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Regulatory Role of Vitamin D and Its Derivatives in the Immune System

A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Nutritional Immunology".

Deadline for manuscript submissions: closed (10 August 2023) | Viewed by 23055

Special Issue Editors


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Guest Editor
Center for Clinical and Experimental Photo-Dermatology, Department of Dermatology, the Saarland University Hospital, 66421 Homburg, Germany
Interests: photobiology; dermato-endocrinology; vitamin D; skin cancer
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Guest Editor
Department of Medicine, Section of Endocrinology, Diabetes and Nutrition, Boston University School of Medicine, Boston, MA 02118, USA
Interests: vitamin D; immune function; metabolic bone disease; Ehlers–Danlos syndrome; vitamin D metabolites and biologic functions; approaches for treating and preventing vitamin D deficiency; photobiology of vitamin D
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

During the last three decades, scientific breakthroughs in laboratory investigations and clinical medicine have revealed new biological functions of vitamin D that are of high importance for human health, and that are closely connected with the immuno-regulatory effects of this seco-steroid hormone. One hallmark was the detection of vitamin D receptors (VDRs) in a broad variety of cell types and tissues that are not associated with the regulation of calcium homeostasis, including activated human macrophages and many other immunoregulatory cells. Another important scientific breakthrough was the recent identification of alternate non-classical vitamin D pathways that are not mediated by the activation of VDRs via the binding of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the classical active form of vitamin D. In contrast, these new pathways exert their effects at least in part via the binding of several endogenously produced vitamin D hydroxy-metabolites to alternate receptors, including retinoid orphan receptors (RORs), the aryl hydrocarbon receptor (AhR) and liver X receptors (LXRs). With AhR having been identified as an immune and bacteria sensor receptor that controls inflammation, these alternate vitamin D pathways are of high importance for the immune system. In summary, a large body of laboratory investigations have now demonstrated that vitamin D is a key factor regulating both innate and adaptive immunity. These laboratory investigations provide convincing supportive evidence for clinical studies in translational medicine that have recently targeted the vitamin D endocrine system as a promising tool for the pharmacological prevention and treatment of a broad variety of pathological inflammatory conditions, including allergies, infections and many autoimmune diseases. This Special Issue of Nutrients summarizes our present understanding of the role of vitamin D for the immune system. We give an outlook on present concepts and future directions of this hot topic that have now opened many new promising research avenues for clinical and laboratory research. 

Prof. Dr. Jörg Reichrath
Prof. Dr. Andrzej Slominski
Dr. Michael F. Holick
Guest Editors

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Keywords

  • immune system
  • vitamin D
  • vitamin D receptor (VDR)
  • alternate non-classical vitamin D pathway
  • 1,25-dihydroxyvitamin D3
  • 1,25(OH)2D3
  • vitamin D hydroxy-metabolites
  • retinoid orphan receptors (RORs)
  • aryl hydrocarbon receptor (AhR)
  • liver X receptors (LXRs)

Published Papers (6 papers)

