pro-inflammatory cytokine levels in this disease. Full article
(This article belongs to the Special Issue Immune Regulation by Vitamin D)
Open AccessReview Immune Modulation by Vitamin D and Its Relevance to Food Allergy
Nutrients 2015, 7(8), 6088-6108; doi:10.3390/nu7085271
Received: 8 May 2015 / Revised: 16 July 2015 / Accepted: 20 July 2015 / Published: 27 July 2015
Cited by 4 | PDF Full-text (288 KB) | HTML Full-text | XML Full-text
Abstract
Apart from its classical function in bone and calcium metabolism, vitamin D is also involved in immune regulation and has been linked to various cancers, immune disorders and allergic diseases. Within the innate and adaptive immune systems, the vitamin D receptor and enzymes
[...] Read more.
Apart from its classical function in bone and calcium metabolism, vitamin D is also involved in immune regulation and has been linked to various cancers, immune disorders and allergic diseases. Within the innate and adaptive immune systems, the vitamin D receptor and enzymes in monocytes, dendritic cells, epithelial cells, T lymphocytes and B lymphocytes mediate the immune modulatory actions of vitamin D. Vitamin D insufficiency/deficiency early in life has been identified as one of the risk factors for food allergy. Several studies have observed an association between increasing latitude and food allergy prevalence, plausibly linked to lower ultraviolet radiation (UVR) exposure and vitamin D synthesis in the skin. Along with mounting epidemiological evidence of a link between vitamin D status and food allergy, mice and human studies have shed light on the modulatory properties of vitamin D on the innate and adaptive immune systems. This review will summarize the literature on the metabolism and immune modulatory properties of vitamin D, with particular reference to food allergy. Full article
(This article belongs to the Special Issue Immune Regulation by Vitamin D)
Open AccessReview Modulation of the Immune Response to Respiratory Viruses by Vitamin D
Nutrients 2015, 7(6), 4240-4270; doi:10.3390/nu7064240
Received: 2 April 2015 / Revised: 17 May 2015 / Accepted: 19 May 2015 / Published: 29 May 2015
Cited by 10 | PDF Full-text (908 KB) | HTML Full-text | XML Full-text
Abstract
Background: Vitamin D deficiency has been shown to be independently associated with increased risk of viral acute respiratory infection (ARI) in a number of observational studies, and meta-analysis of clinical trials of vitamin D supplementation for prevention of ARI has demonstrated protective effects.
[...] Read more.
Background: Vitamin D deficiency has been shown to be independently associated with increased risk of viral acute respiratory infection (ARI) in a number of observational studies, and meta-analysis of clinical trials of vitamin D supplementation for prevention of ARI has demonstrated protective effects. Several cellular studies have investigated the effects of vitamin D metabolites on immune responses to respiratory viruses, but syntheses of these reports are lacking. Scope: In this article, we review the literature reporting results of in vitro experiments investigating immunomodulatory actions of vitamin D metabolites in human respiratory epithelial cells infected with respiratory viruses. Key findings: Vitamin D metabolites do not consistently influence replication or clearance of rhinovirus, respiratory syncytial virus (RSV) or influenza A virus in human respiratory epithelial cell culture, although they do modulate expression and secretion of type 1 interferon, chemokines including CXCL8 and CXCL10 and pro-inflammatory cytokines, such as TNF and IL-6. Future research: More studies are needed to clarify the effects of vitamin D metabolites on respiratory virus-induced expression of cell surface markers mediating viral entry and bacterial adhesion to respiratory epithelial cells. Full article
(This article belongs to the Special Issue Immune Regulation by Vitamin D)
Open AccessReview Vitamin D Every Day to Keep the Infection Away?
Nutrients 2015, 7(6), 4170-4188; doi:10.3390/nu7064170
Received: 31 March 2015 / Revised: 13 May 2015 / Accepted: 15 May 2015 / Published: 29 May 2015
Cited by 8 | PDF Full-text (294 KB) | HTML Full-text | XML Full-text
Abstract
Within the last decade, vitamin D has emerged as a central regulator of host defense against infections. In this regard, vitamin D triggers effective antimicrobial pathways against bacterial, fungal and viral pathogens in cells of the human innate immune system. However, vitamin D
[...] Read more.
Within the last decade, vitamin D has emerged as a central regulator of host defense against infections. In this regard, vitamin D triggers effective antimicrobial pathways against bacterial, fungal and viral pathogens in cells of the human innate immune system. However, vitamin D also mediates potent tolerogenic effects: it is generally believed that vitamin D attenuates inflammation and acquired immunity, and thus potentially limits collateral tissue damage. Nevertheless, several studies indicate that vitamin D promotes aspects of acquired host defense. Clinically, vitamin D deficiency has been associated with an increased risk for various infectious diseases in epidemiological studies; yet, robust data from controlled trials investigating the use of vitamin D as a preventive or therapeutic agent are missing. In this review, we summarize the current knowledge regarding the effect of vitamin D on innate and acquired host defense, and speculate on the difficulties to translate the available molecular medicine data into practical therapeutic or preventive recommendations. Full article
(This article belongs to the Special Issue Immune Regulation by Vitamin D)
Open AccessReview Can Skin Exposure to Sunlight Prevent Liver Inflammation?
Nutrients 2015, 7(5), 3219-3239; doi:10.3390/nu7053219
Received: 28 March 2015 / Revised: 23 April 2015 / Accepted: 27 April 2015 / Published: 5 May 2015
Cited by 4 | PDF Full-text (318 KB) | HTML Full-text | XML Full-text
Abstract
Liver inflammation contributes towards the pathology of non-alcoholic fatty liver disease (NAFLD). Here we discuss how skin exposure to sunlight may suppress liver inflammation and the severity of NAFLD. Following exposure to sunlight-derived ultraviolet radiation (UVR), the skin releases anti-inflammatory mediators such as
[...] Read more.
Liver inflammation contributes towards the pathology of non-alcoholic fatty liver disease (NAFLD). Here we discuss how skin exposure to sunlight may suppress liver inflammation and the severity of NAFLD. Following exposure to sunlight-derived ultraviolet radiation (UVR), the skin releases anti-inflammatory mediators such as vitamin D and nitric oxide. Animal modeling studies suggest that exposure to UVR can prevent the development of NAFLD. Association studies also support a negative link between circulating 25-hydroxyvitamin D and NAFLD incidence or severity. Clinical trials are in their infancy and are yet to demonstrate a clear beneficial effect of vitamin D supplementation. There are a number of potentially interdependent mechanisms whereby vitamin D could dampen liver inflammation, by inhibiting hepatocyte apoptosis and liver fibrosis, modulating the gut microbiome and through altered production and transport of bile acids. While there has been a focus on vitamin D, other mediators induced by sun exposure, such as nitric oxide may also play important roles in curtailing liver inflammation. Full article
(This article belongs to the Special Issue Immune Regulation by Vitamin D)
Open AccessReview Vitamin D and 1,25(OH)2D Regulation of T cells
Nutrients 2015, 7(4), 3011-3021; doi:10.3390/nu7043011
Received: 20 March 2015 / Revised: 14 April 2015 / Accepted: 16 April 2015 / Published: 22 April 2015
Cited by 17 | PDF Full-text (305 KB) | HTML Full-text | XML Full-text
Abstract
Vitamin D is a direct and indirect regulator of T cells. The mechanisms by which vitamin D directly regulates T cells are reviewed and new primary data on the effects of 1,25 dihydroxyvitamin D (1,25(OH)2D) on human invariant natural killer (iNK)T
[...] Read more.
Vitamin D is a direct and indirect regulator of T cells. The mechanisms by which vitamin D directly regulates T cells are reviewed and new primary data on the effects of 1,25 dihydroxyvitamin D (1,25(OH)2D) on human invariant natural killer (iNK)T cells is presented. The in vivo effects of vitamin D on murine T cells include inhibition of T cell proliferation, inhibition of IFN-γ, IL-17 and induction of IL-4. Experiments in mice demonstrate that the effectiveness of 1,25(OH)2D requires NKT cells, IL-10, the IL-10R and IL-4. Comparisons of mouse and human T cells show that 1,25(OH)2D inhibits IL-17 and IFN-γ, and induces T regulatory cells and IL-4. IL-4 was induced by 1,25(OH)2D in mouse and human iNKT cells. Activation for 72h was required for optimal expression of the vitamin D receptor (VDR) in human and mouse T and iNKT cells. In addition, T cells are potential autocrine sources of 1,25(OH)2D but again only 48–72h after activation. Together the data support the late effects of vitamin D on diseases like inflammatory bowel disease and multiple sclerosis where reducing IL-17 and IFN-γ, while inducing IL-4 and IL-10, would be beneficial. Full article
(This article belongs to the Special Issue Immune Regulation by Vitamin D)
Figures

