Allergy

REVIEW ARTICLE

The role of vitamin D in the immunopathogenesis of

allergic skin diseases
A. A. Benson1*, J. A. Toh2*, N. Vernon3 & S. P. Jariwala4
1
Albert Einstein College of Medicine, Bronx; 2Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine,
Bronx; 3Department of Pediatrics, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx; 4Division of Allergy/Immunology,
Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA

To cite this article: Benson AA, Toh JA, Vernon N, Jariwala SP. The role of vitamin D in the immunopathogenesis of allergic skin diseases. Allergy 2012; 67:
296–301.

Keywords Abstract
atopic dermatitis; environment;
epidemiology; vitamin D; urticaria.
Vitamin D plays key roles in innate and adaptive immunity through the stimula-
tion of Toll-like receptors, increasing pro-inflammatory cytokine production, and
Correspondence possibly enhancing T helper type 2 responses. These mechanisms may explain the
Sunit P. Jariwala, Division of Allergy/ growing body of evidence connecting vitamin D to allergic diseases, including
Immunology, Montefiore Medical Center, asthma, food allergies, and allergic rhinitis. The data relating vitamin D to aller-
Albert Einstein College of Medicine, 111 gic skin diseases are equivocal with studies linking both high and low vitamin D
East 210th Street, Bronx, NY 10463, USA. levels to an increased risk of developing atopic dermatitis. In this paper, we
Tel.: +718 920 4321 describe the role of vitamin D in the immunopathogenesis of atopic dermatitis
Fax: +718 405 8074
and other allergic skin diseases.
E-mail: sjariwal@montefiore.org

*These contributed equally to the

preparation and revision of this manuscript.

Accepted for publication 3 November 2011

DOI:10.1111/j.1398-9995.2011.02755.x

Edited by: Hans-Uwe Simon

Vitamin D metabolism (Fig. 1) begins both through

Introduction
absorption in the skin as vitamin D3 (cholecalciferol) and
A growing body of literature has linked decreased serum vita- absorption through the gut as either vitamin D2 (ergocalcif-
min D levels with distinct diseases, both those related to skele- erol) or vitamin D3. Cholecalciferol and ergocalciferol are
tal health and others (1–3). Vitamin D deficiency is defined as then metabolized in the liver to 25-hydroxyvitamin-D
serum 25(OH)D <10 ng/ml, and leads to the development of (25(OH)D), which is the vitamin D pro-hormone usually
vitamin D-related bone disease (e.g. rickets). There is also an used to measure vitamin D levels clinically. 25(OH)D is bene-
increasing concern for vitamin D insufficiency, which is char- ficial clinically since it is stable, has a half life of 3 weeks in
acterized by 25(OH)D levels between 21 and 29 ng/ml (2, 3). human serum, and most accurately represents total vitamin
Several studies have connected lower vitamin D levels with D stores in the body (1, 3). 25(OH)D is subsequently metab-
higher cardiovascular mortality rates, increased risk of diabe- olized in the kidney to its active form, 1,25-dihydroxyvitamin
tes mellitus, increased risk of cancer, and an increased risk of D (1,25(OH)2D), or calcitriol. Calcitriol plays a key role in
infections (2). Vitamin D deficiency has also been inconsis- skeletal as well as extraskeletal functions including immunity
tently associated with atopic diseases, although large-scale and glucose metabolism (2).
prospective and randomized studies are lacking. While many In light of several conflicting hypotheses that are further
of the pathways of vitamin D metabolism in the body are well described in the next section, vitamin D levels have been both
known, the precise mechanisms underlying vitamin D’s effects positively and negatively correlated with allergic disease prev-
on allergic diseases have not been elucidated. alence. For example, high asthma prevalence and increased

296 Allergy 67 (2012) 296–301 ª 2011 John Wiley & Sons A/S
Benson et al. The role of vitamin D in the immunopathogenesis

Skin : Diet:
7-dehydrocholesterol Cholecalciferol (D3)
UVB or Ergocalciferol (D2)
Previtamin D3

