An Overview of Systematic Reviews of the Role of Vitamin D on Inflammation in Patients with Diabetes and the Potentiality of Its Application on Diabetic Patients with COVID-19.

Almost two years have passed since the outbreak reported for the first time in Wuhan of coronavirus disease 2019 (COVID-19), due to severe acute respiratory syndrome (SARS)-CoV-2 coronavirus, rapidly evolved into a pandemic. This infectious disease has stressed global health care systems. The mortality rate is higher, particularly in elderly population and in patients with comorbidities such as hypertension, diabetes mellitus, cardiovascular disease, chronic lung disease, chronic renal disease, and malignancy. Among them, subjects with diabetes have a high risk of developing severe form of COVID-19 and show increased mortality. How diabetes contributes to COVID-19 severity remains unclear. It has been hypothesized that it may be correlated with the effects of hyperglycemia on systemic inflammatory responses and immune system dysfunction. Vitamin D (VD) is a modulator of immune-response. Data from literature showed that vitamin D deficiency in COVID-19 patients increases COVID-19 severity, likely because of its negative impact on immune and inflammatory responses. Therefore, the use of vitamin D might play a role in some aspects of the infection, particularly the inflammatory state and the immune system function of patients. Moreover, a piece of evidence highlighted a link among vitamin D deficiency, obesity and diabetes, all factors associated with COVID-19 severity. Given this background, we performed an overview of the systematic reviews to assess the association between vitamin D supplementation and inflammatory markers in patients with diabetes; furthermore, vitamin D's possible role in COVID-19 patients was assessed as well. Three databases, namely MEDLINE, PubMed Central and the Cochrane Library of Systematic Reviews, were reviewed to retrieve the pertinent data. The aim of this review is to provide insight into the recent advances about the molecular basis of the relationship between vitamin D, immune response, inflammation, diabetes and COVID-19.

Exploring the Immune-Boosting Functions of Vitamins and Minerals as Nutritional Food Bioactive Compounds: A Comprehensive Review.

Food components have long been recognized to play a fundamental role in the growth and development of the human body, conferring protective functionalities against foreign matter that can be severe public health problems. Micronutrients such as vitamins and minerals are essential to the human body, and individuals must meet their daily requirements through dietary sources. Micronutrients act as immunomodulators and protect the host immune response, thus preventing immune evasion by pathogenic organisms. Several experimental investigations have been undertaken to appraise the immunomodulatory functions of vitamins and minerals. Based on these experimental findings, this review describes the immune-boosting functionalities of micronutrients and the mechanisms of action through which these functions are mediated. Deficiencies of vitamins and minerals in plasma concentrations can lead to a reduction in the performance of the immune system functioning, representing a key contributor to unfavorable immunological states. This review provides a descriptive overview of the characteristics of the immune system and the utilization of micronutrients (vitamins and minerals) in preventative strategies designed to reduce morbidity and mortality among patients suffering from immune invasions or autoimmune disorders.

Consumption of Food Supplements during the Three COVID-19 Waves in Poland-Focus on Zinc and Vitamin D.

Food supplements (FS) are a concentrated source of vitamins, minerals, or other ingredients with nutritional or other physiological effects. Due to their easy availability, widespread advertising, and sometimes low price, increased consumption of this group of preparations has been observed. Therefore, the aim of the study was to assess the knowledge and intake of FS during the COVID-19 pandemic in Poland, with particular reference to FS containing zinc and vitamin D. It was noted that both of the above ingredients were used significantly more often by people with higher education (59.0%), with a medical background or related working in the medical field (54.5%), and/or exercising at home (60.1%). Preparations containing vitamin D were used by 22.8% of the respondents in the first wave, 37.6% in the second wave, and 32.9% in the third wave. To sum up, we showed the highest consumption of vitamin and mineral supplements, and preparations containing zinc and vitamin D were taken significantly more often by people with higher medical and related education. This indicates a high awareness of health aspects and the need for preventive measures in these groups.

