Immune Modulation by Vitamin D and Its Relevance to Food Allergy

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.     

Cord blood 25(OH)D levels and the subsequent risk of lower respiratory tract infections in early childhood: the Ulm birth cohort

Lower respiratory tract infections (LRTIs) are a major cause of hospitalization in infants. Research suggests that immunomodulatory properties of vitamin D may influence LRTI risk. This study’s objective was to examine whether 25-hydroxyvitamin D [25(OH)D] concentrations in cord blood influenced susceptibility to LRTI in the first year of life. Data was analyzed from a prospective birth cohort of 777 mother-infant pairs based in Ulm, Germany. Relative risks (RRs) of LRTI in relation to 25(OH)D cord blood levels were estimated by log-binomial regression after adjustment for potential confounders. To account for seasonal variation in both vitamin D levels and infections, we examined the association in different seasons. Analyses were conducted using clinical predefined cutpoints, quartiles, and season-standardized 25(OH)D quartiles. We observed a statistically significant association between 25(OH)D status in cord blood and risk of LRTI across the year using clinical cutpoints. The adjusted RR of LRTI for individuals with vitamin D deficiency (<25 nmol/L) in comparison to the referent category (>50 nmol/L) was 1.32 [95 % confidence interval (CI) 1.00, 1.73]. The association differed by maternal allergy status; children born to mothers without allergy demonstrated a RR of 1.45 (95 % CI 1.03, 2.03). The effect was largely driven by a strong association between 25(OH)D and LRTI in infants born in fall with a RR of 3.07 (95 % CI 1.37, 6.87). Our findings suggest that vitamin D deficiency at birth is associated with increased risk of LRTI particularly in infants born to mothers without allergy. The association seems strongest in infants born in fall.     

Epidemic influenza and vitamin D

In 1981, R. Edgar Hope-Simpson proposed that a 'seasonal stimulus' intimately associated with solar radiation explained the remarkable seasonality of epidemic influenza. Solar radiation triggers robust seasonal vitamin D production in the skin; vitamin D deficiency is common in the winter, and activated vitamin D, 1,25(OH)2D, a steroid hormone, has profound effects on human immunity. 1,25(OH)2D acts as an immune system modulator, preventing excessive expression of inflammatory cytokines and increasing the 'oxidative burst' potential of macrophages. Perhaps most importantly, it dramatically stimulates the expression of potent anti-microbial peptides, which exist in neutrophils, monocytes, natural killer cells, and in epithelial cells lining the respiratory tract where they play a major role in protecting the lung from infection. Volunteers inoculated with live attenuated influenza virus are more likely to develop fever and serological evidence of an immune response in the winter. Vitamin D deficiency predisposes children to respiratory infections. Ultraviolet radiation (either from artificial sources or from sunlight) reduces the incidence of viral respiratory infections, as does cod liver oil (which contains vitamin D). An interventional study showed that vitamin D reduces the incidence of respiratory infections in children. We conclude that vitamin D, or lack of it, may be Hope-Simpson's 'seasonal stimulus'.     

Multiple sclerosis and vitamin D: an update

MS is a chronic, immune-mediated inflammatory and neurodegenerative disease of the central nervous system (CNS), with an etiology that is not yet fully understood. The prevalence of MS is highest where environmental supplies of vitamin D are lowest. It is well recognized that the active hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25-(OH)(2)D), is a natural immunoregulator with anti-inflammatory action. The mechanism by which vitamin D nutrition is thought to influence MS involves paracrine or autocrine metabolism of 25OHD by cells expressing the enzyme 1 alpha-OHase in peripheral tissues involved in immune and neural function. Administration of the active metabolite 1,25-(OH)(2)D in mice and rats with experimental allergic encephalomyelitis (EAE, an animal model of MS) not only prevented, but also reduced disease activity. 1,25-(OH)(2)D alters dendritic cell and T-cell function and regulates macrophages in EAE. Interestingly, 1,25-(OH)(2)D is thought to be operating on CNS constituent cells as well. Vitamin D deficiency is caused by insufficient sunlight exposure or low dietary vitamin D(3) intake. Subtle defects in vitamin D metabolism, including genetic polymorphisms related to vitamin D, might possibly be involved as well. Optimal 25OHD serum concentrations, throughout the year, may be beneficial for patients with MS, both to obtain immune-mediated suppression of disease activity, and also to decrease disease-related complications, including increased bone resorption, fractures, and muscle weakness.     

