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Vitamin D, Immune Response, and Autoimmune Diseases

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A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Micronutrients and Human Health".

Deadline for manuscript submissions: closed (15 July 2023) | Viewed by 35982

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Prof. Dr. Maurizio Cutolo

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Guest Editor

Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology, Department of Internal Medicine and Specialties, University of Genova, 16132 Genova, Italy
Interests: systemic sclerosis; rheumatoid arthritis; polymialgia rheumatica; Raynaud’s phenomenon; COVID-19; capillaroscopy; sex hormones; circadian rhythms; glucocorticoids; DMARDs in rheumatoid arthritis; microcirculation; Mediterranean diet; vitamin D; neuroendocrine immunology
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Emanuele Gotelli

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Guest Editor Assistant

Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology, Department of Internal Medicine and Specialties, University of Genova, 16132 Genova, Italy
Interests: systemic sclerosis; rheumatoid arthritis; polymyalgia rheumatica; Raynaud’s phenomenon; COVID-19; capillaroscopy; sex hormones; circadian rhythms; glucocorticoids; DMARDs in rheumatoid arthritis; microcirculation; Mediterranean diet; vitamin D; neuroendocrine immunology

Special Issue Information

Dear Colleagues,

It is a great pleasure for me to invite you to contribute to this Special Issue concerning the extra-skeletal effects of vitamin D and, in particular, its relationship with the cells involved in the immune response and the risk of developing autoimmune diseases.

In fact, beyond the well-known endocrinological effects on skeletal mineral metabolism, vitamin D, being a steroid hormone, exerts proven antiproliferative and antiviral/antibacterial effects, together with the regulation of the immune system, with an autocrine/paracrine action mechanism.

The current COVID-19 pandemic has sparked renewed interest in the anti-inflammatory properties of vitamin D. Furthermore, the link between hypovitaminosis D and predisposition to autoimmune disease has been deeply investigated over the years, with particular interest in type I diabetes, multiple sclerosis and musculoskeletal/connective tissue diseases (rheumatoid arthritis, psoriatic arthritis, systemic sclerosis, systemic lupus erythematosus). A large plethora of immune cells, such as neutrophils, monocytes/macrophages, and T and B lymphocytes are characterized by the presence of vitamin D receptor (VDR) and synthesize the biologically active form of vitamin D, regulating inflammation and innate and adaptive immunity locally and systematically.

On this basis, the current Special Issue aims to collect the most recent advances concerning immune system modulatory effects exerted by vitamin D, as well as their implications in clinical and therapeutical practice (original articles, reviews, human ex vivo and in vitro translational studies).

Prof. Dr. Maurizio Cutolo
Guest Editor

Dr. Emanuele Gotelli
Guest Editor Assistant

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Keywords

vitamin D
cholecalciferol
calcifediol
calcitriol
rheumatoid arthritis
systemic sclerosis
systemic lupus erythematosus
type 1 diabetes
multiple sclerosis
COVID-19
innate immunity
adaptive immunity
monocytes/macrophages
T lymphocytes
B lymphocytes

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Published Papers (10 papers)

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Research

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19 pages, 4319 KiB

Open AccessArticle

Sex Differences under Vitamin D Supplementation in an Animal Model of Progressive Multiple Sclerosis

by Michaela Tanja Haindl, Muammer Üçal, Cansu Tafrali, Willibald Wonisch, Cigdem Erdogan, Marta Nowakowska, Milena Z. Adzemovic, Christian Enzinger, Michael Khalil and Sonja Hochmeister