[Importance of nutrition for immune defense. The role of milk and its natural components]. / Importancia de la nutrición en la defensa inmunitaria. Papel de la leche y sus componentes naturales.

INTRODUCTION: The immune system is a complex and integrated system whose main function is to protect the body from external aggression by microorganisms, allergens, or toxic agents. Different studies show that maintaining optimal amounts of different nutrients in the body is essential to ensure the synthesis of different factors related to the immune system. Most interesting nutrients and bioactive compounds include: vitamins A, B6, B12, C, D, E, folic acid (B9) and biotin (B7); minerals such as zinc, iron, selenium, magnesium and copper; proteins (lactoferrin) and bioactive peptides; omega-3 fatty acids; and other nutrients and bioactive compounds such as fiber, polyphenols, carotenoids, probiotics, etc. Following a varied and balanced diet, including the servings recommended by food guides for each food group, is essential to achieve nutrient requirements. Food groups to which special attention should be paid are: fruits and vegetables (because of their high content in micronutrients and antioxidant compounds), fatty fish (because it contains omega-3 fatty acids), and dairy products (because this group contains a large number of nutrients). In particular, milk-especially enriched milk-contains many of the nutrients mentioned above. Moreover, their daily consumption, within a balanced diet, can help significantly cover their nutrient reference values. Finally, it is important to consider kind of milks as a good dietary alternative to increase the intake of some important nutrients for the proper functioning of the immune system, most especially some of them such as vitamin D, since a large percentage of the population have nutritional deficiencies.

INTRODUCCIÓN: El sistema inmunitario es un sistema complejo e integrado cuya función principal es proteger al organismo de agresiones externas provocadas por microorganismos, alergenos o agentes tóxicos. Diferentes estudios ponen de manifiesto que el mantenimiento de las cantidades óptimas de diferentes nutrientes es esencial para garantizar la síntesis de diferentes factores y mediadores de este sistema. Entre los nutrientes y compuestos bioactivos con mayor interés destacan: las vitaminas A, B6, B12, C, D, E, ácido fólico (B9) y biotina (B7); minerales como el zinc, hierro, selenio, magnesio y cobre; proteínas (lactoferrina) y péptidos bioactivos; ácidos grasos omega-3, y otros nutrientes y compuestos bioactivos como fibra, polifenoles, carotenoides, probióticos, etc. El seguimiento de una dieta variada y equilibrada que incluya las raciones recomendadas por las guías alimentarias para cada grupo de alimentos es fundamental para alcanzar los requerimientos de estos nutrientes. Y entre los grupos de alimentos a los que se debe prestar especial atención están: las frutas y verduras (por su alto contenido en micronutrientes y compuestos antioxidantes), los pescados azules (por contener omega-3) y los lácteos (por ser alimentos con gran cantidad de nutrientes). En concreto, la leche, especialmente enriquecida, contiene muchos de los nutrientes anteriormente mencionados y su consumo diario, dentro de una dieta equilibrada, puede contribuir a cubrir cantidades importantes de sus valores de referencia. Por último, es importante considerar las leches enriquecidas como una buena alternativa dietética para aumentar la ingesta de muchos nutrientes importantes para el buen funcionamiento del sistema inmune y, en especial, de algunos de ellos, como la vitamina D, en los que un gran porcentaje de la población presenta deficiencias nutricionales.

Public Interest in Immunity and the Justification for Intervention in the Early Stages of the COVID-19 Pandemic: Analysis of Google Trends Data.

