Vitamin D Sensitivity Symptoms
Immunol Allergy Clin North Am. Author manuscript; available in PMC 2011 Aug 1.
Published in final edited form as:
PMCID: PMC2914320
NIHMSID: NIHMS223621
Vitamin D in Atopic Dermatitis, Asthma and Allergic Diseases
Daniel A Searing
aFellow, Department of Pediatrics, Division of Pediatric Allergy and Immunology, National Jewish Health, Denver, Colorado
Donald YM Leung
bHead, Division of Pediatric Allergy and Immunology, National Jewish Health, Denver, Colorado
cProfessor, Department of Pediatrics, University of Colorado Denver, Denver, Colorado
See other articles in PMC that cite the published article.
Synopsis
This review examines the scientific evidence behind the hypothesis that vitamin D plays a role in the pathogenesis of allergic diseases, with a particular focus on emerging data regarding vitamin D and atopic dermatitis. Both elucidated molecular interactions of vitamin D with components of the immune system, as well as clinical data regarding vitamin D deficiency and atopic diseases are discussed. The rationale behind the "sunshine hypothesis," laboratory evidence supporting links between vitamin D deficiency and allergic diseases, the clinical evidence for/and against vitamin D playing a role in allergic diseases, and the emerging evidence regarding the potential use of vitamin D in augmentation of the innate immune response in atopic dermatitis are reviewed.
Keywords: Vitamin D, atopic dermatitis, asthma, allergy
Introduction
Observations by Palm in 1890 and Sniadecki in 1922 of the lower prevalence of rickets in equatorial and rural populations respectively prompted both investigators to hypothesize that sun exposure was the reason for such a difference [1-3]. Subsequent work by Mellanby established cod liver oil as a cure for dogs with rickets [4] and experiments by McCollum demonstrated the existence of a vitamin within cod liver oil [5]. Both cod liver oil and sunlight exposure became known as treatment modalities for rickets. Foods containing cholesterol that were irradiated with light were also shown to cure rickets. Windhaus and colleagues subsequently discovered a cholesterol precursor, 7-dehydrocholesterol (7-DHC). Their Nobel Prize winning work showed that irradiation of 7-DHC with UV light induced formation of vitamin D3 [1,6].
Humans receive at least 80% of their vitamin D through UV induced skin production [7, 8]. According to the Environmental Protection Agency's National Human Activity Pattern Survey (NHAPS), 95% of Americans work indoors [9]. In addition, Americans spend only 10% of available daylight hours outside. One recent study found that during their time outdoors, Americans are exposed to 30% of the available ambient UV light secondary to conditions such as shade [9]. A similar study again using NHAPS data found that children and adolescents spend the same amount of time outside as adults (10% of the day). However, adolescents receive the lowest UV dose of any group [10]. Furthermore, the use of sunscreen with a sun protection factor of eight decreases cutaneous vitamin D production by 97.5% [7].
Data from the National Health and Nutrition Examination Survey (NHANES) from 2001-2004 has shown that, overall, sufficient levels of vitamin D were present in less than a quarter of the adolescent and adult U.S. population studied [11]. More recently, NHANES data looking at children found that 61% of subjects aged 1-21 years were vitamin D insufficient [12]. However, there are potential issues with the validity of the assay utilized for vitamin D data from NHANES. According to the Center for Disease Control and Prevention website, 25-hydroxyvitamin D (the main indicator of the body's vitamin D status as discussed below) data from the 2000-06 NHANES was likely affected by drifts in the assay performance over time [13]. In a group of patients ages 0-18 years with asthma, atopic dermatitis, and/or food allergy, our group has noted 48% of patients with insufficient (<30 ng/mL) levels of serum 25-hydroxyvitamin D (also referred to as 25(OH)D in the literature and referred to as just vitamin D hereafter unless being discussed in the context of metabolism) [14].
Data in adults suggests vitamin D levels less than approximately 30 ng/mL are associated with changes in parathyroid hormone levels, as well as intestinal calcium transport [8]. This has led some to argue that vitamin D levels between 20-30 ng/mL be considered vitamin D insufficient, although no consensus on optimal vitamin D levels exists [8]. A recent clinical report from the American Academy of Pediatrics changed the recommended dosage of vitamin D from 200 to 400 IU per day for all children (infants through adolescents) [15]. Typically, infant and child multivitamin and vitamin D preparations contain 400 IU per dose of vitamin D in either D2 or D3 form (see below). The report cites information from adult studies that have helped create the concept of serum vitamin D insufficiency. The Food and Nutrition Board has convened an expert committee to revisit the dietary reference intake for vitamin D and its report is expected to be released in May of 2010 [16]. Despite these new recommendations, there is concern that intake of 400 IU per day of vitamin D remains inadequate to promote sufficient levels of vitamin D and that the tolerable upper intake level of vitamin D can safely be increased [17]. Graded oral dosing of adults demonstrated that an eight-week course of 400 IU per day of vitamin D3 raises the serum vitamin D concentration by only 4.4 ng/mL [18].
While the relationship of vitamin D deficiency and rickets is well established, only more recently has the role of vitamin D deficiency and insufficiency in allergic disease been debated. Prior to allergic disease entering the debate, epidemiologic research has described links between vitamin D and cancer, type I diabetes, and multiple sclerosis [8, 19]. The International Study of Asthma and Allergies in Childhood (ISAAC) demonstrated the highest prevalence of asthma symptoms in countries such as the United Kingdom, Australia, New Zealand, and the Republic of Ireland [20]. This data helped form the foundation for the description that people living in more westernized, developed nations have higher reported rates of asthma, atopic dermatitis, and hay fever [21]. Studies in various Chinese cities with different socioeconomic profiles demonstrated the greatest amount of asthma and allergic symptoms in Hong Kong, the most westernized city studied [22]. Different authors have hypothesized that westernization, a lifestyle likely to be associated with greater time spent indoors, has fostered a propensity for vitamin D deficiency, which in turn has resulted in more asthma and allergy [19, 23]. The scientific evidence for this hypothesis will be reviewed.