Nutrients 2024, 16(4), 554; https://doi.org/10.3390/nu16040554 - 17 Feb 2024

Viewed by 4105

Abstract

A central role for vitamin D (VD) in immune modulation has recently been recognized linking VD insufficiency to autoimmune disorders that commonly exhibit sex-associated differences. Similar to other autoimmune diseases, there is a higher incidence of multiple sclerosis (MS) in women, but a poorer prognosis in men, often characterized by a more rapid progression. Although sex hormones are most likely involved, this phenomenon is still poorly understood. Oxidative stress, modulated by VD serum levels as well as sex hormones, may act as a contributing factor to demyelination and axonal damage in both MS and the corresponding preclinical models. In this study, we analyzed sex-associated differences and VD effects utilizing an animal model that recapitulates histopathological features of the progressive MS phase (PMS). In contrast to relapsing–remitting MS (RRMS), PMS has been poorly investigated in this context. Male (n = 50) and female (n = 46) Dark Agouti rats received either VD (400 IU per week; VD⁺) or standard rodent food without extra VD (VD⁻) from weaning onwards. Myelination, microglial activation, apoptotic cell death and neuronal viability were assessed using immunohistochemical markers in brain tissue. Additionally, we also used two different histological markers against oxidized lipids along with colorimetric methods to measure protective polyphenols (PP) and total antioxidative capacity (TAC) in serum. Neurofilament light chain serum levels (sNfL) were analyzed using single-molecule array (SIMOA) analysis. We found significant differences between female and male animals. Female rats exhibited a better TAC and higher amounts of PP. Additionally, females showed higher myelin preservation, lower microglial activation and better neuronal survival while showing more apoptotic cells than male rats. We even found a delay in reaching the peak of the disease in females. Overall, both sexes benefitted from VD supplementation, represented by significantly less cortical, neuroaxonal and oxidative damage. Unexpectedly, male rats had an even higher overall benefit, most likely due to differences in oxidative capacity and defense systems. Full article

(This article belongs to the Special Issue Vitamin D, Immune Response, and Autoimmune Diseases)

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14 pages, 2767 KiB

Open AccessArticle

Vitamin D—An Effective Antioxidant in an Animal Model of Progressive Multiple Sclerosis

by Michaela Tanja Haindl, Muammer Üçal, Willibald Wonisch, Michaela Lang, Marta Nowakowska, Milena Z. Adzemovic, Michael Khalil, Christian Enzinger and Sonja Hochmeister

Nutrients 2023, 15(15), 3309; https://doi.org/10.3390/nu15153309 - 26 Jul 2023

Cited by 6 | Viewed by 2247

Abstract

Vitamin D (VD) is the most discussed antioxidant supplement for multiple sclerosis (MS) patients and many studies suggest correlations between a low VD serum level and onset and progression of the disease. While many studies in animals as well as clinical studies focused on the role of VD in the relapsing-remitting MS, knowledge is rather sparse for the progressive phase of the disease and the development of cortical pathology. In this study, we used our established rat model of cortical inflammatory demyelination, resembling features seen in late progressive MS, to address the question about whether VD could have positive effects on reducing cortical pathology, oxidative stress, and neurofilament light chain (NfL) serum levels. For this purpose, we used male Dark Agouti (DA) rats, with one group being supplemented with VD (400 IE per week; VD⁺) from the weaning on at age three weeks; the other group received standard rodent food. The rat brains were assessed using immunohistochemical markers against demyelination, microglial activation, apoptosis, neurons, neurofilament, and reactive astrocytes. To evaluate the effect of VD on oxidative stress and the antioxidant capacity, we used two different oxidized lipid markers (anti- Cu⁺⁺ and HOCl oxidized LDL antibodies) along with colorimetric methods for protective polyphenols (PP) and total antioxidative capacity (TAC). NfL serum levels of VD⁺ and VD⁻ animals were analyzed by fourth generation single-molecule array (SIMOA) analysis. We found significant differences between the VD⁺ and VD⁻ animals both in histopathology as well as in all serum markers. Myelin loss and microglial activation is lower in VD⁺ animals and the number of apoptotic cells is significantly reduced with a higher neuronal survival. VD⁺ animals show significantly lower NfL serum levels, a higher TAC, and more PP. Additionally, there is a significant reduction of oxidized lipid markers in animals under VD supplementation. Our data thus show a positive effect of VD on cellular features of cortical pathology in our animal model, presumably due to protection against reactive oxygen species. In this study, VD enhanced remyelination and prevented neuroaxonal and oxidative damage, such as demyelination and neurodegeneration. However, more studies on VD dose relations are required to establish an optimal response while avoiding overdosing. Full article

