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doi: 10.1111/j.1365-2222.2011.03923.x Clinical & Experimental Allergy , 1–10
I N V I T E D R E V I E W © 2011 Blackwell Publishing Ltd
Vitamin D and its role in allergic diseaseM. Reinholz, T. Ruzicka and J. Schauber
Department of Dermatology and Allergy, Ludwig-Maximilian University, Munich, Germany
Clinical &Experimental
Allergy
Correspondence:
Jürgen Schauber, Klinik und Poliklinik
für Dermatologie und Allergologie,
Ludwig-Maximilians-Universität
München, Frau enlobstr . 9-11,
80337 München, Germany.
E-mail: juergen.schauber@med.
uni-muenchen.de
Abstract
In Western countries, the incidence of atopy and allergic diseases is high and further ris-
ing. While genetic factors certainly play a role, epigenetic or even nutritional factors
might also be important in the pathogenesis of allergies. Vitamin D – the ‘sunshine hor-
mone’ – exerts profound effects on both adaptive and innate immune functions involved
in the development and course of allergic diseases. As also the incidence of vitamin D
insufficiency is surprisingly high in the general population, clinical and experimental
studies have started to investigate if correcting vitamin D levels [measured as serum 25
hydroxy vitamin D -25(OH)D] is beneficial or even protective in patients with allergies or
children at risk. This review highlights current data on the effects of vitamin D on theallergy-mediating immune system and the vitamin D status in atopic patients. Further-
more, the benefits and risks of vitamin D supplementation during pregnancy, childhood
and in adults with respect to the development and course of allergic disease are discussed.
Keywords adult, allergy, asthma, atopy, childhood, pregnancy, Vitamin D, vitamin D
deficiency, vitamin D supplementation
Submitted 06 May 2011; revised 10 October 2011; accepted 10 October 2011
Introduction
Vitamin D can be ingested from foods, but can also beproduced from precursor molecules by man himself.
Initially characterized for its role in bone metabolism it
is now well established that vitamin D also exerts pro-
found effects on our immune system. In particular,
vitamin D regulates the activity of various immune
cells, including monocytes, dendritic cells (DCs), T and
B lymphocytes, as well as immune functions of epithe-
lial cells [1]. Furthermore, some immune cells express
vitamin D-activating enzymes facilitating local conver-
sion of inactive vitamin D into active calcitriol with
subsequent paracrine and autocrine effects [2, 3]. The
impact of vitamin D on immune functions might beparticularly critical as prevalence of hypovitaminosis D
is high with up to 30% in the adult Western population
and up to 70% in the elderly or institutionalized [4].
Similar to this ‘pandemia’ of hypovitaminosis D [5], the
prevalence of disturbed immune functions leading to
atopy in Western countries is high with reported up to
16% in children in Sweden [6]. Furthermore, epidemio-
logical studies suggest that atopic diseases increased
significantly in most Westernized countries [7 – 11].
Actually, low-serum 25 hydroxy vitamin D [25(OH)D]
levels are prevalent in every region studied (e.g. very
low levels are most common in regions such as South
Asia and the Middle East). Older age, female gender,
higher latitude, winter season, darker skin pigmenta-tion, less sunlight exposure, dietary habits, and absence
of dietary vitamin D fortification are the main factors
that are significantly associated with low 25(OH)D
serum levels [4].
As 25(OH)D serum levels are low in individuals and
vitamin D influences allergy-mediating immune cells
such as T cells and the immune functions of cells form-
ing the barriers against allergens such as epithelial
cells, one might speculate that vitamin D plays a role in
allergy development. Consequently, the first scientists
who hypothesized a link between nutritional intake of
vitamin D and allergies were Wjst and Dold in 1999[12]. In 2004, Zitterman et al. suggested an effect of
vitamin D deficiency on allergy risk when they
observed an association between low vitamin D status
and low cord blood levels of the tolerogenic cytokine
interleukin (IL)-10 [13]. Furthermore, Camargo et al.
suggested that regional differences in vitamin D status
were responsible for a strong north – south gradient for
the prescription of EpiPens as emergency treatment for
severe allergic reactions in the USA. [14].
In addition, one has started to ask whether correcting
vitamin D levels affects the incidence and the course of
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(50 ng/mL) might even be associated with
adverse effects [24]. Noteworthy, these concentrations
are mainly reflecting recommendations for vitamin D
and bone health. The concentrations needed for
probable ‘immune’ effects of vitamin D are not known
[30].
Effects of vitamin D on the immune system
As mentioned above, vitamin D has initially been iden-
tified for its role in bone metabolism; however, in
recent years, more and more effects of vitamin D on
immune functions were observed. Interestingly, vitamin
D controls effector immune functions, promotes regula-
tory immune response and induces innate immune
defences. All of these could be relevant in allergic
disease.
Effects of vitamin D on innate immunity
The major task for the immune system is to protect the
individual from external danger. Still, while a powerful
defence against e.g. microbial pathogens has to be
mounted by the immune system in a very short time,
this response has to be fine-tuned to avoid excessinflammation and tissue damage. The human immune
system is divided into two branches: Adaptive and
innate immunity. Broadly defined, innate immune
responses comprise all mechanisms that resist infection,
but do not require specific recognition of the pathogen.
Several aspects of innate immunity are affected by vita-
min D: Vitamin D inhibits the expression of pattern-
recognition receptors, which activate innate immune
responses such as the Toll-like receptors (TLR) on
monocytes and suppresses TLR-mediated inflammation
[31]. Other studies demonstrate that vitamin D decreases
immune receptor expression also on monocyte-derivedDCs, inhibits DC activation by e.g. LPS and reduces the
function of these cells (e.g. chemotaxis, antigen presen-
tation, maturation) [32 – 34]. Furthermore, vitamin D
induces autophagy in human macrophages, which could
be important in the defence against opportunistic infec-
tions [35]. Vitamin D also induces endogenous antimi-
crobial peptide expression in resident epithelial cells in
skin and lung, thereby strengthening the innate barriersagainst environmental allergens [32, 33].