Vitamin D Metabolism
Vitamin D enters the body through either the skin via cutaneous conversion of 7-DHC into pre-vitamin D3 or the gut via food and/or supplement ingestion (see Figure 1) [8]. 7-DHC is converted into pre-vitamin D3 by solar ultraviolet B radiation [8]. Sunlight also converts pre-vitamin D3 and/or vitamin D3 into inert products to prevent vitamin D intoxication [8]. Pre-vitamin D3 isomerizes to vitamin D3, is transferred to the dermal capillaries, and binds with vitamin D–binding protein (DBP) [24]. Ingested vitamin D utilizes chylomicrons and the lymphatic system for transportation to the circulation (Figure 1). Vitamin D from supplements can be ingested as either vitamin D2 (ergocalciferol) from plant derived sources or vitamin D3 (cholecalciferol) from animal derived sources. Vitamin D3 is used to fortify several foods (see Table 1) in the United States, although few foods are fortified with vitamin D in Europe [8]. Vitamin D is also contained naturally in several species of fish and cod liver oil [24] (Table 1).
Vitamin D Metabolism
Vitamin D is produced from 7-dehydrocholesterol in the skin or is ingested in the diet. It is converted in the liver into 25(OH)D, and in kidney into 1,25(OH)2D (1,25-dihydroxyvitamin D), the active form of the vitamin. 1,25(OH)2D stimulates the expression of RANKL, an important regulator of osteoclast maturation and function, on osteoblasts, and enhances the intestinal absorption of calcium and phosphorus in the intestine. DBP, vitamin d-binding protein (α1-globulin).
From Environmental and Nutritional Diseases. In: Kumar V, Abbas AK, Fausto N, Aster JC, editors. Robbins and Cotran Pathologic Basis of Disease, 8th ed. Philadelphia: Saunders/Elsevier; 2010. p. 434.
Table 1
Vitamin D Content of Foods
| Food | Amount | Vitamin D Content (IU) |
|---|---|---|
| Cod Liver Oil, 1 tablespoon | 1 tablespoon | 1,360 |
| Salmon, cooked, 3.5 ounces | 3.5 ounces | 360 |
| Mackerel, cooked, 3.5 ounces | 3.5 ounces | 345 |
| Sardines, canned in oil, drained | 1.75 ounces | 250 |
| Tuna Fish, canned in oil | 3 ounces | 200 |
| Milk, vitamin D-fortified | 1 cup | 98 |
| Margarine, fortified | 1 tablespoon | 60 |
| Ready-to-eat cereal, fortified with 10% of the DV for vitamin D | 0.75-1 cup | 40 |
| Egg, whole | one | 20 |
| Liver, beef | 3.5 ounces | 15 |
| Cheese, Swiss | 1 ounce | 12 |
Vitamin D3 (subsequently referred to as "D") complexed with DBP is transported to the liver and is converted to 25-hydroxyvitamin D or 25(OH)D. 25-hydroxyvitamin D is released into the circulation, binds again to DBP, and is transported to the kidney where it undergoes further hydroxylation by the enzyme 25-hydroxyvitamin D-1 α-hydroxylase (CYP27B1) to 1,25-dihydroxyvitamin D or 1,25(OH)2D (Figure 1). 25-hydroxyvitamin D levels are used to determine the body's vitamin D status as this form has a longer half-life (2-3 weeks) than 1,25-dihydroxyvitamin D (4 hours) [24]. 1,25-dihydroxyvitamin D is the active form of vitamin D. Parathyroid hormone, calcium, phosphorus, fibroblast growth factor 23, and 1,25-dihydroxyvitamin D itself all influence the levels of 1,25-dihydroxyvitamin D through a variety of mechanisms (Figure 1). Finally, the enzyme 25-hydroxyvitamin D-24-hydroxylase (CYP24) catabolizes both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D into biologically inactive, water-soluble calcitroic acid [8].
The Effects of Vitamin D on the Immune System
The scope of vitamin D's biological actions go beyond just calcium homeostasis and bone metabolism. The vitamin D receptor (VDR) was cloned in 1988 and shown to be a member of the nuclear receptor family [25]. VDR has been located in multiple tissues and cells in the human body, including peripheral blood mononuclear cells (PBMCs) and activated T lymphocytes [26]. VDRs are also located on dendritic cells (DCs), important antigen presenting cells [27, 28]. The enzyme responsible for the synthesis of 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D-1-α-hydroxylase, is located on macrophages and DCs [29]. 25-hydroxyvitamin D-24-hydroxylase, which degrades 1,25-dihydroxyvitamin D, is also found in monocytes and macrophages [30]. Normal T and B-lymphocytes have been shown to express the vitamin D receptor after activation with phytohemagglutinin and Ebstein-Barr virus [31].