(This article belongs to the Special Issue Vitamin D, Immune Response, and Autoimmune Diseases)

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13 pages, 835 KiB

Open AccessArticle

Effects of Vitamin D₃ and Marine Omega-3 Fatty Acids Supplementation on Biomarkers of Systemic Inflammation: 4-Year Findings from the VITAL Randomized Trial

by Yanbin Dong, Haidong Zhu, Li Chen, Ying Huang, William Christen, Nancy R. Cook, Trisha Copeland, Samia Mora, Julie E. Buring, I-Min Lee, Karen H. Costenbader and JoAnn E. Manson

Nutrients 2022, 14(24), 5307; https://doi.org/10.3390/nu14245307 - 14 Dec 2022

Cited by 16 | Viewed by 4471

Abstract

Background: The VITAL study was a nationwide, randomized, double-blind, placebo-controlled, 2 × 2 factorial trial of vitamin D₃ (2000 IU/day) and marine n-3 FAs (1 g/day) supplements. We recently reported that vitamin D supplementation with or without omega 3 fatty acids reduced autoimmune disease by 22% in the VITAL study. Objective: To investigate the effects of vitamin D₃ and/or n-3 FAs on changes in systemic inflammatory biomarkers including pro- and anti-inflammatory cytokines over a 4-year period in the VITAL sub-cohort with in-person evaluations at the Center for Clinical Investigations (CCI) in Boston. Design: Serum levels of four inflammatory biomarkers (high-sensitivity C-reactive protein [hs-CRP], interleukin-6, interleukin-10, and tumor necrosis factor-α) were measured in a total of 2713 samples from those 1054 VITAL/CCI participants (aged 64.9 ± 6.5 years, 49% female, 84% white, and 9% black) at baseline, year 2, and year 4 follow-up visits. Results: In multiple-adjusted models, vitamin D₃ supplementation decreased serum hs-CRP levels by 19% at 2-year follow-up (nominal p = 0.007; p-value after multiple comparison adjustment = 0.028), but not at 4-year follow-up (nominal and adjusted p-values > 0.05). The effects of vitamin D₃ on other inflammatory markers were not statistically significant either at year 2 or year 4 (all adjusted p-values > 0.05). Marine n-3 FAs were not significantly associated with changes of all the above inflammatory markers either at years 2 and 4, after multiple comparison adjustment (all p-values > 0.05). Conclusions: Vitamin D₃ supplementation with or without n-3 FAs decreased hs-CRP by 19% at year 2, but not other inflammatory biomarkers at year 2 or year 4, while n-3 FAs with or without vitamin D₃ did not significantly affect these biomarkers at either time point. Our findings support a potential role of vitamin D supplementation in modulating the chronic inflammatory process, systemic inflammation, and possibly autoimmune disease progression. Full article

(This article belongs to the Special Issue Vitamin D, Immune Response, and Autoimmune Diseases)

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10 pages, 483 KiB

Open AccessArticle

Effects on Serum Inflammatory Cytokines of Cholecalciferol Supplementation in Healthy Subjects with Vitamin D Deficiency

by Angelo Fassio, Davide Gatti, Maurizio Rossini, Davide Bertelle, Riccardo Bixio, Ombretta Viapiana, Stefano Milleri, Camilla Benini, Francesca Pistillo, Giulia Zanetti and Giovanni Adami