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Research

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13 pages, 1392 KiB  
Article
Vitamin D Enhances Immune Effector Pathways of NK Cells Thus Providing a Mechanistic Explanation for the Increased Effectiveness of Therapeutic Monoclonal Antibodies
by Konstantinos Christofyllakis, Frank Neumann, Moritz Bewarder, Lorenz Thurner, Dominic Kaddu-Mulindwa, Igor Age Kos, Vadim Lesan and Joerg Thomas Bittenbring
Nutrients 2023, 15(16), 3498; https://doi.org/10.3390/nu15163498 - 8 Aug 2023
Cited by 1 | Viewed by 1401
Abstract
Patients with diffuse large cell lymphoma who have an adequate vitamin D supply derive significantly more benefit from immuno-chemotherapy with rituximab than patients with vitamin D deficiency; this is especially true for female patients. We have already been able to show that vitamin [...] Read more.
Patients with diffuse large cell lymphoma who have an adequate vitamin D supply derive significantly more benefit from immuno-chemotherapy with rituximab than patients with vitamin D deficiency; this is especially true for female patients. We have already been able to show that vitamin D increases the antibody-dependent cytotoxicity (ADCC) of NK cells in a sex-dependent manner, but it is unclear how vitamin D makes NK cells more efficient. Methods: Healthy individuals with vitamin D deficiency were supplemented with vitamin D to sufficient levels. NK cells were isolated from blood samples before and after vitamin D saturation. For transcriptome analysis, we used the Affymetrix Gene-Chip 2.0™. Gene expression analysis as well as supervised and unsupervised pathway analysis were performed. Results: Among others the “NK cell-associated cytotoxicity pathway” increased after vitamin D substitution. Five IFN-α subtypes (2, 4, 6, 7 and 10) and IFN-κ were more highly expressed and are mainly responsible in these pathways. In contrast, the pathway “interferon-gamma response”, as well as other sets in cytokine production and chemotaxis showed a reduction. Toll-like receptor genes (TLR-8, TLR-7, TLR-2) were downregulated and, therefore, are responsible for the decline of these pathways. The same could be shown for the “ubiquitin-ligase” pathway. Conclusions: Increased expression of several IFN-α subtypes may explain the increased ADCC of NK cells in vitamin D-replenished and otherwise healthy subjects. Other regulators of interferon production and ADCC are compensatory upregulated in compensation, such as Toll-like receptors and those of the ubiquitin ligase, and normalize after vitamin D substitution. Full article
(This article belongs to the Special Issue Regulatory Role of Vitamin D and Its Derivatives in the Immune System)
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12 pages, 692 KiB  
Article
Prevalence and Relevance of Vitamin D Deficiency in Newly Diagnosed Breast Cancer Patients: A Pilot Study
by Cosima Zemlin, Laura Altmayer, Caroline Stuhlert, Julia Theresa Schleicher, Carolin Wörmann, Marina Lang, Laura-Sophie Scherer, Ida Clara Thul, Lisanne Sophie Spenner, Jana Alisa Simon, Alina Wind, Elisabeth Kaiser, Regine Weber, Sybelle Goedicke-Fritz, Gudrun Wagenpfeil, Michael Zemlin, Erich-Franz Solomayer, Jörg Reichrath and Carolin Müller
Nutrients 2023, 15(6), 1450; https://doi.org/10.3390/nu15061450 - 17 Mar 2023
Cited by 5 | Viewed by 2161
Abstract
(1) Background: Vitamin D plays an important role in many types of cancer. It was the aim of this study to analyze serum 25-hydroxyvitamin D (25(OH)D) levels in newly diagnosed breast cancer patients, and the association with prognostic and lifestyle factors. (2) Methods: [...] Read more.