Vitamin D and 1,25(OH)2D Regulation of T cells

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.     

Elevated serum parathyroid hormone, calcitonin, and 1,25-dihydroxyvitamin D in lactating women nursing twins

The roles of vitamin D, calcitonin, and parathyroid hormone in calcium metabolism during lactation may be more evident in women secreting very large amounts of milk for a number of months, as in mothers nursing twins. We report significant increases in serum concentrations of parathyroid hormone, calcitonin, and 1,25(OH)2 vitamin D in mothers nursing twins compared to mothers nursing single infants. Serum concentrations of calcium actually increased in both groups during lactation. Maternal intakes of calories, calcium, and phosphorus were significantly higher in mothers nursing twins. Thus, mothers nursing twins were able to compensate for higher calcium losses in breast milk by increased dietary intakes of calcium as well as increased serum concentrations of parathyroid hormone, calcitonin, and 1,25(OH)2 vitamin D.     

Vitamin D and Allergic Disease: Sunlight at the End of the Tunnel?

A role for vitamin D in the regulation of immune function was first proposed after the identification of Vitamin D Receptors in lymphocytes. It has since been recognized that the active form of vitamin D, 1α,25(OH)2D3, has direct affects on naïve and activated helper T cells, regulatory T cells, activated B cells and dendritic cells. There is a growing body of literature linking vitamin D (serum 25(OH)D, oral intake and surrogate indicators such as latitude) to various immune-related conditions, including allergy, although the nature of this relationship is still unclear. This review explores the findings of epidemiological, clinical and laboratory research, and the potential role of vitamin D in promoting the inappropriate immune responses which underpin the rise in a broad range of immune diseases.     

1alpha,25-dihydroxycholecalciferol increases the expression of vascular endothelial growth factor in C3H10T1/2 mouse embryo fibroblasts

Evidence suggests that biologically active vitamin D, 1,25-dihydroxycholecalciferol [1,25(OH)(2)D(3)], may inhibit carcinogenesis. Because angiogenesis is crucial to carcinogenesis, 1,25(OH)(2)D(3) regulation of proangiogenic vascular endothelial growth factor (VEGF) secretion was investigated in cellular models for multistage carcinogenesis. Conditioned media from 1,25(OH)(2)D(3)-treated C3H10T(1/2) mouse fibroblasts and their Harvey ras-oncogene transfected counterparts (rasneo11a cells) induced human umbilical vein endothelial cell (HUVEC) proliferation (1.3 and 0.3 times, respectively, P < 0.05), suggesting that 1,25(OH)(2)D(3) altered the angiogenic phenotype of the cells. Although rasneo11a cells secreted less VEGF than C3H10T(1/2) cells (97%, P < 0.005), 1,25(OH)(2)D(3) induced C3H10T(1/2) and rasneo11a cells to secrete 2 and 3 times, respectively, more VEGF than controls (P < 0.05). Similar effects on VEGF release occurred after 1,25(OH)(2)D(3) treatment of MCF10A and MCF10Aras cells, a human breast epithelial cell model for multistage carcinogenesis. In C3H10T(1/2) cells, 1,25(OH)(2)D(3) activated the VEGF promoter in a dose-dependent (5-100 nmol/L) manner (maximum 60%) and all doses induced VEGF secretion (P < 0.05). 1,25(OH)(2)D(3) induced VEGF mRNA expression ( approximately 50%) from 2 through 24 h; VEGF release was significantly increased at 8 h and sustained for 24 h. VEGF mRNA expression and release declined as C3H10T(1/2) cells grew more confluent, whereas the magnitude of 1,25(OH)(2)D(3)-stimulated changes in VEGF was greater in confluent (3.3 times RNA; 3.5 times release) than in subconfluent (50% RNA; 100% release) cultures (P < 0.05). Thus, 1,25(OH)(2)D(3) increases VEGF secretion, and in C3H10T(1/2) cells, this is likely through activation of the VEGF promoter and induction of gene expression. These data contribute to understanding the role 1,25(OH)(2)D(3) plays in regulation of angiogenesis in normal compared with disease states.     