Nutrients 2022, 14(22), 4823; https://doi.org/10.3390/nu14224823 - 14 Nov 2022

Cited by 4 | Viewed by 2382

Abstract

The effects of different cholecalciferol supplementation regimens on serum inflammatory cytokines in healthy subjects with vitamin D deficiency are still lacking. This is a single-center, open-label, randomized, parallel group study involving healthy subjects deficient in vitamin D (baseline 25OHD < 20 ng/mL) receiving oral cholecalciferol with three different dosing regimens: Group A: 10,000 IU/day for 8 weeks followed by 1000 IU/day for 4 weeks; Group B: 50,000 IU/week for 12 weeks and Group C: 100,000 IU every other week for 12 weeks. IL-17A, IL-6, IL-8, IL-10, IL-23 and TNFα were measured at baseline and at week 4, 8, 12, and 16. 75 healthy subjects were enrolled (58.7% female), with an average age of 34.1 ± 10.2 years. No statistical differences were observed among groups at baseline for either IL-6, IL-17A, IL-23, IL-8 or IL-10 at any time point; TNFα was indetectable. Concerning the whole sample, the time trend analysis showed a statistically significant linear trend for decreasing values over the treatment period for IL-6 (p = 0.016) and IL-17A (p = 0.006), while no significant time trends were observed for the other teste cytokines. No significant differences were found in the serum concentrations of the tested cytokines between week 12 and week 16. In young healthy individuals deficient in vitamin D, cholecalciferol administration showed a decrease in the serum IL-6 and IL-17A concentrations, without marked differences using the three regimens. Full article

(This article belongs to the Special Issue Vitamin D, Immune Response, and Autoimmune Diseases)

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15 pages, 793 KiB

Open AccessReview

The Role of Vitamin D in Neuroprotection in Multiple Sclerosis: An Update

by Amarpreet Sangha, Michaela Quon, Gerald Pfeffer and Sarah-Michelle Orton

Nutrients 2023, 15(13), 2978; https://doi.org/10.3390/nu15132978 - 30 Jun 2023

Cited by 12 | Viewed by 4332

Abstract

Multiple sclerosis (MS) is a complex neurological condition that involves both inflammatory demyelinating and neurodegenerative components. MS research and treatments have traditionally focused on immunomodulation, with less investigation of neuroprotection, and this holds true for the role of vitamin D in MS. Researchers have already established that vitamin D plays an anti-inflammatory role in modulating the immune system in MS. More recently, researchers have begun investigating the potential neuroprotective role of vitamin D in MS. The active form of vitamin D, 1,25(OH)₂D₃, has a range of neuroprotective properties, which may be important in remyelination and/or the prevention of demyelination. The most notable finding relevant to MS is that 1,25(OH)₂D₃ promotes stem cell proliferation and drives the differentiation of neural stem cells into oligodendrocytes, which carry out remyelination. In addition, 1,25(OH)₂D₃ counteracts neurodegeneration and oxidative stress by suppressing the activation of reactive astrocytes and M1 microglia. 1,25(OH)₂D₃ also promotes the expression of various neuroprotective factors, including neurotrophins and antioxidant enzymes. 1,25(OH)₂D₃ decreases blood–brain barrier permeability, reducing leukocyte recruitment into the central nervous system. These neuroprotective effects, stimulated by 1,25(OH)₂D₃, all enhance neuronal survival. This review summarizes and connects the current evidence supporting the vitamin D-mediated mechanisms of action for neuroprotection in MS. Full article

(This article belongs to the Special Issue Vitamin D, Immune Response, and Autoimmune Diseases)

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13 pages, 1085 KiB

Open AccessReview

The Vitamin D Serum Levels in Pregnant Women Affected by COVID-19: A Systematic Review and Meta-Analysis

by Luiza Szarpak, Stepan Feduniw, Michal Pruc, Michal Ciebiera, Basar Cander, Mansur Rahnama-Hezavah and Łukasz Szarpak