BACKGROUND: The use of social big data is an important emerging concern in public health. Internet search volumes are useful data that can sensitively detect trends of the public's attention during a pandemic outbreak situation. OBJECTIVE: Our study aimed to analyze the public's interest in COVID-19 proliferation, identify the correlation between the proliferation of COVID-19 and interest in immunity and products that have been reported to confer an enhancement of immunity, and suggest measures for interventions that should be implemented from a health and medical point of view. METHODS: To assess the level of public interest in infectious diseases during the initial days of the COVID-19 outbreak, we extracted Google search data from January 20, 2020, onward and compared them to data from March 15, 2020, which was approximately 2 months after the COVID-19 outbreak began. In order to determine whether the public became interested in the immune system, we selected coronavirus, immune, and vitamin as our final search terms. RESULTS: The increase in the cumulative number of confirmed COVID-19 cases that occurred after January 20, 2020, had a strong positive correlation with the search volumes for the terms coronavirus (R=0.786; P<.001), immune (R=0.745; P<.001), and vitamin (R=0.778; P<.001), and the correlations between variables were all mutually statistically significant. Moreover, these correlations were confirmed on a country basis when we restricted our analyses to the United States, the United Kingdom, Italy, and Korea. Our findings revealed that increases in search volumes for the terms coronavirus and immune preceded the actual occurrences of confirmed cases. CONCLUSIONS: Our study shows that during the initial phase of the COVID-19 crisis, the public's desire and actions of strengthening their own immune systems were enhanced. Further, in the early stage of a pandemic, social media platforms have a high potential for informing the public about potentially helpful measures to prevent the spread of an infectious disease and provide relevant information about immunity, thereby increasing the public's knowledge.

The Role of Nutrition in COVID-19 Susceptibility and Severity of Disease: A Systematic Review.

BACKGROUND: Many nutrients have powerful immunomodulatory actions with the potential to alter susceptibility to coronavirus disease 2019 (COVID-19) infection, progression to symptoms, likelihood of severe disease, and survival. OBJECTIVE: The aim was to review the latest evidence on how malnutrition across all its forms (under- and overnutrition and micronutrient status) may influence both susceptibility to, and progression of, COVID-19. METHODS: We synthesized information on 13 nutrition-related components and their potential interactions with COVID-19: overweight, obesity, and diabetes; protein-energy malnutrition; anemia; vitamins A, C, D, and E; PUFAs; iron; selenium; zinc; antioxidants; and nutritional support. For each section we provide: 1) a landscape review of pertinent material; 2) a systematic search of the literature in PubMed and EMBASE databases, including a wide range of preprint servers; and 3) a screen of 6 clinical trial registries. All original research was considered, without restriction to study design, and included if it covered: 1) severe acute respiratory syndrome coronavirus (CoV) 2 (SARS-CoV-2), Middle East respiratory syndrome CoV (MERS-CoV), or SARS-CoV viruses and 2) disease susceptibility or 3) disease progression, and 4) the nutritional component of interest. Searches took place between 16 May and 11 August 2020. RESULTS: Across the 13 searches, 2732 articles from PubMed and EMBASE, 4164 articles from the preprint servers, and 433 trials were returned. In the final narrative synthesis, we include 22 published articles, 38 preprint articles, and 79 trials. CONCLUSIONS: Currently there is limited evidence that high-dose supplements of micronutrients will either prevent severe disease or speed up recovery. However, results of clinical trials are eagerly awaited. Given the known impacts of all forms of malnutrition on the immune system, public health strategies to reduce micronutrient deficiencies and undernutrition remain of critical importance. Furthermore, there is strong evidence that prevention of obesity and type 2 diabetes will reduce the risk of serious COVID-19 outcomes. This review is registered at PROSPERO as CRD42020186194.

Immunomodulatory diet in pediatric age.