Vitamin D and Crohn's Disease in the Adult Patient

Crohn's disease (CD) is characterized as a chronic immune‐mediated inflammatory disorder of the gastrointestinal tract. Current consensus surrounding the cause of the disease suggests a complex interplay between genetic susceptibility, the intestinal microbiome and environmental factors, leading to the aberrant Th1 and Th17 immune cell mediated response. Vitamin D deficiency is common in CD patients, and long‐standing deficiency has been associated with reduced bone mineral density (BMD). Accumulating evidence now suggests that in addition to maintaining skeletal integrity, vitamin D also plays an integral role in regulating the general immune response, a function employed via its genomic actions on the vitamin D receptor (VDR). The VDR is expressed in all immune cells and both directly and indirectly targeted by the bioactive form of vitamin D, 1,25‐Dihydroxyvitamin D (1,25[OH]₂D). Impaired regulation or deficiency of the vitamin has been linked to the promotion of self‐reactive T cell development, loss of immune tolerance to self‐structures, and experimental colitis in animal models, whereas the subsequent administration of the vitamin in these models resulted in the improvement of immune‐mediated symptoms. In addition, low vitamin D has been associated with disease activity in CD patients, and supplementation appears to be beneficial in improving clinical scores and reducing inflammation. Therefore, the primary aims of this article were to review the molecular evidence supporting the immunoregulatory roles of vitamin D and its supplementation in the CD patient, based on existing literature. The physiological processes, accepted serum concentration values, and its well‐recognized role in bone health were also summarized.     

25-Hydroxyvitamin D and 1,25-dihydroxyvitamin D of D2 and D3 origin in maternal and umbilical cord serum after vitamin D2 supplementation in human pregnancy

Serum concentrations of 25-hydroxyvitamin D (25-OHD) and 1,25-dihydroxyvitamin D [1,25-(OH)2D] of vitamin D2 and D3 origin were determined separately in 10 women before vitamin intake in early pregnancy, and repeated in maternal and cord serum obtained at delivery after 20 to 30 wk of vitamin D2 supplementation in a dose of 400 IU/day. Before supplementation 25-OHD2 and 1,25-(OH)D2D2 were present in just traceable or nondetectable concentrations, but the levels increased in all to a mean +/- 1 SD of 7.3 +/- 3.7 ng/ml and 37.2 +/- 18.1 pg/ml, respectively (p less than 0.0025), by the time of delivery. At delivery the total 25-OHD and 1,25-(OH)2D levels were always lower in the cord than in the maternal serum (30.7 +/- 14.2 versus 20.1 +/- 9.1 ng/ml, and 90.1 +/- 31.2 versus 37.3 +/- 11.6 pg/ml, p less than 0.0025). The paired concentrations of 25-OHD were closely related (r = 0.89, p less than 0.0005), while the association for 1,25-(OH)2D was not statistically significant (r = 0.53, p less than .01). The 25-OHD of D2 and D3 origin accounted for a similar proportion of the total 25-OHD in the maternal and cord serum (ratio of 25-OHD2 to 25-OHD3: 0.40 +/- 0.28 versus 0.45 +/- 0.29, p = NS), as did the respective 1,25-(OH)2D metabolites [ratio of 1,25-(OH)2D2 to 1,25-(OH)2D3: 0.73 +/- 0.35 versus 0.90 +/- 0.50, p = NS].(ABSTRACT TRUNCATED AT 250 WORDS)     

Vitamin D,Its Role in Recovery after Muscular Damage Following Exercise

Aside from its role in bone metabolism, vitamin D is a key immunomodulatory micronutrient. The active form of vitamin D (1,25(OH)D) seems to modulate the innate immune system through different mechanisms. The vitamin is involved in the differentiation of monocytes into macrophages, increasing the phagocytic and chemotactic functions of these cells. At the same time, vitamin D enables efferocytosis and prevents immunopathology. In addition, vitamin D is involved in other processes related to immune function, such as inflammation. Regarding muscle tissue, vitamin D plays an active role in muscle inflammatory response, protein synthesis, and regulation of skeletal muscle function. Two mechanisms have been proposed: A direct role of 1,25(OH)D binding to vitamin D receptors (VDRs) in muscle cells and the modulation of calcium transport in the sarcoplasmic reticulum. This second mechanism needs additional investigation. In conclusion, vitamin D seems to be effective in cases of deficiency and/or if there is a great muscular commitment, such as in high intensity exercises.     