Nutrients 2023, 15(11), 2588; https://doi.org/10.3390/nu15112588 - 31 May 2023

Cited by 2 | Viewed by 2356

Abstract

Vitamin D can modulate immune responses, and its deficiency is linked to increased autoimmunity and susceptibility to infection. In the general population, it has been observed that serum vitamin D levels are connected with the risk of COVID-19 and its severity. Our study aims to examine reported findings on the effect of vitamin D serum levels on infection of COVID-19 during pregnancy. PubMed, Web of Science, Embase, and Cochrane Library were searched for relevant studies. Serum vitamin D serum levels in COVID-19-positive and COVID-19-negative pregnant women were 24.61 ± 20.86 ng/mL and 24.12 ± 17.33 ng/mL, respectively. In mild vs. moderate to critical COVID-19 pregnant women, vitamin D serum levels were 16.71 ± 9.04 ng/mL vs. 10.7 ± 9.37 ng/mL and severe vs. non-severe were 13.21 ± 11.47 ng/mL vs. 15.76 ± 10.0 ng/mL. Only one study reported vitamin D serum levels in the placenta of COVID-19-positive pregnant women compared with the control and results varied and amounted to 14.06 ± 0.51 ng/mL vs. 12.45 ± 0.58 ng/mL, respectively. Vitamin D deficiency tends to be common in pregnant women who have COVID-19, and the level of this vitamin has been demonstrated to have a strong correlation with the severity of the illness. As vitamin D serum levels correlate with COVID-19 symptoms and even with its occurrence, appropriate vitamin D supplementation in the prenatal period is suggested. Full article

(This article belongs to the Special Issue Vitamin D, Immune Response, and Autoimmune Diseases)

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13 pages, 603 KiB

Open AccessReview

Vitamin D and COVID-19: Narrative Review after 3 Years of Pandemic

by Emanuele Gotelli, Stefano Soldano, Elvis Hysa, Sabrina Paolino, Rosanna Campitiello, Carmen Pizzorni, Alberto Sulli, Vanessa Smith and Maurizio Cutolo

Nutrients 2022, 14(22), 4907; https://doi.org/10.3390/nu14224907 - 20 Nov 2022

Cited by 11 | Viewed by 4259

Abstract

Active vitamin D [1,25(OH)₂D₃—calcitriol] is a secosteroid hormone whose receptor is expressed on all cells of the immune system. Vitamin D has a global anti-inflammatory effect and its role in the management of a SARS-CoV-2 infection has been investigated since the beginning of the COVID-19 pandemic. In this narrative review, the laboratory and clinical results of a vitamin D supplementation have been collected from both open-label and blinded randomized clinical trials. The results are generally in favor of the utility of maintaining the serum concentrations of calcifediol [25(OH)D₃] at around 40 ng/mL and of the absolute usefulness of its supplementation in subjects with deficient serum levels. However, two very recent large-scale studies (one open-label, one placebo-controlled) have called into question the contribution of vitamin D to clinical practice in the era of COVID-19 vaccinations. The precise role of a vitamin D supplementation in the anti-COVID-19 armamentarium requires further investigations in light of the breakthrough which has been achieved with mass vaccinations. Full article

(This article belongs to the Special Issue Vitamin D, Immune Response, and Autoimmune Diseases)

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15 pages, 524 KiB

Open AccessReview

Vitamin D in Systemic Sclerosis: A Review

by Mattia Perazzi, Enrico Gallina, Giulia Francesca Manfredi, Filippo Patrucco, Antonio Acquaviva, Donato Colangelo, Mario Pirisi and Mattia Bellan

Nutrients 2022, 14(19), 3908; https://doi.org/10.3390/nu14193908 - 21 Sep 2022

Cited by 8 | Viewed by 2706

Abstract

(1) Background: In the present paper we aimed to review the evidence about the potential implication of vitamin D in the pathogenesis and management of systemic sclerosis (SSc); (2) Methods: we performed a review of the literature looking for studies evaluating the potential role of vitamin D and its analogs in SSc. We searched the PubMed, Medline, Embase, and Cochrane libraries using the following strings: (vitamin D OR cholecalciferol) AND (systemic sclerosis OR scleroderma). We included cohort studies, case-control studies, randomized controlled trials, and observational studies. (3) Results: we identified nine pre-clinical and 21 clinical studies. Pre-clinical data suggest that vitamin D and its analogs may suppress fibrogenesis. Clinical data are concordant in reporting a high prevalence of hypovitaminosis D and osteoporosis in SSc patients; data about the association with clinical manifestations and phenotypes of SSc are, conversely, far less consistent; (4) Conclusions: in vitro data suggest that vitamin D may play an antifibrotic role in SSc, but clinical data confirming this finding are currently lacking. Hypovitaminosis D is common among SSc patients and should be treated to reduce the risk of osteoporosis. Full article