In the last few decades, the importance of a functioning immune system and health status has become more evident. Multiple factors are able to influence the development of chronic diseases and diet is one of the most important environmental factors. Evidence demonstrates that dietary patterns high in fat and low in fiber are associated with the development of non-communicable diseases. Moreover, optimal nutritional status can modulate immune maturation and response to inflammation. During inflammatory conditions, nutritional deficiencies may occur, establishing a vicious circle, consequently a balanced nutritional status is essential to prevent and counteract infections. Dietary diversity can prevent allergic diseases and nutrients such as DHA, arginine, vitamins and trace elements have an impact on physical barriers (such as gut mucosal barrier and skin), on the immune system response and on microbiome modulation. Protein deficiencies can compromise innate and adaptive immune functions; arginine availability can affect the immune response in injured states and other disease processes; EPA and DHA can modulate both innate and adaptive immunity; prebiotics have a beneficial effect on the functioning of the immune system. Zinc, copper, selenium and iron are involved in the correct development and function of the immune system. Vitamins D, E, A, B and C have a role on immune system through different mechanisms of action. Since a complex interplay exists between diet, microbiome and epigenetic factors which determine nutrient-induced changes on the immune function, the effect of each single nutrient may be difficult to study. Well-designed intervention studies, investigating the effects of whole dietary pattern, should be performed to clarify impact of foods on the immune function and disease risk.

Importancia de la nutrición en la defensa inmunitaria. Papel de la leche y sus componentes naturales / Importance of nutrition for immune defense. The role of milk and its natural components

El sistema inmunitario es un sistema complejo e integrado cuya función principal es proteger al organismo de agresiones externas provocadas por microorganismos, alergenos o agentes tóxicos. Diferentes estudios ponen de manifiesto que el mantenimiento de las cantidades óptimas de diferentes nutrientes es esencial para garantizar la síntesis de diferentes factores y mediadores de este sistema. Entre los nutrientes y compuestos bioactivos con mayor interés destacan: las vitaminas A, B6, B12, C, D, E, ácido fólico (B9) y biotina (B7); minerales como el zinc, hierro, selenio, magnesio y cobre; proteínas (lactoferrina) y péptidos bioactivos; ácidos grasos omega-3, y otros nutrientes y compuestos bioactivos como fibra, polifenoles, carotenoides, probióticos, etc. El seguimiento de una dieta variada y equilibrada que incluya las raciones recomendadas por las guías alimentarias para cada grupo de alimentos es fundamental para alcanzar los requerimientos de estos nutrientes. Y entre los grupos de alimentos a los que se debe prestar especial atención están: las frutas y verduras (por su alto contenido en micronutrientes y compuestos antioxidantes), los pescados azules (por contener omega-3) y los lácteos (por ser alimentos con gran cantidad de nutrientes). En concreto, la leche, especialmente enriquecida, contiene muchos de los nutrientes anteriormente mencionados y su consumo diario, dentro de una dieta equilibrada, puede contribuir a cubrir cantidades importantes de sus valores de referencia. Por último, es importante considerar las leches enriquecidas como una buena alternativa dietética para aumentar la ingesta de muchos nutrientes importantes para el buen funcionamiento del sistema inmune y, en especial, de algunos de ellos, como la vitamina D, en los que un gran porcentaje de la población presenta deficiencias nutricionales. (AU)

The immune system is a complex and integrated system whose main function is to protect the body from external aggression by microorganisms, allergens, or toxic agents. Different studies show that maintaining optimal amounts of different nutrients in the body is essential to ensure the synthesis of different factors related to the immune system. Most interesting nutrients and bioactive compounds include: vitamins A, B6, B12, C, D, E, folic acid (B9) and biotin (B7); minerals such as zinc, iron, selenium, magnesium and copper; proteins (lactoferrin) and bioactive peptides; omega-3 fatty acids; and other nutrients and bioactive compounds such as fiber, polyphenols, carotenoids, probiotics, etc. Following a varied and balanced diet, including the servings recommended by food guides for each food group, is essential to achieve nutrient requirements. Food groups to which special attention should be paid are: fruits and vegetables (because of their high content in micronutrients and antioxidant compounds), fatty fish (because it contains omega-3 fatty acids), and dairy products (because this group contains a large number of nutrients). In particular, milk–especially enriched milk–contains many of the nutrients mentioned above. Moreover, their daily consumption, within a balanced diet, can help significantly cover their nutrient reference values. Finally, it is important to consider enriched kind of milk as a good dietary alternative to increase the intake of some important nutrients for the proper functioning of the immune system, most especially some of them such as vitamin D, since a large percentage of the population have nutritional deficiencies. (AU)

VitaminD supplementation for the prevention and treatment of COVID-19: a position statement from the Spanish Society of Geriatrics and Gerontology.