Open AccessReview Meta-Analysis of the Association between Vitamin D and Autoimmune Thyroid Disease
Nutrients 2015, 7(4), 2485-2498; doi:10.3390/nu7042485
Received: 15 January 2015 / Revised: 10 February 2015 / Accepted: 16 March 2015 / Published: 3 April 2015
Cited by 12 | PDF Full-text (200 KB) | HTML Full-text | XML Full-text
Abstract
Although emerging evidence suggests that low levels of vitamin D may contribute to the development of autoimmune disease, the relationship between vitamin D reduction and autoimmune thyroid disease (AITD), which includes Graves’ disease (GD) and Hashimoto thyroiditis (HT), is still controversial. The aim
[...] Read more.
Although emerging evidence suggests that low levels of vitamin D may contribute to the development of autoimmune disease, the relationship between vitamin D reduction and autoimmune thyroid disease (AITD), which includes Graves’ disease (GD) and Hashimoto thyroiditis (HT), is still controversial. The aim was to evaluate the association between vitamin D levels and AITD through systematic literature review. We identified all studies that assessed the association between vitamin D and AITD from PubMed, Embase, CENTRAL, and China National Knowledge Infrastructure (CNKI) databases. We included studies that compared vitamin D levels between AITD cases and controls as well as those that measured the odds of vitamin D deficiency by AITD status. We combined the standardized mean differences (SMD) or the odds ratios (OR) in a random effects model. Twenty case-control studies provided data for a quantitative meta-analysis. Compared to controls, AITD patients had lower levels of 25(OH)D (SMD: −0.99, 95% CI: −1.31, −0.66) and were more likely to be deficient in 25(OH)D (OR 2.99, 95% CI: 1.88, 4.74). Furthermore, subgroup analyses result showed that GD and HT patients also had lower 25(OH)D levels and were more likely to have a 25(OH)D deficiency, suggesting that low levels of serum 25(OH)D was related to AITD. Full article
(This article belongs to the Special Issue Immune Regulation by Vitamin D)
Open AccessReview Can We Translate Vitamin D Immunomodulating Effect on Innate and Adaptive Immunity to Vaccine Response?
Nutrients 2015, 7(3), 2044-2060; doi:10.3390/nu7032044
Received: 25 February 2015 / Revised: 9 March 2015 / Accepted: 12 March 2015 / Published: 20 March 2015
Cited by 9 | PDF Full-text (479 KB) | HTML Full-text | XML Full-text
Abstract
Vitamin D (VitD), which is well known for its classic role in the maintenance of bone mineral density, has now become increasingly studied for its extra-skeletal roles. It has an important influence on the body’s immune system and modulates both innate and adaptive
[...] Read more.
Vitamin D (VitD), which is well known for its classic role in the maintenance of bone mineral density, has now become increasingly studied for its extra-skeletal roles. It has an important influence on the body’s immune system and modulates both innate and adaptive immunity and regulates the inflammatory cascade. In this review our aim was to describe how VitD might influence immune responsiveness and its potential modulating role in vaccine immunogenicity. In the first instance, we consider the literature that may provide molecular and genetic support to the idea that VitD status may be related to innate and/or adaptive immune response with a particular focus on vaccine immunogenicity and then discuss observational studies and controlled trials of VitD supplementation conducted in humans. Finally, we conclude with some knowledge gaps surrounding VitD and vaccine response, and that it is still premature to recommend “booster” of VitD at vaccination time to enhance vaccine response. Full article
(This article belongs to the Special Issue Immune Regulation by Vitamin D)