(1) Background: Vitamin D plays an important role in many types of cancer. It was the aim of this study to analyze serum 25-hydroxyvitamin D (25(OH)D) levels in newly diagnosed breast cancer patients, and the association with prognostic and lifestyle factors. (2) Methods: 110 non-metastatic breast cancer patients were included in the prospective observational “BEGYN” study at Saarland University Medical Center between September 2019 and January 2021. At the initiation visit, serum 25(OH)D levels were measured. Clinicopathological data on prognosis, nutrition, and lifestyle were extracted from data files and obtained using a questionnaire. (3) Results: Median serum 25(OH)D in breast cancer patients was 24 ng/mL (range 5–65 ng/mL), with 64.8% of patients being vitamin D deficient. 25(OH)D was higher among patients that reported the use of vitamin D supplements (43 ng/mL versus 22 ng/mL; p < 0.001), and in summer compared to other seasons (p = 0.03). Patients with moderate vitamin D deficiency were less likely to have triple negative breast cancer (p = 0.047). (4) Conclusions: Routinely measured vitamin D deficiency is common in breast cancer patients and needs to be detected and treated. However, our results do not support the hypothesis that vitamin D deficiency may be a main prognostic factor for breast cancer. Full article
(This article belongs to the Special Issue Regulatory Role of Vitamin D and Its Derivatives in the Immune System)
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17 pages, 3466 KiB  
Article
Effects of Different Routes and Forms of Vitamin D Administration on Mesenteric Lymph Node CD4+ T Cell Polarization and Intestinal Injury in Obese Mice Complicated with Polymicrobial Sepsis
by Chiu-Li Yeh, Jin-Ming Wu, Kuen-Yuan Chen, Ming-Hsun Wu, Po-Jen Yang, Po-Chu Lee, Po-Da Chen, Sung-Ling Yeh and Ming-Tsan Lin
Nutrients 2022, 14(17), 3557; https://doi.org/10.3390/nu14173557 - 29 Aug 2022
Cited by 6 | Viewed by 2342
Abstract
This study compared the efficacies of enteral cholecalciferol and/or intravenous (IV) calcitriol administration on mesenteric lymph node (MLN) cluster-of-differentiation-4-positive (CD4+) T cell distribution and intestinal barrier damage in obese mice complicated with sepsis. Mice were fed a high-fat diet for 16 weeks and [...] Read more.
This study compared the efficacies of enteral cholecalciferol and/or intravenous (IV) calcitriol administration on mesenteric lymph node (MLN) cluster-of-differentiation-4-positive (CD4+) T cell distribution and intestinal barrier damage in obese mice complicated with sepsis. Mice were fed a high-fat diet for 16 weeks and then sepsis was induced by cecal ligation and puncture (CLP). Mice were divided into the following sepsis groups: without vitamin D (VD) (S); with oral cholecalciferol 1 day before CLP (G); with IV calcitriol 1 h after CLP (V); and with both cholecalciferol before and IV calcitriol after CLP (GV). All mice were sacrificed at 12 or 24 h after CLP. The findings show that the S group had a higher T helper (Th)17 percentage than the VD-treated groups at 12 h after CLP. The V group exhibited a higher Th1 percentage and Th1/Th2 ratio than the other groups at 24 h, whereas the V and GV groups had a lower Th17/regulatory T (Treg) ratio 12 h post-CLP in MLNs. In ileum tissues, the VD-treated groups had higher tight junction protein and cathelicidin levels, and higher mucin gene expression than the S group at 24 h post-CLP. Also, aryl hydrocarbon receptor (AhR) and its associated cytochrome P450 1A1 and interleukin 22 gene expressions were upregulated. In contrast, levels of lipid peroxides and inflammatory mediators in ileum tissues were lower in the groups with VD treatment after CLP. These results suggest that IV calcitriol seemed to have a more-pronounced effect on modulating the homeostasis of Th/Treg subsets in MLNs. Both oral cholecalciferol before and IV calcitriol after CLP promoted cathelicidin secretion, alleviated intestinal inflammation, and ameliorated the epithelial integrity in obese mice complicated with sepsis possibly via VD receptor and AhR signaling pathways. Full article
(This article belongs to the Special Issue Regulatory Role of Vitamin D and Its Derivatives in the Immune System)
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Review