Further research has demonstrated that Vitamin D has multiple cytokine modulating effects through several different cells of the immune system. Tsoukas and colleagues in showed that picomolar concentrations of 1,25-dihydroxyvitamin D decreased IL-2 activity and inhibited the proliferation of mitogen-activated lymphocytes [32]. Mahon and colleagues showed that quiescent CD4+ T cells, in addition to activated T cells, expressed VDRs [33]. Furthermore, 1,25-dihydroxyvitamin D decreased proliferation of both Th1 and Th2 cells, as well as lowered the production of IFN-γ, IL-2, and IL-5. In contrast, IL-4 production by Th2 cells was increased by 1,25-dihydroxyvitamin D [33]. Froicu and colleagues performed experiments with VDR knockout (KO) mice. In comparison to wild type (WT) mice, VDR KO mice produced more IFN-γ. However, VDR KO mice also produced less IL-2, IL-4, IL-5 than WT mice [34]. Boonstra et al demonstrated that vitamin D inhibits IFN-γ production and promotes IL-4, IL-5, and IL-10 production in a mouse model [35]. These studies suggest that deficiencies in vitamin D levels and/or signaling would favor a predominant Th1 response and that the presence of vitamin D, while suppressing Th1 effects, also promotes Th2 respones.
Evidence also exists that vitamin D plays an inhibitory role in Th2 responses. In a murine model of pulmonary eosinophilic inflammation, early treatment with vitamin D supported allergen-induced T-cell proliferation along with IL-4, IL-13, and IgE production. However, the bronchoalveolar lavage fluid and lung tissue had impaired recruitment of eosinophils and low levels of IL-5 [36]. A study by Pichler and colleagues looked at the effects of 1,25-dihydroxyvitamin D on naïve CD4+ T helper and CD8+ cytotoxic T cells from human cord cell cultures. They found that 1,25-dihydroxyvitamin D had inhibitory effects in the naïve cells on IFN-γ production induced by IL-12, as well as IL-4 and IL-13 production induced by IL-4 [37]. This would suggest that vitamin D also helps blunt the Th2 response. Whether or not vitamin D favors a shift in the helper T cell balance toward Th1 versus Th2 dominance remains unclear. These variable results may be secondary to differences in the absolute amount of vitamin D exposure, the baseline vitamin D status (deficiency vs insufficiency vs sufficiency), and the timing of exposure (naïve versus mature cell lines). More likely, at pharmacologic levels, vitamin D may inhibit both Th1 and Th2 cell activation. Whether these known immune effects have translated into significant relationships between vitamin D levels and allergies, asthma, and atopic dermatitis is discussed below.
Vitamin D and Allergy
Several large birth cohort studies have examined the relationship between infant vitamin D supplementation and subsequent development of allergy and asthma. One study looked at a segment of the Northern Finland Birth Cohort from 1966 in which infants were supplemented with vitamin D in the first year of life. Mothers reported the frequency and dose of vitamin D supplementation and the daily dose of vitamin D was calculated based on this information. 83% of the subjects received 50 μg/day (2,000 IU/day) of vitamin D [38]. Subjects received several follow-ups, including at 31 years of age where the presence of asthma and atopy was assessed. After adjustment for social factors, the prevalence of atopy and allergic rhinitis at age 31 was higher in subjects who received vitamin D supplementation as infants [38]. Another prospective birth cohort of over 4,000 infants in whom 98% were supplemented with vitamin A and D (400 IU/day of vitamin D) in either a water-soluble or peanut oil form showed that infants who received water-soluble supplements had a greater risk of asthma, food hypersensitivity, and aeroallergen sensitization at age 4 than infants given peanut oil based supplements [39]. No significant associations were seen for eczema or allergic rhinitis [39]. However, additional prospective work looking at maternal vitamin D dietary intake during pregnancy by Camargo and colleagues demonstrated that women in the highest quartile of vitamin D intake had a lower risk of having a child with recurrent wheeze at 3 years of age [23]. These results may indicate that the timing of intervention in vitamin D levels may factor in subsequent allergic disease. An alternative explanation is that different absolute amounts of vitamin D have alternate physiologic effects on allergic pathogenesis. Furthermore, although beyond the scope of this review, vitamin D may also affect the body's susceptibility and response to infectious organisms, a major trigger of wheezing at a young age. The topic of vitamin D and infection in the setting of asthma has been reviewed elsewhere [40].
Several surrogate markers of vitamin D deficiency have been evaluated in the context of allergy and asthma prevalence. People living at higher latitudes are known to be at greater risk for vitamin D deficiency [24]. A review of 166 pediatric cases of clinical rickets from 1986 to 2003 commented that in the 5 studies involving rickets in white children, all involved subjects were from northern states [41]. People who live at northern latitudes above 35° are unable to synthesize vitamin D from November through February [8]. Given the variations in latitude in the United States that may contribute to differences in sun exposure, the potential exists to compare populations in various geographic environments with respect to allergic disease. An exploratory study on surrogate markers for vitamin D and EpiPen/EpiPen Jr (Dey, Napa, Calif) prescriptions revealed that states in the New England region had a higher prescription rate than southern states after controlling for socioeconmic factors [42]. A surrogate marker of sunshine exposure, melanoma incidence, was inversely correlated with EpiPen prescription rate, although average temperature and average precipitation were not [42]. An inverse relationship exists between body mass index and vitamin D status secondary to decreased bioavailability [8]. Prevalence of allergic disease in patients who underwent routine vitamin D screening as part of their care at an obesity clinic showed no association between vitamin D status and the prevalence of asthma or allergic rhinitis [43]. However, patients with vitamin D deficiency were more likely to report atopic dermatitis [43].
Vitamin D and Asthma
Of the different disorders associated with allergic inflammation, perhaps asthma has been the most closely examined in the context of vitamin D. Consistent with prior sections, evidence exists both in support and against vitamin D deficiency contributing to the asthma epidemic. Extensive reviews of both sides of the argument have been published previously [19, 44].