Effects of vitamin D on adaptive immunity
Adaptive immunity comprises cells that specifically rec-
ognize and remember pathogens. Lymphocytes such as
T cells with Th1 or Th2 polarization are major players
in adaptive immunity and vitamin D modulates their
functions: Vitamin D decreases pro-inflammatory cyto-
kine release from peripheral mononuclear blood cells
(PMBC) in general and from T cells in particular [36,
37]. In addition, vitamin D inhibits T-cell proliferation
through decreased Th1 cytokine secretion [38, 39]. The
effects on Th2 cells are less clear, one study finds that
vitamin D induces IL-4, IL-5 and IL-13 in vitro, whereasanother study finds no effect [40 – 42]. However, vitamin
D supplementation does not induce Th2 responses
in vivo [43]. Furthermore, pro-inflammatory Th17responses are also blocked by administration of vitamin
D in mice and man [44]. Also, vitamin D increases
IL-10 and decreases IL-2 production, thereby inducing
a state of hyporesponsiveness in T regulatory cells (Treg)
cells – an effect which is also seen with anti-allergic
therapies such as corticosteroids or allergen immuno-
therapy [36, 45]. Finally, application of vitamin D leadsto inhibition of effector T cells, and vitamin D defi-
ciency may promote autoimmunity by favouring the
inordinate production of Th17 and Th9 cells at the
expense of IL-10-producing Tregs [46].
Effects of vitamin D on IgE secretion, mast cells and eosinophils
Vitamin D also effects B lymphocyte functions and
modulates the humoral immune response including
secretion of IgE [47]. Allergy-mediating cells such as
mast cells and eosinophils are further vitamin D targets:Increased cutaneous vitamin D synthesis increases IL-10
production in mast cells, which leads to suppression of
skin inflammation [48]. Also, vitamin D-treated mice
showed reduced airway hyperresponsiveness and
decreased infiltration of eosinophils in the lung [49].
Vitamin D insufficiency in Western countries?
Observations that vitamin D influences immune func-
tions involved in allergic disease have prompted the
question if 25(OH)D serum levels correlate with the risk
Table 1. Classification of vitamin D status as measured by the serum
level of 25 hydroxy vitamin D [25(OH)D] and as outlined by the
Institute of Medicine (IOM). (24) Nota bene: The IOM suggests that 25
(OH)D serum levels above 75 nmol/L are not associated with increased
benefit
Classification of vitamin D status [25(OH)D serum level]
Deficiency
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databases performed by Nurmatov et al., who concluded
that high maternal dietary vitamin D and E intakes dur-
ing pregnancy were protective against the development
of childhood wheezing [71]. In another study, those
results were reproduced, and reduced maternal intake of
vitamin E, vitamin D and zinc during pregnancy was
associated with increased wheezing outcomes inchildren [72].
On a molecular level, maternal vitamin D intake dur-
ing pregnancy increases the mRNA levels of the leuco-
cyte receptors ILT3 and ILT4 in umbilical cord blood.
As ILT3 and ILT4 are critical for the generation of T
suppressor cells and induction of immunological toler-
ance, this finding may point towards an early induction
of tolerogenic immune responses by maternal vitamin
D intake in the developing child [73].
Still, high vitamin D intake during pregnancy might
also be harmful with respect to allergic disease develop-
ment: children whose mothers had a 25(OH)D concen-
tration during pregnancy greater than 75 nmol/L had
an increased risk of atopic eczema on examination at
9 months (odds ratio, OR 3.26) and asthma at the age
of 9 years (OR 5.40) compared with children whose
mothers had a concentration of < 30 nmol/L [74].
Vitamin D status and allergic disease in children
As first symptoms of allergic disease are typically seen
during childhood, several studies analysed 25(OH)D
serum levels and allergic disease in children. Indeed, in
children and adolescents, allergic sensitization to 11 of
17 investigated allergens was more common in thosewith vitamin D deficiency. In particular, 25(OH)D levels
below 15 ng/mL were associated with peanut (OR 2.39),
ragweed (OR 1.83) and oak (OR, 4.75) allergy [75]. In
children with atopic eczema (AE), mean 25(OH)D serum
levels were significantly higher in patients with mild
disease compared with those with moderate or severe
AE [76].
Moreover, Mullins et al. showed significantly higher
rates of food allergy in children born autumn/winter
(compared with spring/summer), suggesting a relation-
ship between relative food allergy rates and monthly
UV irradiation [77]. They hypothesized that UV lightexposure/vitamin D status may be one of many poten-
tial factors contributing to the pathogenesis of
childhood food allergy.
As a mechanism, a multiple hit model was suggested
in which the lack of vitamin D impairs the epithelial
barrier integrity, which leads to increased and inappro-
priate mucosal exposure to food antigens. In this model,
vitamin D deficiency would also promote a pro-sensiti-
zation immune imbalance that compromises immuno-
logical tolerance. Thus, the authors suggest that early
correction of vitamin D deficiency might promote
mucosal defence, maintain healthy microbial ecology
and allergen tolerance, and thereby limit food allergies
in children [78, 79].
Concerning childhood asthma, Brehm et al. observed
that children with asthma had low serum 25(OH)D even
in Costa Rica (probably due to an undersupply of vita-
min D). Of 616 children with asthma, 21 (3.4%) had 25(OH)D serum levels less than 20 ng/mL (considered defi-
cient), and an additional 152 (24.6%) had levels
between 20 and 30 ng/mL (considered insufficient) [80].