Vitamin D and intervention trials in prostate cancer: from theory to therapy

Studies of vitamin D and prostate cancer have advanced rapidly from the hypothesis that vitamin D deficiency increases the risk of prostate cancer to intervention trials of vitamin D administration in clinical cancer. The hormonal form of vitamin D, 1,25(OH)(2)D, exerts prodifferentiating, antiproliferative, anti-invasive, and antimetastatic effects on prostate cells. Moreover, normal prostate cells synthesize 1,25(OH)(2)D from serum levels of the prohormone, 25-hydroxyvitamin D. The autocrine synthesis of 1,25(OH)(2)D by prostatic cells provides a biochemical mechanism whereby vitamin D may prevent prostate cancer. Many prostate cancer cells have lost the ability to synthesize 1,25(OH)(2)D but still possess 1,25(OH)(2)D receptors. This suggests that whereas vitamin D (e.g., cholecalciferol) might prevent prostate cancer, existing prostate tumors likely would require treatment with 1,25(OH)(2)D and/or its analogs. The major obstacle to the use of 1,25(OH)(2)D in patients therapeutically is the risk of hypercalcemia. Several maneuvers to reduce this risk, including pulse dosing and the use of less calcemic 1,25(OH)(2)D analogs, have been explored in Phase I-III clinical trials. Once merely a promise, vitamin D-based therapies for prostate cancer may soon be medical practice.     

Mechanisms Underlying the Regulation of Innate and Adaptive Immunity by Vitamin D

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.     

维生素D及衍生物治疗银屑病的研究现状

银屑病是一种常见的慢性复发性炎症性皮肤病,全球大约2.5％的人群罹患此病.紫外线光疗是治疗方法之一,可促使表皮产生1,25(OH)2D.维生素D活性代谢产物1,25(OH)2D及其衍生物通过其细胞核受体即维生素D受体发挥重要的生理作用,除了经典的调节钙、磷代谢外,1,25(OH)2D及其衍生物抗增殖及促分化的免疫调节作用正在被逐渐认识.它可能通过调节皮肤局部的免疫反应、抑制角质细胞的增殖并诱导分化从而有效地治疗银屑病.因此,进一步了解维生素D及衍生物在银屑病中的作用机制,对于更有效地治疗银屑病具有重要的意义.     

纯母乳喂养小婴儿及其母亲维生素D水平相关性研究

目的 分析出生28~42 d出现佝偻病临床表现的纯母乳喂养儿的血清维生素D水平及与其母亲血维生素D水平的相关性,为预防婴儿早期营养性佝偻病的发生提供理论依据。方法 对2016年4月-2017年10月来西北妇女儿童医院儿童保健科正常体检的年龄为28~42 d、并且表现有佝偻病早期症状和(或)体征的119例纯母乳喂养儿及其母亲静脉血25-羟维生素D[25-(OH)D]进行相关性分析。结果 119例母亲血25-(OH)D＞30 ng/ml者15例(12.61%),≤30 ng/ml者104例(87.39%);孕期平均每日补充维生素D≥400 U的母亲19例,血25-(OH)D中位数为28.8 ng/ml,每日补充维生素D＜400 U母亲100例,血25-(OH)D中位数为16.1 ng/ml,两组血25-(OH)D差异有统计学意义(P<0.05);在119例婴儿中补充和未补充维生素D组的婴儿血25-(OH)D中位数分别为20.0 ng/ml和9.5 ng/ml,两者差异有统计学意义(P<0.05);婴儿血25-(OH)D与其母亲血清25-(OH)D水平呈正相关(r=0.349,P<0.01)。婴儿血25-(OH)D水平(＞20 ng/ml和≤20 ng/ml)与其出现佝偻病的症状、体征之间无统计学意义。结论 婴儿及其母亲维生素D整体处于不足水平,两者之间维生素D水平存在相关性。婴儿血25-(OH)D＞20 ng/ml并没有降低其发生营养性佝偻病的风险。建议母亲孕期应积极补充维生素D,同时提倡从新生儿一出生即开始补充维生素D,预防婴儿早期营养性佝偻病的发生。     

Vitamin D in pregnancy and lactation: maternal, fetal, and neonatal outcomes from human and animal studies