Experimental models of asthma have been utilized to help test the vitamin D hypothesis. As mentioned previously, vitamin D has been shown in a murine model of eosinophilic inflammation to induce impaired recruitment of eosinophils and reduce levels of IL-5 [36]. Data is also emerging that vitamin D effects glucocorticoid signaling pathyways. Xystrakis and colleagues reported that the addition of vitamin D and dexamethasone to cultures of CD4+ T regulatory cells from steroid resistant asthmatics enhanced IL-10 secretion from these cells to levels comparable from cells of steroid sensitive patients treated with dexamethasone alone [45]. Zhang and colleagues have also demonstrated that vitamin D enhances dexamethasone-induced MAP kinase phosphatase-1 (MKP-1) expression in peripheral blood mononuclear cells [46], a pathway by which glucocorticoids exert their anti-inflammatory effects. In patients referred to our institution with asthma, we have noted that serum vitamin D levels are inversely correlated with corticosteroid usage [14]. These laboratory and clinical observations raise the question of vitamin D supplementation potentially having a steroid sparing effect in asthma.
While the studies mentioned in the prior paragraph suggest a supportive role for vitamin D in asthma control, some experiments in KO mice do not support this association. Experimental allergic asthma induction was performed by Wittke and colleagues in VDR KO and WT mice. The WT mice developed asthma, as expected. However, VDR KO mice failed to develop asthma after allergen induction. The administration of 1,25-dihydroxyvitamin D to WT mice had no effect on asthma severity, but did increase expression of two Th2-related genes [47]. Some studies have described an association between VDR genetic polymorphisms and asthma, but this has not been replicated in subsequent experiments [19].
Several clinical studies exist supporting a positive relationship between vitamin D status and asthma (see Table 2). An analysis of over 14,000 patients age 20 and above using the NHANES database between 1988-1994 showed that subjects whose vitamin D level was in the highest quintile had significantly higher FEV1 and FVC [48]. A recent paper on children with asthma from Costa Rica showed a significant association between rising vitamin D levels and reduced use of antiinflammatory medication in the previous year [49].
Table 2
Summary data on Vitamin D and Asthma and/or Recurrent Wheeze
| Investigator | Population Studied | Results | Reference |
|---|---|---|---|
| Black et al. | >14,000 adults using the NHANES database | ↑FEV1 and ↑FVC in subjects whose vitamin D level was in the highest quintile | 48 |
| Brehm et al. | Asthmatic children from Costa Rica | Log10 ↑ in vitamin D level associated with ↓hospitalizations, ↓antiinflammatory medication, and ↓markers of allergy | 49 |
| Camargo et al. | Mother-child pre-birth cohort | Mothers in highest quartile of vitamin D intake had lower risk for child at age 3 with recurrent wheeze | 23 |
| Devereux et al. | Mother-child pre-birth cohort | Mothers in highest quintile of vitamin D intake had lower risk for child at age 5 to have ever wheezed, wheezing in the previous year, and persistent wheezing. No association of vitamin D levels with asthma, spirometry, or atopic sensitization. | 50 |
| Gale et al. | Mother-child pre-birth cohort | Maternal 25(OH)D concentrations above 30 ng/mL associated with an ↑risk of eczema at 9 months and ↑risk of asthma at 9 years | 51 |
Conflicting data exists on the influence of maternal vitamin D status and subsequent development of asthma. As mentioned previously, maternal intake of vitamin D has been associated with lower prevalence of wheezing at 3 years of age [23]. Another birth cohort from Scotland with information on maternal vitamin D intake had outcome measures analyzed at 5 years of age. The highest quintiles of maternal vitamin D intake were associated with reduced risk for ever wheezing, wheezing in the previous year, and persistent wheezing at ages 2 and 5 [50]. Associations were independent of the children's vitamin D intake. Interestingly, despite the wheezing associations, maternal vitamin D intake was not associated with asthma at age 5. In addition, maternal vitamin D intake was not associated with lower spirometry values or atopic sensitization [50]. A group of children from the United Kingdom were followed prospectively after vitamin D levels from their mothers were collected during pregnancy. The investigators found an increased risk of eczema at 9 months and asthma at 9 years in children whose mother's had a vitamin D level >75 nmol/L (>30 ng/mL), although only 30% of patients were available for follow up at 9 years [51].
Vitamin D and Atopic Dermatitis
A large amount of data has emerged regarding the molecular effects of vitamin D in the skin. VDR expression in the skin was first confirmed after rats injected with radio-labeled 1,25-dihydroxyvitamin D demonstrated radioactivity concentrated in the nuclei of the epidermis along with a variety of other tissues [52]. 1,25-dihydroxyvitamin D has been shown to enhance keratinocyte differentiation, as well as have either stimulatory or suppressive effects on keratinocyte growth that is concentration dependent [53]. VDR expression on keratinocytes appears to be present only in proliferating cells and consequently, the basal keratinocyte is the main VDR containing cell in the epidermis. Variable VDR expression based on the proliferating and differentiating state of the keratinocyte, as well as local cytokine-mediated interactions may provide an explanation for vitamin D's observed inhibitory effects in psoriatic skin and proliferative effects in normal skin [53]. Vitamin D has been shown to increase synthesis of PDGF promoting wound healing, and TNFα promoting keratinocyte differentiation [54, 55]. Decreased synthesis of IL-1α, IL-6, and RANTES secondary to vitamin D has resulted in decreased inflammation in epidermal keratinocytes [56-58]. Both the enzyme responsible for the intial hydroxylation of vitamin D to 25-hydroxyvitamin D, as well as the enzyme responsible for the conversion of 25-hydroxyvitamin D into active CYP27B1 are found in keratinocytes [59]. Vitamin D has also been demonstrated to have a beneficial effect on the permeability barrier in the epidermis. Bikle and colleagues studied mice null for the expression of 25-hydroxyvitamin D-1α-hydroxylase (1OHase). Lower levels of multiple proteins necessary for formation of the stratum corneum, including filaggrin, were lower in the null mice compared to the wild-type controls [60]. Following tape disruption, null mice had a significantly delayed barrier recovery compared to wild type mice [60].