The coronavirus disease 2019 (COVID-19) produces severe respiratory symptoms such as bilateral pneumonia associated to a high morbidity and mortality, especially in patients of advanced age. Vitamin D deficiency has been reported in several chronic conditions associated with increased inflammation and dysregulation of the immune system. Vitamin D in modulates immune function too. Vitamin D receptor (VDR) is expressed by most immune cells, including B and T lymphocytes, monocytes, macrophages, and dendritic cells and the signalling of vitamin D and VDR together has an anti-inflammatory effect. Some studies have reported that vitamin D treatment could be useful for the prevention and treatment of COVID-19 because vitamin D plays an important role as a modulator of immunocompetence. Over the last few months, some studies have hypothesized the possible beneficial effect of vitamin D supplementation in patients with COVID-19 in order to improve the immune balance and prevent the hyperinflammatory cytokine storm. Some preliminary studies have already shown promising results with vitamin D supplementation in hospitalized COVID-19 patients. Vitamin D should be administered daily until adequate levels are achieved due to vitamin D behaves as a negative acute phase reactant (APR). Despite the lack of evidence on specific doses of vitamin D to treat COVID-19 in older adults, authors consider it is necessary to standardize the use in clinical practice. These recommendations advice supplement vitamin D in a protocoled fashion based on expert opinions, level of evidence 5.

Suppressive effects of vitamin C-treated induced-regulatory T cells on heart allograft rejection under vitamin C-deficient or -sufficient conditions.

Foxp3 stability of vitamin C-treated induced-regulatory T cells (V-iTregs) is superior to that of conventional iTregs (C-iTregs). However, the role of V-iTregs in allograft rejection under vitamin C-deficient conditions, such as those seen in humans, remains unclear. We aimed to elucidate the role of vitamin C treatment on generation and maintenance of iTregs from gulo knockout (Gulo-KO) mice as well as wild type (WT) mice, and in vitro and in vivo suppressive effects of V-iTregs on heart allograft rejection in either Gulo-KO or WT recipient mice. Conversion efficiency of iTregs was similar between C- and V-iTregs in both WT and Gulo-KO mice. V-iTregs from WT or Gulo-KO mice showed better in vitro Foxp3 stability than C-iTregs, although there was no difference between WT V-iTregs and Gulo-KO V-iTregs. Furthermore, V-iTregs from WT or Gulo-KO mice suppressed in vitro T cell proliferation better than C-iTregs. Heterotrophic heart transplantation from BALB/c mice to WT or vitamin C-deficient Gulo-KO C57BL/6J mice was performed following adoptive transfer of C- or V-iTregs. V-iTregs as well as C-iTregs prolonged heart allograft survival in WT and Gulo-KO mice. However, there was no difference between the C- and V-iTreg groups. Supplementation of low- or high-dose vitamin C did not induce significant changes in heart allograft survival in Gulo-KO recipients that had received V-iTregs. In conclusion, V-iTregs do not exert better suppressive effects on heart allograft survival than C-iTregs in either WT or vitamin C-deficient recipients.

The contribution of gut bacterial metabolites in the human immune signaling pathway of non-communicable diseases.