During pregnancy and lactation, mothers require significant amounts of calcium to pass on to the developing fetus and suckling neonate, respectively. Given the dependence of adult calcium concentrations and bone metabolism on vitamin D, one might anticipate that vitamin D sufficiency would be even more critical during pregnancy and lactation. However, maternal adaptations during pregnancy and lactation and fetal adaptations provide the necessary calcium relatively independently of vitamin D status. It is the vitamin D-deficient or insufficient neonate who is at risk of problems, including hypocalcemia and rickets. Due to poor penetrance of vitamin D and 25-hydroxyvitamin D [25(OH)D] into milk, exclusively breastfed infants are at higher risk of vitamin D deficiency than are formula-fed infants. Dosing recommendations for women during pregnancy and lactation might be best directed toward ensuring that the neonate is vitamin D-sufficient and that this sufficiency is maintained during infancy and beyond. A dose of vitamin D that provides 25(OH)D sufficiency in the mother during pregnancy should provide normal cord blood concentrations of 25(OH)D. Research has shown that during lactation, supplements administered directly to the infant can easily achieve vitamin D sufficiency; the mother needs much higher doses (100 mug or 4000 IU per day) to achieve adult-normal 25(OH)D concentrations in her exclusively breastfed infant. In addition, the relation (if any) of vitamin D insufficiency in the fetus or neonate to long-term nonskeletal outcomes such as type 1 diabetes and other chronic diseases needs to be investigated.     

Role of Vitamin D in Cognitive Dysfunction: New Molecular Concepts and Discrepancies between Animal and Human Findings

Purpose of review: increasing evidence suggests that besides the several metabolic, endocrine, and immune functions of 1alpha,25-dihydroxyvitamin D (1,25(OH)2D), the neuronal effects of 1,25(OH)2D should also be considered an essential contributor to the development of cognition in the early years and its maintenance in aging. The developmental disabilities induced by vitamin D deficiency (VDD) include neurological disorders (e.g., attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia) characterized by cognitive dysfunction. On the other hand, VDD has frequently been associated with dementia of aging and neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s disease). Recent findings: various cells (i.e., neurons, astrocytes, and microglia) within the central nervous system (CNS) express vitamin D receptors (VDR). Moreover, some of them are capable of synthesizing and catabolizing 1,25(OH)2D via 25-hydroxyvitamin D 1alpha-hydroxylase (CYP27B1) and 25-hydroxyvitamin D 24-hydroxylase (CYP24A1) enzymes, respectively. Both 1,25(OH)2D and 25-hydroxyvitamin D were determined from different areas of the brain and their uneven distribution suggests that vitamin D signaling might have a paracrine or autocrine nature in the CNS. Although both cholecalciferol and 25-hydroxyvitamin D pass the blood–brain barrier, the influence of supplementation has not yet demonstrated to have a direct impact on neuronal functions. So, this review summarizes the existing evidence for the action of vitamin D on cognitive function in animal models and humans and discusses the possible pitfalls of therapeutic clinical translation.     

新生儿脐血维生素D水平与IgE水平的相关性研究

目的 了解新生儿脐血维生素D水平及其与IgE水平的相关性。方法 测定185名新生儿脐血25-羟维生素D[25(OH)D]及总IgE值;采用问卷调查形式收集孕妇的健康状况及新生儿出生史;跟踪随访新生儿一年,了解其在随访期限内过敏性疾病发作情况。结果 新生儿脐血25(OH)D平均浓度为(49.63±16.56)nmol/L,中位数49.50nmol/L;脐血总IgE平均水平为(513.85±116.54)U/L;随访期限内共有38名婴儿有过敏状况发生;过敏组新生儿脐血25(OH)D水平(38.88±12.33)nmol/L,非过敏组新生儿脐血25(OH)D水平(52.41±16.41)nmol/L,两组对比差异有统计学意义(P<0.05);过敏组新生儿脐血IgE水平为(574.13±109.86)U/L,非过敏组新生儿脐血IgE水平(498.27±113.44)U/L,两组对比差异有统计学意义(P<0.05);采用多因素方差分析表明,家族过敏史与出生时脐血25(OH)D水平对脐血IgE水平产生影响(P<0.05);回归分析表明脐血25(OH)D水平与脐血IgE水平呈线性负相关(r²=0.576,P<0.05)。结论 脐血维生素D水平与IgE水平呈负相关,脐血维生素D水平的降低可能是生后一年内婴儿过敏症发生的危险因素。     

Vitamin D for the prevention of preeclampsia? A hypothesis

Preeclampsia has been suggested to result from a partial breakdown of tolerance to the developing fetus after maternal immune maladaptation. Several of the proposed immunomodulatory properties of the hormonal vitamin D system could potentially have beneficial effects for successful maintenance of pregnancy. Preeclampsia is characterized by marked changes in vitamin D metabolism. This paper reviews the evidence suggesting that the immunomodulatory properties of 1,25(OH)2D may play a key role in maintaining immunological tolerance in pregnancy, and proposes that ensuring adequate vitamin D status/intake may help in the prevention and management of preeclampsia.