As mentioned previously, VDRs are located on macrophages and DCs, as is CYP27B1. 1,25-dihydroxyvitamin D has been shown to have inhibitory effects on the differentiation of DCs [28]. In vitro treatment of DCs with vitamin D leads to decreased IL-12 and enhanced IL-10. These cytokine effects, along with inhibitory effects on DC maturation, promote tolerogenic properties and suppressor T cell induction [28]. A short treatment course of 1,25-dihydroxyvitamin D in mice induced tolerogenic DCs and increased T regulatory cells [61].
The pathogenesis of atopic dermatitis involves both epidermal barrier and immunologic dysfunction. Atopic dermatitis patients can have defects of both the permeability barrier and the antimicrobial barrier of the stratum corneum [62]. The permeability barrier consists of hydrophobic lipids that percolate the extracellular environment of the stratum cornuem and prevent water loss into the outside environment [62]. Overactivity of serine proteases secondary to genetic defects, such as filaggrin and environmental stimuli, such as alkaline soaps, promotes reduction of hydration and extracellular lipids in the stratum corneum, introduction of antigens, and promotion of inflammation [62]. Loss of function mutations in the gene encoding filaggrin (FLG, located on chromosome 1q21 in a locus termed the epidermal differentiation complex) are associated with atopic dermatitis [63] (see also article by Irvine and O'Carrol in this issue). Population based studies in European children show a 3-fold increased risk for atopic dermatitis in subjects with FLG variants and 18 to 48% of patients with atopic dermatitis carry a FLG null allele [64].
An important part of the antimicrobial barrier are antimicrobial peptides (AMPs). AMPs are secreted on the surface of the skin as a first-line defense against infection. The release of AMPs can be triggered by toll-like receptors (TLRs). AMPs are secreted by many different cells in the skin, including keratinocytes and mast cells. Aside from their antimicrobial properties, they are thought to play a role in immune system signaling [65]. Cathelicidin is one of the most well known AMPs. Cathelicidin deficiency in the skin is known to be associated with atopic dermatitis. Ong et al, demonstrated significantly decreased immunostaining for cathelicidins in acute and chronic atopic dermatitis lesions compared to psoriatic skin lesions [66]. This finding supports the differences in skin infections between patient with these two diseases. Amongst patients with atopic dermatitis, those with a history of herpes simplex virus (HSV) superinfection have significantly lower cathelicidin levels [67]. Antiviral assays have shown that cathelicidin has activity against HSV [67]. Skin from cathelicidin deficient mice has also been shown to have reduced ability to limit vaccinia virus proliferation [68]. A mulitcenter study to determine phenotypes associated with eczema herpeticum (ADEH) showed that ADEH patients were more likely to experience cutaneous skin infections and have more Th2 polarized disease [69].
Vitamin D has been shown to have a significant role in cathelicidin expression in the skin [65]. Wang and colleagues demonstrated that promoters of cathelicidin and beta2 defensin (another AMP) genes contain consensus vitamin D response elements and that 1,25-dihydroxyvitamin D promotes antimicrobial peptide gene expression [70]. Liu and colleagues reported that activation of toll-like receptors by M. tuberculosis–derived lipopeptide resulted in increased expression of both VDR, as well as CYP27B1 (the enzyme responsible for conversion of vitamin D into the active form) causing cathelicidin induction [71]. Therefore, it has been proposed that skin infection or injury leads to activation of CYP27B1 and upregulated VDR expression, which in turn leads to increased production of activated vitamin D and antimicrobial peptides [65, 71].
Given the potential for vitamin D to suppress inflammatory responses, enhance antimicrobial peptide activity, and promote the integrity of the permeability barrier, supplementation provides a possible therapeutic intervention for a variety of skin disorders, including atopic dermatitis. In a sample of 14 patients with moderate to severe atopic dermatitis who received 4,000 IU/day of vitamin D3 for 21 days, biopsied lesional skin showed a significant increase in cathelicidin expression [72]. A double-blind randomized controlled trial in children with winter-related atopic dermatitis (primarily mild) was performed utilizing a regimen of 1,000 IU/day of vitamin D for one month during the winter. Five subjects received supplementation versus placebo in six subjects. Baseline changes in global assessments of skin showed that the vitamin D treatment group had a significant improvement in baseline score compared to placebo [73]. Future trials involving larger sample sizes and longer treatment periods will be necessary to more fully assess vitamin D as a therapeutic strategy in atopic dermatitis.
Summary
Vitamin D insufficiency data is expanding to include evidence on its role in asthma, allergic disorders, and atopic dermatitis. In addition to its well-documented relationship with rickets and bone metabolism, vitamin D is now recognized as an immunomodulator. However, conflicting data exists with respect to the role of vitamin D in the pathogenesis of allergic diseases. Future research on vitamin D supplementation will help determine if the sunshine vitamin can serve as an adjuvant treatment for asthma and atopic dermatitis.