The interaction disorder between gut microbiota and its host has been documented in different non-communicable diseases (NCDs) such as metabolic syndrome, neurodegenerative disease, and autoimmune disease. The majority of these altered interactions arise through metabolic cross-talk between gut microbiota and host immune system, inducing a low-grade chronic inflammation that characterizes all NCDs. In this review, we discuss the contribution of bacterial metabolites to immune signaling pathways involved in NCDs. We then review recent advances that aid to rationally design microbial therapeutics. A deeper understanding of these intersections between host and gut microbiota metabolism using metabolomics-based system biology platform promises to reveal the fundamental mechanisms that drive metabolic predispositions to disease and suggest new avenues to use microbial therapeutic opportunities for NCDs treatment and prevention. Abbreviations: NCDs: non-communicable disease, IBD: inflammatory bowel disease, IL: interleukin, T2D: type 2 diabetes, SCFAs: short-chain fatty acids, HDAC: histone deacetylases, GPCR: G-protein coupled receptors, 5-HT: 5-hydroxytryptamine receptor signaling, DCs: dendritic cells, IECs: intestinal epithelial cells, T-reg: T regulatory cell, NF-κB: nuclear factor κB, TNF-α: tumor necrosis factor alpha, Th: T helper cell, CNS: central nervous system, ECs: enterochromaffin cells, NSAIDs: non-steroidal anti-inflammatory drugs, AhR: aryl hydrocarbon receptor, IDO: indoleamine 2,3-dioxygenase, QUIN: quinolinic acid, PC: phosphatidylcholine, TMA: trimethylamine, TMAO: trimethylamine N-oxide, CVD: cardiovascular disease, NASH: nonalcoholic steatohepatitis, BAs: bile acids, FXR: farnesoid X receptor, CDCA: chenodeoxycholic acid, DCA: deoxycholic acid, LCA: lithocholic acid, UDCA: ursodeoxycholic acid, CB: cannabinoid receptor, COBRA: constraint-based reconstruction and analysis.

Unraveling the roles of vitamin D status and melanin during Covid­19 (Review).

As the coronavirus disease 2019 (COVID­19) continues to spread worldwide, it has become evident that the morbidity and mortality rates clearly vary across nations. Although several factors may account for this disparity, striking differences within and between populations indicate that ethnicity might impact COVID­19 clinical outcomes, reflecting the 'color of disease'. Therefore, the role of key biological variables that could interplay with viral spreading and severity indices has attracted increasing attention, particularly among non­Caucasian populations. Although the links between vitamin D status and the incidence and severity of COVID-19 remain elusive, several lines of emerging evidence suggest that vitamin D signaling, targeting several immune­mediated pathways, may offer potential benefits at different stages of SARS-CoV-2 infection. Given that the vitamin D status is modulated by several intrinsic and extrinsic factors, including skin type (pigmentation), melanin polymers may also play a role in variable COVID­19 outcomes among diverse population settings. Moreover, apart from the well­known limiting effects of melanin on the endogenous production of vitamin D, the potential crosstalk between the pigmentary and immune system may also require special attention concerning the current pandemic. The present review article aimed to shed light on a range of mostly overlooked host factors, such as vitamin D status and melanin pigments, that may influence the course and outcome of COVID­19.

Immune-boosting role of vitamins D, C, E, zinc, selenium and omega-3 fatty acids: Could they help against COVID-19?

The world is currently in the grips of the coronavirus disease (COVID-19) pandemic, caused by the SARS-CoV-2 virus, which has mutated to allow human-to-human spread. Infection can cause fever, dry cough, fatigue, severe pneumonia, respiratory distress syndrome and in some instances death. COVID-19 affects the immune system by producing a systemic inflammatory response, or cytokine release syndrome. Patients with COVID-19 have shown a high level of pro-inflammatory cytokines and chemokines. There are currently no effective anti-SARS-CoV-2 viral drugs or vaccines. COVID-19 disproportionately affects the elderly, both directly, and through a number of significant age-related comorbidities. Undoubtedly, nutrition is a key determinant of maintaining good health. Key dietary components such as vitamins C, D, E, zinc, selenium and the omega 3 fatty acids have well-established immunomodulatory effects, with benefits in infectious disease. Some of these nutrients have also been shown to have a potential role in the management of COVID-19. In this paper, evidence surrounding the role of these dietary components in immunity as well as their specific effect in COVID-19 patients are discussed. In addition, how supplementation of these nutrients may be used as therapeutic modalities potentially to decrease the morbidity and mortality rates of patients with COVID-19 is discussed.