Other studies failed to confirm these results, and
Hughes et al. found no association between any of the
UVR- or vitamin D-related measures and childhood
asthma. In contrast, greater time in the sun in winter
between the ages 6 and 15 years increased the odds of
having hayfever, and oral supplementation with cod
liver oil in childhood even increased the odds of a
history of having both asthma and hayfever [81].
Attempts to increase serum vitamin D in allergic
diseases and their effects
Vitamin D supplementation and allergic disease inchildren
As serum 25(OH)D can be influenced by either oral sup-
plementation or UVB exposure, and vitamin D might
have an impact on the development of allergic disease,
several investigators examined the outcome of vitamin
D supplementation on the course of allergic disease.
Bäck et al. showed that children who were supple-
mented with vitamin D (> 13.1 lg/day) showed anincreased risk to develop either atopic eczema, AR or
allergic asthma [82]. In particular, vitamin D intake led
to an increased risk of developing atopic eczema at the
age of 6 when a positive family history for atopic
eczema was already reported. Similarly, Hyppönen et al.
showed that dietary intake of vitamin D during infancy
promoted allergic disease at age 31 [83]. Further sup-
porting a deleterious role for vitamin D supplementa-
tion, Milner et al. found that early vitamin
supplementation in children was associated with
increased risk for asthma and food allergies [84]. These
results have prompted the question whether the modeof application of vitamin D might also be important for
promoting allergic diseases. Indeed, Kull et al. could
show that vitamin D in water-soluble form seemed to
increase the risk of allergic disease up to the age of
4 years compared with supplementation of vitamin D
given in peanut oil [85].
Nevertheless, there might be beneficial effects of vita-
min supplementation in specific patient groups: A pro-
spective study published only recently suggested that
vitamin D supplementation in children with asthma
reduces the risk for recurrent respiratory infections and
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thus the risk for disease exacerbation [86]. Furthermore,
Urashima et al. showed in one of the first randomized
controlled trials (RCT) that vitamin D supplementation
in children during the winter months reduced the rate
of influenza A infections and the frequency of asthma
attacks [87]. Also, a recent pilot RCT demonstrated a
favourable effect of vitamin D supplementation on AE
symptoms in children during winter months [88]. This
effect again could have been mediated by the induction
of endogenous antimicrobial peptides in the skin in AE
by oral vitamin D supplementation [89].
Concluding remarks
There are many unanswered questions concerning the
role of vitamin D in the prevention or the treatment of
allergic disease. Undoubtedly, vitamin D insufficiency
[25(OH)D < 50 nmol/L] is very common in the general
Table 2. Summary of clinical studies on the role of vitamin D in allergic disease
Author Year Outcome
Adults
Black [59] 2005 ▲ Serum 25D levels correlate with pulmonary function.
Pinto [57] 2008 ▲ Serum 25D levels are lower in patients with chronic rhinosinusitis.
Wjst [64] 2009 ♦ The incidence of allergic rhinitis correlates with increased vitamin D supplementation.
Hypponen [63] 2009 ■ High or low 25D levels are associated with elevated serum IgE.
Searing [62] 2010 ▲ Vitamin D enhances the immunosuppressive function of dexamethasone ex vivo.
Devereux [58] 2010 ■ 25D serum levels do not differ between asthmatics and controls.
Li [56] 2010 ▲ Low serum 25D correlates with decreased FEV1, but not with IgE-levels.
Pregnancy
Devereux [68] 2007 ▲ Maternal vitamin D intake during pregnancy decreases risk of wheeze symptoms
in early childhood.
Camargo [66] 2007 ▲ High maternal vitamin D intake during pregnancy decreases risk of recurrent wheeze in
early childhood.
Gale [74] 2008 ♦ Very high maternal serum 25D increases risk of eczema on examination at 9 months
and asthma at the age of 9 years.
Erkkola [69] 2009 ▲ High maternal vitamin D intake is negatively associated with the risk of asthma and
allergic rhinitis in childhood.
Nwaru [70] 2010 ▲
Increased vitamin D intake during pregnancy is negatively associated with the risk of food allergies at the age of 5.
Camargo [67] 2010 ▲ High 25D serum levels are inversely associated with risk of childhood wheezing, but
not with incident asthma.
Nurmatov [71] 2011 ▲ Elevated vitamin D intake during pregnancy is protective for the development of
childhood wheezing (meta-analysis).
Children
Brehm [80] 2009 ▲ Low serum concentrations of 25D in children in Costa-Rica are associated with asthma.
Hughes [81] 2010 ♦ Oral supplementation with cod liver oil increases risk for asthma, hayfever. UV
exposure in childhood leads to allergic sensitization.
Peroni [76] 2010 ▲ 25D serum levels were significantly higher in patients with mild atopic eczema
compared to severe disease.
Vasallo [78, 79] 2010 ▲ Seasonal fluctuations in UVB irradiation and perhaps vitamin D are involved in the
pathogenesis of food allergy in children.
Mullins [77] 2011 ▲ Reduced UV exposure/vitamin D status might be responsible for higher rates of foodallergy of children born in autumn/winter.
Sharief [75] 2011 ▲ Low 25D serum levels are associated with higher incidence of IgE sensitizations.
Children vitamin D supplementation
Hypponen [83] 2004 ♦ Vitamin D supplementation in infancy increases the risk for atopic eczema and allergic
rhinitis at age 31.
Kull [85] 2006 ♦ Vitamin D intake in a water-soluble form increases the risk of allergic disease (vitamin
D in oil has no effect).
Sidbury [88] 2008 ▲ Vitamin D supplementation reduces symptoms in winter-related atopic eczema.
Bäck [82] 2009 ♦ Atopic manifestations are more prevalent in children with higher intake of vitamin D.