Acknowledgments
This work is supported by NIH Grants AR 41256 and N01 AI 40029
Abbreviations
| 1OHase | 25-hydroxyvitamin D-1α-hydroxylase |
| 25(OH)D | serum 25-hydroxyvitamin D |
| 7-DHC | 7-dehydrocholesterol |
| ADEH | eczema herpeticum |
| AMPs | antimicrobial peptides |
| CYP24 | enzyme 25-hydroxyvitamin D-24-hydroxylase |
| CYP27B1 | enzyme 25-hydroxyvitamin D-1α-hydroxylase |
| D | vitamin D3 |
| DBP | vitamin D–binding protein |
| DCs | dendritic cells |
| HSV | herpes simplex virus |
| ISAAC | International Study of Asthma and Allergies in Childhood |
| KO | knockout |
| MKP-1 | MAP kinase phosphatase-1 |
| NHAPS | EPA's National Human Activity Pattern Survey |
| PBMC | peripheral blood mononuclear cells |
| TLRs | toll-like receptors |
| VDR | vitamin D receptor |
| WT | wild type mice |
Footnotes
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References
1. Mohr SB. A brief history of vitamin D and cancer prevention. Ann Epidemiol. 2009;19(2):79–83. [PubMed] [Google Scholar]
2. Palm T. The geographical distribution and etiology of rickets. The Practioner. 1890;45(270–9):321–42. [Google Scholar]
3. Mozolowski W, Sniadecki J. On the cure of rickets. Nature. 1939;143:121. [Google Scholar]
4. Mellanby T. The part played by an 'accessory factor' in the production of experimental rickets. J Physiol. 1918;52:11–4. [Google Scholar]
5. McCollum EV, Simmonds N, Becker JE, Shipley PG. Studies on experimental rickets. XXI. An experimental demonstration of the existence of a vitamin which promotes calcium deposition. J Biol Chem. 1922;53:293–312. [PubMed] [Google Scholar]
6. Windaus A, Schenck F, von Werder F. On the antirachitic active irradiation product from 7-dehydrocholesterol. Physiol Chem. 1936;241:100–3. [Google Scholar]
7. Holick M. Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health. Curr Opin Endocrinol Diab. 2002;9(1):87–98. [Google Scholar]
8. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266–81. [PubMed] [Google Scholar]
9. Godar DE, Wengraitis SP, Shreffler J, Sliney DH. UV doses of Americans. Photochem Photobiol. 2001;73(6):621–9. [PubMed] [Google Scholar]
10. Godar DE. UV doses of American children and adolescents. Photochem Photobiol. 2001;74(6):787–93. [PubMed] [Google Scholar]
11. Ginde AA, Liu MC, Camargo CA., Jr. Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch Intern Med. 2009;169(6):626–32. [PMC free article] [PubMed] [Google Scholar]
12. Kumar J, Muntner P, Kaskel FJ, Hailpern SM, Melamed ML. Prevalence and associations of 25-hydroxyvitamin D deficiency in US children: NHANES 2001-2004. Pediatrics. 2009;124:e362–e70. [PMC free article] [PubMed] [Google Scholar]
14. Searing DA, Murphy J, Hauk P, et al. Vitamin D levels in children with asthma, atopic dermatitis, and food allergy. J Allergy Clin Immunol. 2010 in press. [PMC free article] [PubMed] [Google Scholar]
15. Wagner CL, Greer FR. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics. 2008;122(5):1142–52. [PubMed] [Google Scholar]
17. Vieth R, Bischoff-Ferrari H, Boucher BJ, et al. The urgent need to recommend an intake of vitamin D that is effective. Am J Clin Nutr. 2007;85(3):649–50. [PubMed] [Google Scholar]
18. Barger-Lux MJ, Heaney RP, Dowell S, Chen TC, Holick MF. Vitamin D and its major metabolites: serum levels after graded oral dosing in healthy men. Osteoporos Int. 1998;8(3):222–30. [PubMed] [Google Scholar]
19. Litonjua AA, Weiss ST. Is vitamin D deficiency to blame for the asthma epidemic? J Allergy Clin Immunol. 2007;120(5):1031–5. [PubMed] [Google Scholar]
20. Asher M, ISAAC Worldwide variations in the prevalence of asthma symptoms: the International Study of Asthma and Allergies in Childhood (ISAAC) Eur Respir J. 1998;12(2):315–35. [PubMed] [Google Scholar]
21. Von Mutius E, Leung DYM, Sampson HA, Geha RS, Szefler SJ. Pediatric Allergy Principles and Practice. St. Louis; Mosby: 2003. Epidemiology of allergic disease. [Google Scholar]
22. Zhao T, Wang HJ, Chen Y, et al. Prevalence of childhood asthma, allergic rhinitis and eczema in Urumqi and Beijing. J Paediatr Child Health. 2000;36(2):128–33. [PubMed] [Google Scholar]
23. Camargo CA, Jr., Rifas-Shiman SL, Litonjua AA, et al. Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age. Am J Clin Nutr. 2007;85(3):788–95. [PMC free article] [PubMed] [Google Scholar]
24. Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics. 2008;122(2):398–417. [PubMed] [Google Scholar]
25. Baker AR, McDonnell DP, Hughes M, et al. Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci U S A. 1988;85(10):3294–8. [PMC free article] [PubMed] [Google Scholar]
26. Bhalla AK, Amento EP, Clemens TL, Holick MF, Krane SM. Specific high-affinity receptors for 1,25-dihydroxyvitamin D3 in human peripheral blood mononuclear cells: presence in monocytes and induction in T lymphocytes following activation. J Clin Endocrinol Metab. 1983;57(6):1308–10. [PubMed] [Google Scholar]