(This article belongs to the Special Issue Vitamin D, Immune Response, and Autoimmune Diseases)

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15 pages, 1961 KiB

Open AccessSystematic Review

Psoriasis and Vitamin D: A Systematic Review and Meta-Analysis

by Elena Formisano, Elisa Proietti, Consuelo Borgarelli and Livia Pisciotta

Nutrients 2023, 15(15), 3387; https://doi.org/10.3390/nu15153387 - 30 Jul 2023

Cited by 11 | Viewed by 5220

Abstract

Psoriasis is a chronic immune-dysregulated inflammatory disease and hypovitaminosis D is considered a risk factor. We conducted an online database search to review and meta-analyze the relationship between vitamin D, other bone metabolism parameters, and psoriasis. The efficacy of oral vitamin D supplementation in improving Psoriasis Area and Severity Index (PASI) was also evaluated. Non-original articles, case reports, and animal studies were excluded. Bias risk was assessed according to the Cochrane Collaboration’s tool and the Newcastle–Ottawa scale in randomized controlled trials (RCTs) and case–control studies, respectively. Unstandardized mean differences were used for data synthesis. Twenty-three studies reported serum 25 hydroxyvitamin D (25(OH)D) levels in 1876 psoriasis patients and 7532 controls. Psoriasis patients had significantly lower 25(OH)D levels than controls (21.0 ± 8.3 vs. 27.3 ± 9.8, p < 0.00001). Conversely, 450 psoriasis patients had lower levels of parathormone than 417 controls (38.7 ± 12.8 vs. 43.7 ± 16.5, p = 0.015). Four RCTs examined the effect of oral vitamin D supplementation on psoriasis for 173 patients and 160 patients were treated with placebo. No significant differences were found in PASI after 3, 6, and 12 months of supplementation. It is shown that 25(OH)D serum levels are significantly lower in psoriasis, but, although the granularity of RCT methodology may have influenced the pooled analysis, vitamin D supplementation did not seem to improve clinical manifestations. Full article

(This article belongs to the Special Issue Vitamin D, Immune Response, and Autoimmune Diseases)

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20 pages, 758 KiB

Open AccessSystematic Review

Clinical and Imaging Outcomes after Vitamin D Supplementation in Patients with Multiple Sclerosis: A Systematic Review

by Julie Langlois and Damien Denimal

Nutrients 2023, 15(8), 1945; https://doi.org/10.3390/nu15081945 - 18 Apr 2023

Cited by 8 | Viewed by 2376

Abstract

The link between vitamin D and multiple sclerosis (MS) has been suggested in epidemiological, genetic, immunological, and clinical studies. The aim of the present systematic review of the literature was to assess the effects of vitamin D supplementation on clinical and imaging outcomes in patients with MS. The outcomes we assessed included relapse events, disability progression, and magnetic resonance imaging (MRI) lesions. The search was conducted using PubMed, ClinicalTrials.gov, and EudraCT databases, and it included records published up until 28 February 2023. The systematic review was reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines. Nineteen independent clinical studies (corresponding to 24 records) were included in the systematic review. The risk of bias in randomized controlled trials (RCTs) was analyzed using the Cochrane risk-of-bias tool. Fifteen trials investigated relapse events, and most of them reported no significant effect of vitamin D supplementation. Eight of 13 RCTs found that vitamin D supplementation had no effect on disability [assessed by Expanded Disability Status Scale (EDSS) scores] compared to controls. Interestingly, recent RCTs reported a significant reduction in new MRI lesions in the central nervous system of MS patients during supplementation with vitamin D3. Full article

(This article belongs to the Special Issue Vitamin D, Immune Response, and Autoimmune Diseases)

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