Urashima [87] 2010 ▲ Vitamin D supplementation in children in winter reduces the rate of influenza infection
and frequency of asthma attacks.
Majak [86] 2011 ▲ Vitamin D supplementation in children may prevent asthma exacerbation triggered by
acute respiratory infection.
(▲ protective role of vitamin D; ♦ deleterious role of vitamin D; ■ no role for vitamin D)
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population [50] as is the prevalence of atopy and aller-
gic diseases. As vitamin D exerts profound effects on
immune cells involved in the development and the
course of allergies, it is tempting to hypothesize that
there might be a link. However, while experimental and
pre-clinical data point towards a protective role of vita-
min D, the clinical results available to date draw a lessclear picture. Indeed, the results of the available studies
are very heterogeneous, and from the data available, no
clear recommendation for vitamin D supplementation
can be derived (Table 2).
In particular, no clear association between vitamin D
status and allergies in adults was detected in observa-
tional studies. Asthmatic patients might be the only
ones who could benefit from vitamin D supplementa-
tion; however, data on an appropriate dosage or treat-
ment intervals are currently missing [90]. A little bit
more consistent are data derived from studies investi-
gating the influence of vitamin D status during preg-
nancy and the incidence of allergic diseases in the
offspring. Here, most studies are in favour of a protec-
tive role of vitamin D. Childhood wheezing is the dis-
ease that is probably most likely to be prevented by
sufficient vitamin D during pregnancy. While not inves-
tigated in larger clinical studies, vitamin D derived from
nutritional sources might be most suitable, especially as
very high serum levels of 25(OH)D (which could result
from the intake of large quantities of vitamin D supple-
ments) are associated with adverse effects and an
increased risk for childhood eczema and asthma. In
children, lower 25(OH)D serum levels are also associated
with increased risks for allergic disease. Most publishedclinical studies, however, report a link between oral
intake of vitamin D or multivitamin supplements and
increased risks for asthma, hayfever and atopic eczema
[82 – 84].
Unfortunately, the evidence for beneficial (or adverse)
effects of vitamin D on allergic diseases is primarily
based on observational, and often retrospective, studies.
Questionnaires to record intake of vitamin D supple-ments or consumption of vitamin D containing nutri-
tion are often used and might not reflect reality,
especially when filled in retrospectively. Also, timing,
length of consumption, combination with other nutri-
ents and even the form of application (water-soluble
vitamin D vs. in peanut oil [85]) are factors among
many, which could influence the effect of vitamin D on
the immune functions, and hence allergic disease.
Nevertheless, some promising data from smaller RCTs
were recently published, which indicate a link between
vitamin D deficiency, immune vulnerability and an
increased rate of asthma exacerbations, and winter-
related atopic eczema [87, 88]. While these trials are in
favour a protective role of vitamin D, unfortunately,
until data from larger multicentric prospective studies
become available, no clear recommendation on the use
of vitamin D in the prevention or supportive treatment
of allergies can be formulated.
Acknowledgements
This study was funded by the Deutsche Forschungs-
gemeinschaft (Emmy Noether Program SCHA 979/3-1
to J.S.) and the Fritz Thyssen Stiftung.
Conflict of interest: The authors declare no conflict of interest.
References
1 Hewison M. Vitamin D and innate and
adaptive immunity. Vitam Horm 2011;
86:23 – 62. Epub 2011/03/23.
2 Baeke F, Takiishi T, Korf H, Gysemans
C, Mathieu C. Vitamin D: modulator of
the immune system. Curr Opin Pharma-
col 2011; 10:482 – 96. Epub 2010/04/30.
3 Akbar NA, Zacharek MA. Vitamin D:immunomodulation of asthma, allergic
rhinitis, and chronic rhinosinusitis.
Curr Opin Otolaryngol Head Neck Surg
2011; 19:224 – 8. Epub 2011/04/19.
4 Mithal A, Wahl DA, Bonjour JP,
Burckhardt P, Dawson-Hughes B,
Eisman JA et al. Global vitamin D
status and determinants of hypovita-
minosis D. Osteoporos Int 2009; 20:
1807 – 20. Epub 2009/06/23.
5 Holick MF, Chen TC. Vitamin D defi-
ciency: a worldwide problem with
health consequences. Am J Clin Nutr
2008; 87:1080S – 6S. Epub 2008/04/11.
6 Williams H, Robertson C, Stewart A,
Ait-Khaled N, Anabwani G, Anderson
R et al. Worldwide variations in the
prevalence of symptoms of atopic
eczema in the International Study of
Asthma and Allergies in Childhood. J
Allergy Clin Immunol 1999; 103:
125 –
38. Epub 1999/01/20.7 Gershon AS, Guan J, Wang C, To T.
Trends in asthma prevalence and inci-
dence in Ontario, Canada, 1996 – 2005:
a population study. Am J Epidemiol.
2010; 172:728 – 36. Epub 2010/08/19.
8 Manning PJ, Goodman P, O’Sullivan A,
Clancy L. Rising prevalence of asthma
but declining wheeze in teenagers (1995
– 2003): ISAAC protocol. Ir Med J 2007;
100:614 – 5. Epub 2008/02/19.
9 Fukutomi Y, Taniguchi M, Watanabe
J, Nakamura H, Komase Y, Ohta K
et al. Time Trend in the Prevalence of
Adult Asthma in Japan: Findings
from Population-Based Surveys in
Fujieda City in 1985, 1999, and 2006.
Allergol Int 2011; 60:443 – 8. Epub
2011/05/20.
10 Bos JD, Brenninkmeijer EE, Schram
ME, Middelkamp-Hup MA, Spuls PI,
Smitt JH. Atopic eczema or atopiform
dermatitis. Exp Dermatol 2010; 19:325 – 31. Epub 2010/01/27.