27. Brennan A, Katz DR, Nunn JD, et al. Dendritic cells from human tissues express receptors for the immunoregulatory vitamin D3 metabolite, dihydroxycholecalciferol. Immunology. 1987;61(4):457–61. [PMC free article] [PubMed] [Google Scholar]
28. Adorini L, Penna G, Giarratana N, et al. Dendritic cells as key targets for immunomodulation by Vitamin D receptor ligands. J Steroid Biochem Mol Biol. 2004;89-90(1-5):437–41. [PubMed] [Google Scholar]
29. Adams JS, Gacad MA. Characterization of 1 alpha-hydroxylation of vitamin D3 sterols by cultured alveolar macrophages from patients with sarcoidosis. J Exp Med. 1985;161(4):755–65. [PMC free article] [PubMed] [Google Scholar]
30. Chen KS, DeLuca HF. Cloning of the human 1 alpha,25-dihydroxyvitamin D-3 24-hydroxylase gene promoter and identification of two vitamin D-responsive elements. Biochim Biophys Acta. 1995;1263(1):1–9. [PubMed] [Google Scholar]
31. Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC. 1,25-dihydroxyvitamin D3 receptors in human leukocytes. Science. 1983;221(4616):1181–3. [PubMed] [Google Scholar]
32. Tsoukas CD, Provvedini DM, Manolagas SC. 1,25-dihydroxyvitamin D3: a novel immunoregulatory hormone. Science. 1984;224(4656):1438–40. [PubMed] [Google Scholar]
33. Mahon BD, Wittke A, Weaver V, Cantorna MT. The targets of vitamin D depend on the differentiation and activation status of CD4 positive T cells. J Cell Biochem. 2003;89(5):922–32. [PubMed] [Google Scholar]
34. Froicu M, Weaver V, Wynn TA, et al. A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases. Mol Endocrinol. 2003;17(12):2386–92. [PubMed] [Google Scholar]
35. Boonstra A, Barrat FJ, Crain C, et al. 1alpha, 25-Dihydroxyvitamin D3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol. 2001;167(9):4974–80. [PubMed] [Google Scholar]
36. Matheu V, Back O, Mondoc E, EIssazadeh-Navikas S. Dual effects of vitamin D-induced alteration of TH1/TH2 cytokine expression: enhancing IgE production and decreasing airway eosinophilia in murine allergic airway disease. J Allergy Clin Immunol. 2003;112(3):585–92. [PubMed] [Google Scholar]
37. Pichler J, Gerstmayr M, Szepfalusi Z, et al. 1 alpha, 25(OH)2D3 inhibits not only Th1 but also Th2 differentiation in human cord blood T cells. Pediatr Res. 2002;52(1):12–8. [PubMed] [Google Scholar]
38. Hypponen E, Sovio U, Wjst M, et al. Infant vitamin D supplementation and allergic conditions in adulthood: northern Finland birth cohort 1966. Ann N Y Acad Sci. 2004;1037:84–95. [PubMed] [Google Scholar]
39. Kull I, Bergstrom A, Melen E, et al. Early-life supplementation of vitamins A and D, in water-soluble form or in peanut oil, and allergic diseases during childhood. J Allergy Clin Immunol. 2006;118(6):1299–304. [PubMed] [Google Scholar]
40. Ginde AA, Mansbach JM, Camargo CA., Jr. Vitamin D, respiratory infections, and asthma. Curr Allergy Asthma Rep. 2009;9(1):81–7. [PubMed] [Google Scholar]
41. Weisberg P, Scanlon KS, Li R, Cogswell ME. Nutritional rickets among children in the United States: review of cases reported between 1986 and 2003. Am J Clin Nutr. 2004;80(6 Suppl):1697S–705S. [PubMed] [Google Scholar]
42. Camargo CA, Jr., Clark S, Kaplan MS, Lieberman P, Wood RA. Regional differences in EpiPen prescriptions in the United States: the potential role of vitamin D. J Allergy Clin Immunol. 2007;120(1):131–6. [PubMed] [Google Scholar]
43. Oren E, Banerji A, Camargo CA., Jr. Vitamin D and atopic disorders in an obese population screened for vitamin D deficiency. J Allergy Clin Immunol. 2008;121(2):533–4. [PubMed] [Google Scholar]
44. Wjst M. The vitamin D slant on allergy. Pediatr Allergy Immunol. 2006;17(7):477–83. [PubMed] [Google Scholar]
45. Xystrakis E, Kusumakar S, Boswell S, et al. Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest. 2006;116(1):146–55. [PMC free article] [PubMed] [Google Scholar]
46. Zhang Y, Goleva E, Leung DY. Vitamin D enhances glucocorticoid-induced mitogen-activated protein kinase phosphatase-1 (MKP-1) expression and their anti-proliferative effect in peripheral blood mononuclear cells. J Allergy Clin Immunol. 2009;123(2):S121. [Google Scholar]
47. Wittke A, Weaver V, Mahon BD, August A, Cantorna MT. Vitamin D receptor-deficient mice fail to develop experimental allergic asthma. J Immunol. 2004;173(5):3432–6. [PubMed] [Google Scholar]
48. Black PN, Scragg R. Relationship between serum 25-hydroxyvitamin d and pulmonary function in the third national health and nutrition examination survey. Chest. 2005;128(6):3792–8. [PubMed] [Google Scholar]
49. Brehm JM, Celedon JC, Soto-Quiros ME, et al. Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica. Am J Respir Crit Care Med. 2009;179(9):765–71. [PMC free article] [PubMed] [Google Scholar]
50. Devereux G, Litonjua AA, Turner SW, et al. Maternal vitamin D intake during pregnancy and early childhood wheezing. Am J Clin Nutr. 2007;85(3):853–9. [PubMed] [Google Scholar]