Cytokine storm in aged people with CoV-2: possible role of vitamins as therapy or preventive strategy.

BACKGROUND: In December 2019, a novel human-infecting coronavirus, SARS-CoV-2, had emerged. The WHO has classified the epidemic as a "public health emergency of international concern". A dramatic situation has unfolded with thousands of deaths, occurring mainly in the aged and very ill people. Epidemiological studies suggest that immune system function is impaired in elderly individuals and these subjects often present a deficiency in fat-soluble and hydrosoluble vitamins. METHODS: We searched for reviews describing the characteristics of autoimmune diseases and the available therapeutic protocols for their treatment. We set them as a paradigm with the purpose to uncover common pathogenetic mechanisms between these pathological conditions and SARS-CoV-2 infection. Furthermore, we searched for studies describing the possible efficacy of vitamins A, D, E, and C in improving the immune system function. RESULTS: SARS-CoV-2 infection induces strong immune system dysfunction characterized by the development of an intense proinflammatory response in the host, and the development of a life-threatening condition defined as cytokine release syndrome (CRS). This leads to acute respiratory syndrome (ARDS), mainly in aged people. High mortality and lethality rates have been observed in elderly subjects with CoV-2-related infection. CONCLUSIONS: Vitamins may shift the proinflammatory Th17-mediated immune response arising in autoimmune diseases towards a T-cell regulatory phenotype. This review discusses the possible activity of vitamins A, D, E, and C in restoring normal antiviral immune system function and the potential therapeutic role of these micronutrients as part of a therapeutic strategy against SARS-CoV-2 infection.

Immunologic Effects of Vitamin D on Human Health and Disease.

Vitamin D is responsible for regulation of calcium and phosphate metabolism and maintaining a healthy mineralized skeleton. It is also known as an immunomodulatory hormone. Experimental studies have shown that 1,25-dihydroxyvitamin D, the active form of vitamin D, exerts immunologic activities on multiple components of the innate and adaptive immune system as well as endothelial membrane stability. Association between low levels of serum 25-hydroxyvitamin D and increased risk of developing several immune-related diseases and disorders, including psoriasis, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, tuberculosis, sepsis, respiratory infection, and COVID-19, has been observed. Accordingly, a number of clinical trials aiming to determine the efficacy of administration of vitamin D and its metabolites for treatment of these diseases have been conducted with variable outcomes. Interestingly, recent evidence suggests that some individuals might benefit from vitamin D more or less than others as high inter-individual difference in broad gene expression in human peripheral blood mononuclear cells in response to vitamin D supplementation has been observed. Although it is still debatable what level of serum 25-hydroxyvitamin D is optimal, it is advisable to increase vitamin D intake and have sensible sunlight exposure to maintain serum 25-hydroxyvitamin D at least 30 ng/mL (75 nmol/L), and preferably at 40-60 ng/mL (100-150 nmol/L) to achieve the optimal overall health benefits of vitamin D.

Vitamin D and connective tissue diseases.

OBJECTIVE AND DESIGN: Recently, many studies have shown that the biologically active form of vitamin D-1,25(OH)2 D-is involved in many biological processes, including immune system modulation, and patients affected by various autoimmune diseases, such as connective tissue diseases (CTD), showed low levels of vitamin D. It is not clear if vitamin D deficiency is involved in the pathogenesis of autoimmune diseases or it is a consequence. MATERIAL: We carried out a review of literature to summarize the existing connections between 25-OH vitamin D and CTD. METHODS: We searched for articles on PubMed by keywords: vitamin D, connective tissue diseases, systemic lupus erythematosus, Sjogren's syndrome, systemic sclerosis, undifferentiated connective tissue disease. RESULTS: The relationship between vitamin D and CTD is still not very clear, despite many studies having been performed and some data suggest a connection between these diseases and 25-OH vitamin D levels. CONCLUSIONS: The limitations of the study, such as the heterogeneity of patients, methods used to measure vitamin D serum concentration and other biases, do not lead to unequivocal results to demonstrate a direct link between low vitamin D serum levels and autoimmune diseases. Further studies are needed to resolve conflicting results.