11 Asher MI, Montefort S, Bjorksten B,
Lai CK, Strachan DP, Weiland SK et al.
Worldwide time trends in the preva-
lence of symptoms of asthma, allergic
rhinoconjunctivitis, and eczema in
childhood: ISAAC Phases One and
Three repeat multicountry cross-
sectional surveys. Lancet 2006;
368:733 – 43. Epub 2006/08/29.
12 Wjst M, Dold S. Genes, factor X, and
allergens: what causes allergic dis-
© 2011 Blackwell Publishing Ltd, Clinical & Experimental Allergy , 1–
10
Vitamin D and allergic disease 7
8/19/2019 D 2011
8/10
eases? Allergy 1999; 54:757 – 9. Epub
1999/08/12.
13 Zittermann A, Dembinski J, Stehle P.
Low vitamin D status is associated with
low cord blood levels of the immuno-
suppressive cytokine interleukin-10.
Pediatr Allergy Immunol 2004;15:
242 –
6. Epub 2004/06/24.
14 Camargo CA Jr, Clark S, Kaplan MS,
Lieberman P, Wood RA. Regional dif-
ferences in EpiPen prescriptions in the
United States: the potential role of
vitamin D. J Allergy Clin Immunol
2007; 120:131 – 6. Epub 2007/06/15.
15 Thacher TD, Clarke BL. Vitamin D
insufficiency. Mayo Clin Proc 2011;
86:50 – 60. Epub 2011/01/05.
16 Bischoff-Ferrari HA, Willett WC, Wong
JB, Stuck AE, Staehelin HB, Orav EJ
et al. Prevention of nonvertebral frac-
tures with oral vitamin D and dosedependency: a meta-analysis of ran-
domized controlled trials. Arch Intern
Med 2009; 169:551 – 61. Epub 2009/03/
25.
17 Lehmann B, Meurer M. Vitamin D
metabolism. Dermatol Ther 2010; 23:2
– 12. Epub 2010/02/09.
18 Lehmann B, Tiebel O, Meurer M.
Expression of vitamin D3 25-hydroxy-
lase (CYP27) mRNA after induction by
vitamin D3 or UVB radiation in kerati-
nocytes of human skin equivalents – a
preliminary study. Arch Dermatol Res
1999; 291:507 –
10. Epub 1999/10/29.
19 Lehmann B, Sauter W, Knuschke P,
Dressler S, Meurer M. Demonstration
of UVB-induced synthesis of 1
alpha,25-dihydroxyvitamin D3 (calcit-
riol) in human skin by microdialysis.
Arch Dermatol Res 2003; 295:24 – 8.
Epub 2003/04/24.
20 Welsh J. Vitamin D metabolism in
mammary gland and breast cancer.
Mol Cell Endocrinol 2011; 347:55 – 60.
Epub 2011/06/15.
21 Holick MF, Biancuzzo RM, Chen TC,
Klein EK, Young A, Bibuld D et al. Vitamin D2 is as effective as vitamin
D3 in maintaining circulating concen-
trations of 25-hydroxyvitamin D.
J Clin Endocrinol Metab 2008; 93:677 –
81. Epub 2007/12/20.
22 Commission Directive 2008/100/EC .
Communities TCotE, ed. Official Journal
of the European Union, Publications
Office, Promotion and Dissemination
Unit, Luxembourg: The Commision of
the European Communities, 2008:
9 – 12.
23 Lanham-New SA, Buttriss JL, Miles
LM, Ashwell M, Berry JL, Boucher BJ
et al. Proceedings of the Rank Forum
on Vitamin D. Br J Nutr 2011;
105:144 – 56. Epub 2010/12/08.
24 Dietary Reference Intakes for Calcium
and Vitamin D. Committee to Review
Dietary Reference Intakes for Vitamin
D and Calcium. Washington: Food and
Nutrition Board, Institute of Medicine
2010 30 November. ISBN-10: 0-309-
16394-3
25 Onal H, Adal E, Alpaslan S, Ersen A,
Aydin A. Is daily 400 IU of vitamin D
supplementation appropriate for every
country: a cross-sectional study. Eur J
Nutr 2010; 49:395 – 400. Epub 2010/
02/20.
26 Holick MF. Vitamin D: evolutionary,
physiological and health perspectives.
Curr Drug Targets 2011; 12:4 –
18.Epub 2010/08/28.
27 Vieth R. Vitamin D supplementation,
25-hydroxyvitamin D concentrations,
and safety. Am J Clin Nutr 1999;
69:842 – 56. Epub 1999/05/08.
28 Holick MF, Chen TC, Lu Z, Sauter E.
Vitamin D and skin physiology: a D-
lightful story. J Bone Miner Res
2007;22Suppl 2:V28 – 33. Epub 2008/
03/20.
29 Chel VG, Ooms ME, Pavel S, de Gruijl
F, Brand A, Lips P. Prevention and
treatment of vitamin D deficiency in
Dutch psychogeriatric nursing home
residents by weekly half-body UVB
exposure after showering: a pilot
study. Age Ageing 2011; 40:211 – 4.
Epub 2010/12/25.
30 Gomez Alonso C, Naves Diaz M, Rodri-
guez Garcia M, Fernandez Martin JL,
Cannata Andia JB. [Review of the con-
cept of vitamin D “sufficiency and
insufficiency”]. Nefrologia 2003; 23
Suppl 2:73 – 7. Epub 2003/06/05.
Revision del concepto de “suficiencia e
insuficiencia” de vitamina D.