Other

Jump to: Review

Open AccessCommentary Live Longer with Vitamin D?
Nutrients 2015, 7(3), 1871-1880; doi:10.3390/nu7031871
Received: 17 December 2014 / Revised: 25 February 2015 / Accepted: 3 March 2015 / Published: 12 March 2015
Cited by 10 | PDF Full-text (177 KB) | HTML Full-text | XML Full-text
Abstract
The global burden of vitamin D deficiency or insufficiency is of great concern for public health. According to recent studies, vitamin D deficiency is an important etiological factor in the pathogenesis of many chronic diseases. Whether or not there is a connection between
[...] Read more.
The global burden of vitamin D deficiency or insufficiency is of great concern for public health. According to recent studies, vitamin D deficiency is an important etiological factor in the pathogenesis of many chronic diseases. Whether or not there is a connection between 25-hydoxyvitamin D (25(OH)D) status and overall mortality is a matter of considerable debate. A new meta-analysis confirmed that low 25(OH)D levels were associated with a significant increased risk for all-cause mortality. Individuals with severe vitamin D deficiency have almost twice the mortality rate as those with 25(OH)D level ≥ 30 ng/mL, (≥75 nmol/L). Unlike previous meta-analyses which suggested that serum 25(OH)D > 50 ng/mL was associated with increased mortality, this new analysis found that there was no increased risk even when 25(OH)D levels were ≥70 ng/mL. In general, closer attention should be paid to vitamin D deficiency in medical and pharmaceutical practice than has been the case hitherto. The results of these studies are consistent with the recommendation to improve the general vitamin D status in children and adults by means of a healthy approach to sunlight exposure, consumption of foods containing vitamin D and supplementation with vitamin D preparations. Full article
(This article belongs to the Special Issue Immune Regulation by Vitamin D)

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