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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

© 2011 Blackwell Publishing Ltd, Clinical & Experimental Allergy , 1–

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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.

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