31 Sadeghi K, Wessner B, Laggner U,Ploder M, Tamandl D, Friedl J et al.
Vitamin D3 down-regulates mono-
cyte TLR expression and triggers
hyporesponsiveness to pathogen-asso-
ciated molecular patterns. Eur J
Immunol 2006; 36:361 – 70. Epub 2006/
01/13.
32 Schauber J, Dorschner RA, Yamasaki
K, Brouha B, Gallo RL. Control of the
innate epithelial antimicrobial response
is cell-type specific and dependent on
relevant microenvironmental stimuli.
Immunology 2006; 118:509 – 19. Epub
2006/08/10.
33 Gorman S, Judge MA, Hart PH.
Immune-modifying properties of topi-
cal vitamin D: focus on dendritic cells
and T cells. J Steroid Biochem Mol Biol
2010; 121:247 – 9. Epub 2010/03/10.
34 Piemonti L, Monti P, Sironi M, Frati-
celli P, Leone BE, Dal Cin E et al. Vita-
min D3 affects differentiation,
maturation, and function of human
monocyte-derived dendritic cells. J
Immunol 2000; 164:4443 – 51. Epub
2000/04/26.
35 Campbell GR, Spector SA. Hormonally
Active Vitamin D3 (1{alpha},25-
Dihydroxycholecalciferol) Triggers
Autophagy in Human Macrophages
That Inhibits HIV-1 Infection. J Biol
Chem 2011; 286:18890 – 902. Epub
2011/04/02.36 Khoo AL, Chai LY, Koenen HJ, Sweep
FC, Joosten I, Netea MG et al. Regula-
tion of cytokine responses by seasonal-
ity of vitamin D status in healthy
individuals. Clin Exp Immunol 2011;
164:72 – 9. Epub 2011/02/18.
37 Muthian G, Raikwar HP, Rajasingh J,
Bright JJ. 1,25 Dihydroxyvitamin-D3
modulates JAK-STAT pathway in IL-
12/IFNgamma axis leading to Th1
response in experimental allergic
encephalomyelitis. J Neurosci Res
2006; 83:1299 – 309. Epub 2006/03/21.
38 Jirapongsananuruk O, Melamed I,
Leung DY. Additive immunosuppres-
sive effects of 1,25-dihydroxyvitamin
D3 and corticosteroids on TH1, but not
TH2, responses. J Allergy Clin Immunol
2000; 106:981 – 5. Epub 2000/11/18.
39 Lemire JM, Archer DC, Beck L, Spiegel-
berg HL. Immunosuppressive actions of
1,25-dihydroxyvitamin D3: preferential
inhibition of Th1 functions. J Nutr
1995; 1256 Suppl:1704S – 8S. Epub
1995/06/01.
40 Matheu V, Back O, Mondoc E,
Issazadeh-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;
112:585 – 92. Epub 2003/09/19.
41 Daynes RA, Enioutina EY, Butler S, Mu
HH, McGee ZA, Araneo BA. Induction
of common mucosal immunity by hor-
monally immunomodulated peripheral
immunization. Infect Immun 1996;
64:1100 – 9. Epub 1996/04/01.
© 2011 Blackwell Publishing Ltd, Clinical & Experimental Allergy , 1–
10
8 M. Reinholz et al
8/19/2019 D 2011
9/10
42 Jorde R, Sneve M, Torjesen PA, Figens-
chau Y, Goransson LG, Omdal R. No
effect of supplementation with chole-
calciferol on cytokines and markers of
inflammation in overweight and obese
subjects. Cytokine 2010; 50:175 – 80.
Epub 2010/02/04.
43 Kreindler JL, Steele C, Nguyen N, Chan
YR, Pilewski JM, Alcorn JF et al. Vita-
min D3 attenuates Th2 responses to
Aspergillus fumigatus mounted by
CD4 + T cells from cystic fibrosis
patients with allergic bronchopulmo-
nary aspergillosis. J Clin Invest 2010;
120:3242 – 54. Epub 2010/08/18.
44 Chang JH, Cha HR, Lee DS, Seo KY,
Kweon MN. 1,25-Dihydroxyvitamin D3
inhibits the differentiation and migra-
tion of T(H)17 cells to protect against
experimental autoimmune encephalo-
myelitis. PLoS ONE 2010; 5:e12925.Epub 2010/10/05.
45 Robinson DS. Regulatory T cells and
asthma. Clin Exp Allergy 2009;
39:1314 – 23. Epub 2009/06/23.
46 Palmer MT, Lee YK, Maynard CL, Oliver
JR, Bikle DD, Jetten AM et al. Lineage-
specific effects of 1,25-dihydroxyvita-
min D(3) on the development of effector
CD4 T cells. J Biol Chem 2011; 286:997
– 1004. Epub 2010/11/05.
47 Hartmann B, Heine G, Babina M,
Steinmeyer A, Zugel U, Radbruch A
et al. Targeting the vitamin D receptor
inhibits the B cell-dependent allergic
immune response. Allergy 2010;
66:540 – 8. Epub 2010/12/03.
48 Biggs L, Yu C, Fedoric B, Lopez AF,
Galli SJ, Grimbaldeston MA. Evidence
that vitamin D(3) promotes mast cell-
dependent reduction of chronic UVB-
induced skin pathology in mice. J Exp
Med 2010; 207:455 – 63. Epub 2010/03/
03.
49 Gorman S, Judge MA, Burchell JT,
Turner DJ, Hart PH. 1,25-dihydroxyvi-
tamin D3 enhances the ability of trans-
ferred CD4 + CD25 + cells tomodulate T helper type 2-driven asth-
matic responses. Immunology 2010;
130:181 – 92. Epub 2010/01/12.
50 Bogh MK, Schmedes AV, Philipsen PA,
Thieden E, Wulf HC. Vitamin D pro-
duction after UVB exposure depends
on baseline vitamin D and total cho-
lesterol but not on skin pigmentation.