51. Gale CR, Robinson SM, Harvey NC, et al. Maternal vitamin D status during pregnancy and child outcomes. Eur J Clin Nutr. 2008;62(1):68–77. [PMC free article] [PubMed] [Google Scholar]
52. Stumpf WE, Sar M, Reid FA, Tanaka Y, DeLuca HF. Target cells for 1,25-dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin, pituitary, and parathyroid. Science. 1979;206(4423):1188–90. [PubMed] [Google Scholar]
53. Gurlek A, Pittelkow MR, Kumar R. Modulation of growth factor/cytokine synthesis and signaling by 1alpha,25-dihydroxyvitamin D(3): implications in cell growth and differentiation. Endocr Rev. 2002;23(6):763–86. [PubMed] [Google Scholar]
54. Zhang JZ, Maruyama K, Ono I, Kaneko F. Production and secretion of platelet-derived growth factor AB by cultured human keratinocytes: regulatory effects of phorbol 12-myristate 13-acetate, etretinate, 1,25-dihydroxyvitamin D3, and several cytokines. J Dermatol. 1995;22(5):305–9. [PubMed] [Google Scholar]
55. Geilen CC, Bektas M, Wieder T, et al. 1alpha,25-dihydroxyvitamin D3 induces sphingomyelin hydrolysis in HaCaT cells via tumor necrosis factor alpha. J Biol Chem. 1997;272(14):8997–9001. [PubMed] [Google Scholar]
56. Zhang JZ, Maruyama K, Ono I, Iwatsuki K, Kaneko F. Regulatory effects of 1,25-dihydroxyvitamin D3 and a novel vitamin D3 analogue MC903 on secretion of interleukin-1 alpha (IL-1 alpha) and IL-8 by normal human keratinocytes and a human squamous cell carcinoma cell line (HSC-1) J Dermatol Sci. 1994;7(1):24–31. [PubMed] [Google Scholar]
57. Komine M, Watabe Y, Shimaoka S, et al. The action of a novel vitamin D3 analogue, OCT, on immunomodulatory function of keratinocytes and lymphocytes. Arch Dermatol Res. 1999;291(9):500–6. [PubMed] [Google Scholar]
58. Fukuoka M, Ogino Y, Sato H, et al. RANTES expression in psoriatic skin, and regulation of RANTES and IL-8 production in cultured epidermal keratinocytes by active vitamin D3 (tacalcitol) Br J Dermatol. 1998;138(1):63–70. [PubMed] [Google Scholar]
59. Bikle DD, Chang S, Crumrine D, et al. 25 Hydroxyvitamin D 1 alpha-hydroxylase is required for optimal epidermal differentiation and permeability barrier homeostasis. J Invest Dermatol. 2004;122(4):984–92. [PubMed] [Google Scholar]
60. Bikle DD, Pillai S, Gee E, Hincenbergs M. Regulation of 1,25-dihydroxyvitamin D production in human keratinocytes by interferon-gamma. Endocrinology. 1989;124(2):655–60. [PubMed] [Google Scholar]
61. Gregori S, Casorati M, Amuchastegui S, et al. Regulatory T cells induced by 1 alpha,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J Immunol. 2001;167(4):1945–53. [PubMed] [Google Scholar]
62. Elias PM, Hatano Y, Williams ML. Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms. J Allergy Clin Immunol. 2008;121(6):1337–43. [PMC free article] [PubMed] [Google Scholar]
63. O'Regan GM, Sandilands A, McLean WH, Irvine AD. Filaggrin in atopic dermatitis. J Allergy Clin Immunol. 2008;122(4):689–93. [PubMed] [Google Scholar]
64. Irvine AD. Fleshing out filaggrin phenotypes. J Invest Dermatol. 2007;127(3):504–7. [PubMed] [Google Scholar]
65. Schauber J, Gallo RL. Antimicrobial peptides and the skin immune defense system. J Allergy Clin Immunol. 2008;122(2):261–6. [PMC free article] [PubMed] [Google Scholar]
66. Ong PY, Ohtake T, Brandt C, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002;347(15):1151–60. [PubMed] [Google Scholar]
67. Howell MD, Wollenberg A, Gallo RL, et al. Cathelicidin deficiency predisposes to eczema herpeticum. J Allergy Clin Immunol. 2006;117(4):836–41. [PMC free article] [PubMed] [Google Scholar]
68. Howell MD, Gallo RL, Boguniewicz M, et al. Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus. Immunity. 2006;24(3):341–8. [PubMed] [Google Scholar]
69. Beck LA, Boguniewicz M, Hata T, et al. Phenotype of atopic dermatitis subjects with a history of eczema herpeticum. J Allergy Clin Immunol. 2009;124(2):260–9. [PMC free article] [PubMed] [Google Scholar]
70. Wang TT, Nestel FP, Bourdeau V, et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol. 2004;173(5):2909–12. [PubMed] [Google Scholar]
71. Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311(5768):1770–3. [PubMed] [Google Scholar]
72. Hata TR, Kotol P, Jackson M, et al. Administration of oral vitamin D induces cathelicidin production in atopic individuals. J Allergy Clin Immunol. 2008;122(4):829–31. [PMC free article] [PubMed] [Google Scholar]
73. Sidbury R, Sullivan AF, Thadhani RI, Camargo CA., Jr. Randomized controlled trial of vitamin D supplementation for winter-related atopic dermatitis in Boston: a pilot study. Br J Dermatol. 2008;159(1):245–7. [PubMed] [Google Scholar]
Vitamin D Sensitivity Symptoms
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2914320/
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