The role and mechanism of vitamin D-mediated regulation of Treg/Th17 balance in recurrent pregnancy loss.

PROBLEM: Vitamin D has a pivotal role in regulating immune responses in women with recurrent pregnancy loss (RPL), but the underlying mechanism has not been completely clarified. This study aimed to determine the correlation between vitamin D and Treg/Th17 and the effects of vitamin D supplementation on Treg/Th17 balance in RPL patients. METHODS OF STUDY: The level of vitamin D was determined in women with normal pregnancy and RPL by electrochemiluminescence. The percentages of CD4+ Foxp3+ Treg, CD4+ IL-17+ Th17, and CD4+ Foxp3+ IL-17+ T cells were determined by flow cytometry before and after vitamin D supplementation. Changes about Treg/Th17 balance after culturing with active vitamin D in vitro were determined. Vitamin D metabolic activity of peripheral blood mononuclear cells was also detected by RT-PCR. RESULTS: Compared with normal pregnancy, both the level of vitamin D and the Treg/Th17 ratio were significantly decreased in women with RPL. There was a positive correlation between the level of vitamin D and the Treg/Th17 ratio in the RPL group. Within the RPL group, those who received 2 months of vitamin D supplementation showed a significantly increased Treg/Th17 ratio compared with those without vitamin D supplementation. In vitro analysis showed that adding different concentrations of active vitamin D increased the Treg/Th17 ratio, also the mRNA levels of the vitamin D receptor and the metabolic enzyme CYP24A1 increased significantly. CONCLUSION: The occurrence of RPL may be related to vitamin D insufficiency and Treg/Th17 imbalance. The Treg/Th17 imbalance seen in women with RPL can be restored by vitamin D supplementation both in vivo and in vitro. The effects of vitamin D on the immune regulation of RPL indicate that vitamin D might be used as an alternative therapy in the future.

Vitamin D deficiency and graft-versus-host disease in hematopoietic stem cell transplant population.

Vitamins are the organic compounds that have long been known to play a significant role in our body by functioning as hormones and antioxidants. Vitamin D, a fat-soluble vitamin, is the main regulator of calcium hemostasis in our body. At the same time, it is also known to show its potential effects on the immune system by modulating the differentiation, activation, and proliferation of T and B lymphocytes. The immunomodulatory properties of vitamin D are also known to have a crucial role in the prevention and treatment of graft-versus-host disease. Patients undergoing hematopoietic stem cell transplantation are particularly at risk of vitamin D deficiency. This review article expands our understanding of vitamin D, its immunomodulatory effects, and its role in prevention and treatment of graft-versus-host disease.

Vitamin D: Effect on Haematopoiesis and Immune System and Clinical Applications.

Vitamin D is a steroid-like hormone which acts by binding to vitamin D receptor (VDR). It plays a main role in the calcium homeostasis and metabolism. In addition, vitamin D display other important effects called "non-classical actions." Among them, vitamin D regulates immune cells function and hematopoietic cells differentiation and proliferation. Based on these effects, it is currently being evaluated for the treatment of hematologic malignancies. In addition, vitamin D levels have been correlated with patients' outcome after allogeneic stem cell transplantation, where it might regulate immune response and, accordingly, might influence the risk of graft-versus-host disease. Here, we present recent advances regarding its clinical applications both in the treatment of hematologic malignancies and in the transplant setting.