J Invest Dermatol 2010; 130:546 – 53.
Epub 2009/10/09.
51 Hypponen E, Power C. Hypovitamino-
sis D in British adults at age 45 y:
nationwide cohort study of dietary and
lifestyle predictors. Am J Clin Nutr
2007; 85:860 – 8. Epub 2007/03/09.
52 Vahavihu K, Ala-Houhala M, Peric M,
Karisola P, Kautiainen H, Hasan T
et al. Narrowband ultraviolet B treat-
ment improves vitamin D balance and
alters antimicrobial peptide expression
in skin lesions of psoriasis and atopic
dermatitis. Br J Dermatol 2010;
163:321 – 8. Epub 2010/03/25.
53 Hintzpeter B, Mensink GB, Thierfelder
W, Muller MJ, Scheidt-Nave C. Vita-
min D status and health correlates
among German adults. Eur J Clin Nutr
2008; 62:1079 – 89. Epub 2007/06/01.
54 Hintzpeter B, Scheidt-Nave C, Muller
MJ, Schenk L, Mensink GB. Higher
prevalence of vitamin D deficiency is
associated with immigrant background
among children and adolescents inGermany. J Nutr 2008; 138:1482 – 90.
Epub 2008/07/22.
55 Looker AC, Johnson CL, Lacher DA,
Pfeiffer CM, Schleicher RL, Sempos CT.
Vitamin d status: United States, 2001 –
2006. NCHS Data Brief . 2011: 59:1 – 8.
Epub 2011/05/20.
56 Li F, Peng M, Jiang L, Sun Q, Zhang K,
Lian F et al. Vitamin D Deficiency Is
Associated with Decreased Lung Func-
tion in Chinese Adults with Asthma.
Respiration 2010; 81:469 – 75. Epub
2010/12/03.
57 Pinto JM, Schneider J, Perez R, DeTi-
neo M, Baroody FM, Naclerio RM.
Serum 25-hydroxyvitamin D levels are
lower in urban African American sub-
jects with chronic rhinosinusitis. J
Allergy Clin Immunol 2008; 122:415 –
7. Epub 2008/07/01.
58 Devereux G, Wilson A, Avenell A,
McNeill G, Fraser WD. A case-control
study of vitamin D status and asthma
in adults. Allergy 2010; 65:666 – 7.
Epub 2009/10/23.
59 Black PN, Scragg R. Relationship
between serum 25-hydroxyvitamin dand pulmonary function in the third
national health and nutrition examina-
tion survey. Chest 2005; 128:3792 – 8.
Epub 2005/12/16.
60 Janssens W, Mathieu C, Boonen S,
Decramer M. Vitamin d deficiency and
chronic obstructive pulmonary disease
a vicious circle. Vitam Horm 2011;
86:379 – 99. Epub 2011/03/23.
61 Herr C, Greulich T, Koczulla RA, Meyer
S, Zakharkina T, Branscheidt M et al.
The role of vitamin D in pulmonary
disease: COPD, asthma, infection, and
cancer. Respir Res 2011; 12:31. Epub
2011/03/23.
62 Searing DA, Zhang Y, Murphy JR,
Hauk PJ, Goleva E, Leung DY.
Decreased serum vitamin D levels in
children with asthma are associated
with increased corticosteroid use. J
Allergy Clin Immunol 2010; 125:995 –
1000. Epub 2010/04/13.
63 Hypponen E, Berry DJ, Wjst M, Power
C. Serum 25-hydroxyvitamin D and
IgE – a significant but nonlinear rela-
tionship. Allergy 2009; 64:613 – 20.
Epub 2009/01/22.
64 Wjst M. Introduction of oral vitamin D
supplementation and the rise of the
allergy pandemic. Allergy Asthma Clin
Immunol 2009; 5:8. Epub 2009/12/18.
65 Cranney A, Horsley T, O’Donnell S,
Weiler H, Puil L, Ooi D et al. Effective-ness and safety of vitamin D in rela-
tion to bone health. Evid Rep Technol
Assess (Full Rep) 2007; 158:1 – 235.
Epub 2007/12/20.
66 Camargo CA Jr, Rifas-Shiman SL, Li-
tonjua AA, Rich-Edwards JW, Weiss
ST, Gold DR 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; 85:788 –
95. Epub 2007/03/09.
67 Camargo CA Jr, Ingham T, Wickens K,
Thadhani R, Silvers KM, Epton MJ
et al. Cord-blood 25-hydroxyvitamin D
levels and risk of respiratory infection,
wheezing, and asthma. Pediatrics
2010; 127:e180 – 7. Epub 2010/12/29.
68 Devereux G, Litonjua AA, Turner SW,
Craig LC, McNeill G, Martindale S
et al. Maternal vitamin D intake during
pregnancy and early childhood wheez-
ing. Am J Clin Nutr 2007; 85:853 – 9.
Epub 2007/03/09.
69 Erkkola M, Kaila M, Nwaru BI, Kron-
berg-Kippila C, Ahonen S, Nevalainen
J et al. Maternal vitamin D intake dur-
ing pregnancy is inversely associatedwith asthma and allergic rhinitis in
5-year-old children. Clin Exp Allergy
2009; 39:875 – 82. Epub 2009/06/16.
70 Nwaru BI, Ahonen S, Kaila M, Erkkola
M, Haapala AM, Kronberg-Kippila C
et al. Maternal diet during pregnancy
and allergic sensitization in the off-
spring by 5 yrs of age: a prospective
cohort study. Pediatr Allergy Immunol
2010; 1:29 – 37. Epub 2009/12/17.