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19 pages, 707 KiB  
Review
Immunomodulatory Properties of Vitamin D in the Intestinal and Respiratory Systems
by Fatheia N. Hamza, Sarah Daher, Hana M. A. Fakhoury, William B. Grant, Peter R. Kvietys and Khaled Al-Kattan
Nutrients 2023, 15(7), 1696; https://doi.org/10.3390/nu15071696 - 30 Mar 2023
Cited by 9 | Viewed by 4902
Abstract
Vitamin D plays a crucial role in modulating the innate immune response by interacting with its intracellular receptor, VDR. In this review, we address vitamin D/VDR signaling and how it contributes to the regulation of intestinal and respiratory microbiota. We additionally review some [...] Read more.
Vitamin D plays a crucial role in modulating the innate immune response by interacting with its intracellular receptor, VDR. In this review, we address vitamin D/VDR signaling and how it contributes to the regulation of intestinal and respiratory microbiota. We additionally review some components of the innate immune system, such as the barrier function of the pulmonary and intestinal epithelial membranes and secretion of mucus, with their respective modulation by vitamin D. We also explore the mechanisms by which this vitamin D/VDR signaling mounts an antimicrobial response through the transduction of microbial signals and the production of antimicrobial peptides that constitute one of the body’s first lines of defense against pathogens. Additionally, we highlight the role of vitamin D in clinical diseases, namely inflammatory bowel disease and acute respiratory distress syndrome, where excessive inflammatory responses and dysbiosis are hallmarks. Increasing evidence suggests that vitamin D supplementation may have potentially beneficial effects on those diseases. Full article
(This article belongs to the Special Issue Regulatory Role of Vitamin D and Its Derivatives in the Immune System)
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20 pages, 1859 KiB  
Review
Vitamin D and Its Analogues: From Differences in Molecular Mechanisms to Potential Benefits of Adapted Use in the Treatment of Alzheimer’s Disease
by Andrea Thiel, Carina Hermanns, Anna Andrea Lauer, Jörg Reichrath, Tobias Erhardt, Tobias Hartmann, Marcus Otto Walter Grimm and Heike Sabine Grimm
Nutrients 2023, 15(7), 1684; https://doi.org/10.3390/nu15071684 - 30 Mar 2023
Cited by 9 | Viewed by 3963
Abstract
Lifestyle habits and insufficient sunlight exposure lead to a high prevalence of vitamin D hypovitaminosis, especially in the elderly. Recent studies suggest that in central Europe more than 50% of people over 60 years are not sufficiently supplied with vitamin D. Since vitamin [...] Read more.
Lifestyle habits and insufficient sunlight exposure lead to a high prevalence of vitamin D hypovitaminosis, especially in the elderly. Recent studies suggest that in central Europe more than 50% of people over 60 years are not sufficiently supplied with vitamin D. Since vitamin D hypovitaminosis is associated with many diseases, such as Alzheimer’s disease (AD), vitamin D supplementation seems to be particularly useful for this vulnerable age population. Importantly, in addition to vitamin D, several analogues are known and used for different medical purposes. These vitamin D analogues differ not only in their pharmacokinetics and binding affinity to the vitamin D receptor, but also in their potential side effects. Here, we discuss these aspects, especially those of the commonly used vitamin D analogues alfacalcidol, paricalcitol, doxercalciferol, tacalcitol, calcipotriol, and eldecalcitol. In addition to their pleiotropic effects on mechanisms relevant to AD, potential effects of vitamin D analogues on comorbidities common in the context of geriatric diseases are summarized. AD is defined as a complex neurodegenerative disease of the central nervous system and is commonly represented in the elderly population. It is usually caused by extracellular accumulation of amyloidogenic plaques, consisting of amyloid (Aβ) peptides. Furthermore, the formation of intracellular neurofibrillary tangles involving hyperphosphorylated tau proteins contributes to the pathology of AD. In conclusion, this review emphasizes the importance of an adequate vitamin D supply and discusses the specifics of administering various vitamin D analogues compared with vitamin D in geriatric patients, especially those suffering from AD. Full article
(This article belongs to the Special Issue Regulatory Role of Vitamin D and Its Derivatives in the Immune System)
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13 pages, 341 KiB  
Review
Genomic or Non-Genomic? A Question about the Pleiotropic Roles of Vitamin D in Inflammatory-Based Diseases
by Michael F. Holick, Luciana Mazzei, Sebastián García Menéndez, Virna Margarita Martín Giménez, Fatme Al Anouti and Walter Manucha
Nutrients 2023, 15(3), 767; https://doi.org/10.3390/nu15030767 - 2 Feb 2023
Cited by 9 | Viewed by 7338
Abstract
Vitamin D (vit D) is widely known for its role in calcium metabolism and its importance for the bone system. However, various studies have revealed a myriad of extra-skeletal functions, including cell differentiation and proliferation, antibacterial, antioxidant, immunomodulatory, and anti-inflammatory properties in various [...] Read more.
Vitamin D (vit D) is widely known for its role in calcium metabolism and its importance for the bone system. However, various studies have revealed a myriad of extra-skeletal functions, including cell differentiation and proliferation, antibacterial, antioxidant, immunomodulatory, and anti-inflammatory properties in various cells and tissues. Vit D mediates its function via regulation of gene expression by binding to its receptor (VDR) which is expressed in almost all cells within the body. This review summarizes the pleiotropic effects of vit D, emphasizing its anti-inflammatory effect on different organ systems. It also provides a comprehensive overview of the genetic and epigenetic effects of vit D and VDR on the expression of genes pertaining to immunity and anti-inflammation. We speculate that in the context of inflammation, vit D and its receptor VDR might fulfill their roles as gene regulators through not only direct gene regulation but also through epigenetic mechanisms. Full article
(This article belongs to the Special Issue Regulatory Role of Vitamin D and Its Derivatives in the Immune System)
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