71 Nurmatov U, Devereux G, Sheikh A.
Nutrients and foods for the primary
© 2011 Blackwell Publishing Ltd, Clinical & Experimental Allergy , 1–
10
Vitamin D and allergic disease 9
8/19/2019 D 2011
10/10
prevention of asthma and allergy:
Systematic review and meta-analysis. J
Allergy Clin Immunol 2011; 127:724 –
33. Epub 2010/12/28.
72 De Luca G, Olivieri F, Melotti G, Aiello
G, Lubrano L, Boner AL. Fetal and
early postnatal life roots of asthma. J
Matern Fetal Neonatal Med 2010;
23Suppl 3:80 – 3. Epub 2010/10/12.
73 Rochat MK, Ege MJ, Plabst D, Steinle
J, Bitter S, Braun-Fahrlander C et al.
Maternal vitamin D intake during
pregnancy increases gene expression
of ILT3 and ILT4 in cord blood. Clin
Exp Allergy 2010; 40:786 – 94. Epub
2009/12/25.
74 Gale CR, Robinson SM, Harvey NC, Jav-
aid MK, Jiang B, Martyn CN et al.
Maternal vitamin D status during preg-
nancy and child outcomes. Eur J Clin
Nutr 2008; 62:68 –
77. Epub 2007/02/22.75 Sharief S, Jariwala S, Kumar J, Munt-
ner P, Melamed ML. Vitamin D levels
and food and environmental allergies
in the United States: Results from the
National Health and Nutrition Exami-
nation Survey 2005-2006. J Allergy
Clin Immunol 2011; 127:1195 – 202.
Epub 2011/02/19.
76 Peroni DG, Piacentini GL, Cametti E,
Chinellato I, Boner AL. Correlation
between serum 25 (OH)-vitamin D levels
and severity of atopic dermatitis in
children Br J Dermatol 2010; 164:
1078 –
82. Epub 2010/11/20.
77 Mullins RJ, Clark S, Katelaris C, Smith
V, Solley G, Camargo CA Jr. Season of
birth and childhood food allergy in
Australia. Pediatr Allergy Immunol
2011; 22:583 – 9. Epub 2011/02/24.
78 Vassallo MF, Camargo CA Jr. Potential
mechanisms for the hypothesized link
between sunshine, vitamin D, and food
allergy in children. J Allergy Clin
Immunol 2010; 126:217 – 22. Epub
2010/07/14.
79 Vassallo MF, Banerji A, Rudders SA,
Clark S, Mullins RJ, Camargo CA Jr.
Season of birth and food allergy in
children. Ann Allergy Asthma Immunol
2010; 104:307 – 13. Epub 2010/04/23.
80 Brehm JM, Celedon JC, Soto-Quiros
ME, Avila L, Hunninghake GM, Forno
E et al. Serum vitamin D levels and
markers of severity of childhood
asthma in Costa Rica. Am J Respir Crit
Care Med 2009; 179:765 – 71. Epub
2009/01/31.
81 Hughes AM, Lucas RM, Ponsonby AL,
Chapman C, Coulthard A, Dear K et al.
The role of latitude, ultraviolet radia-tion exposure and vitamin D in child-
hood asthma and hayfever: an
Australian multicenter study. Pediatr
Allergy Immunol 2010; 22:327 – 33.
Epub 2010/10/01.
82 Back O, Blomquist HK, Hernell O, Sten-
berg B. Does vitamin D intake during
infancy promote the development of
atopic allergy? Acta Derm Venereol
2009; 89:28 – 32. Epub 2009/02/07.
83 Hypponen E, Sovio U, Wjst M, Patel S,
Pekkanen J, Hartikainen AL et al.
Infant vitamin d supplementation and
allergic conditions in adulthood:
northern Finland birth cohort 1966.
Ann NY Acad Sci 2004; 1037:84 – 95.
Epub 2005/02/09.
84 Milner JD, Stein DM, McCarter R,
Moon RY. Early infant multivitamin
supplementation is associated with
increased risk for food allergy and
asthma. Pediatrics 2004; 114:27 – 32.
Epub 2004/07/03.
85 Kull I, Bergstrom A, Melen E, Lilja G,
van Hage M, Pershagen G et al. Early-
life supplementation of vitamins A and
D, in water-soluble form or in peanut
oil, and allergic diseases during child-
hood. J Allergy Clin Immunol 2006;
118:1299 – 304. Epub 2006/12/13.
86 Majak P, Olszowiec-Chlebna M,
Smejda K, Stelmach I. Vitamin D sup-
plementation in children may prevent
asthma exacerbation triggered by acute
respiratory infection. J Allergy Clin
Immunol 2011; 127:1294 – 6. Epub
2011/02/15.
87 Urashima M, Segawa T, Okazaki M,
Kurihara M, Wada Y, Ida H. Random-
ized trial of vitamin D supplementationto prevent seasonal influenza A in
schoolchildren. Am J Clin Nutr 2010;
91:1255 – 60. Epub 2010/03/12.
88 Sidbury R, Sullivan AF, Thadhani RI,
Camargo CA Jr. Randomized controlled
trial of vitamin D supplementation for
winter-related atopic dermatitis in Bos-
ton: a pilot study. Br J Dermatol 2008;
159:245 – 7. Epub 2008/05/21.
89 Hata TR, Kotol P, Jackson M, Nguyen
M, Paik A, Udall D et al. Administra-
tion of oral vitamin D induces cath-
elicidin production in atopic
individuals. J Allergy Clin Immunol2008; 122:829 – 31. Epub 2008/11/19.
90 Sandhu MS, Casale TB. The role of
vitamin D in asthma. Ann Allergy
Asthma Immunol 2010; 2:17. Epub
2010/08/31.
© 2011 Blackwell Publishing Ltd, Clinical & Experimental Allergy , 1–
10
10 M. Reinholz et al
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