Cholecalciferol (D3)

Liver:
D2 and D3
25-hydroxylase

25-hydroxyvitamin D
(25(OH)D)

Kidney:
(25(OH)D)
1,α-hydroxylase

1,25-dihydroxyvitamin D
(1,25(OH)2D or calcitriol)

Figure 1 Metabolism of Vitamin D.

asthma symptoms have been observed in patients with low mechanisms begin with the binding of 1,25(OH)2D to the
vitamin D levels and in children whose mothers had low VDR, a nuclear hormone receptor, which leads to VDR
intake of vitamin D during pregnancy (4–12). In addition, dimerization with the retinoid X receptor (RXR) (19–21)
higher Epi-pen prescription rates and higher emergency room (Fig. 3). The 1,25(OH)2D-RXR-VDR complex then binds to
visit rates for acute allergic reactions have been observed in Vitamin D response elements (VDRE) on DNA. Further-
geographic areas in which people have less sun exposure and more, the VDR shows enhanced expression in immature
therefore lower vitamin D skin absorption (13–15). Recently, monocytes and contributes to increased nitric oxide produc-
vitamin D deficiency has been shown to correlate with many tion by macrophages in the setting of infection (22). Vitamin
food and environmental allergies in children (16). Conversely, D also impacts the innate immune system by stimulating the
other studies have shown an association between high vita- production of cathelicidin, which is an anti-microbial peptide
min D levels and the development of allergic rhinitis (17, 18). that is activated through toll-like receptors (TLRs), particu-
Since most vitamin D is absorbed via the skin, the impact of larly TLR2 and TLR4 (19, 20, 23, 24). With regards to adap-
vitamin D levels on allergic skin diseases is of particular tive immunity, the VDR-RXR complex binds to target genes
interest and may be unique. This paper reviews the immuno- to moderate gene expression in DCs, macrophages, and other
logic mechanisms of vitamin D, specifically as they relate to antigen presenting cells (25). Vitamin D may also have anti-
atopy, and examines the data connecting vitamin D to the inflammatory properties, as observed by the 1,25(OH)2D-
development of allergic skin diseases. mediated reduction of DC maturation (26). Furthermore,
1,25(OH)2D inhibits DC migration and IL-12 and IL-23
cytokine production (19).
Vitamin D and immunologic mechanisms
Through its inhibition of adaptive immune responses, vita-
Vitamin D plays a key role in the immune responses gener- min D may suppress the production of IL-12, thereby reducing
ated by lymphocytes and antigen-presenting cells. Its role on the production of T helper type 1 (Th1) cells and potentially
the regulation of cells of the immune system has been recog- leading to increased proliferation of allergy-associated T helper
nized recently with the discovery of Vitamin D receptors type 2 (Th2) cells (27). Upon stimulation by vitamin D, naı̈ve
(VDRs) on distinct cell types. Specifically, VDRs have been CD4+ T cells have also been shown to lead to a Th2 response
identified on nearly all cells of the immune system including and increase production of IL-4, IL-5, and IL-10 (28). In con-
T cells, B cells, neutrophils, macrophages, and dendritic cells trast to these findings, other studies have shown that vitamin
(DCs) (19). The continued elucidation of the mechanisms sur- D contributes to the conversion of CD4+ T cells to T regula-
rounding vitamin D’s actions through VDRs helped clarify tory cells, which have been shown to play a role in the suppres-
the link between vitamin D and immune functions. sion of pro-allergic mechanisms (29).
Recent data have suggested that vitamin D affects both Two seemingly contradictory hypotheses have emerged
innate and adaptive immune mechanisms (Fig. 2). These regarding the role of vitamin D in the generation of allergic

Allergy 67 (2012) 296–301 ª 2011 John Wiley & Sons A/S 297
The role of vitamin D in the immunopathogenesis Benson et al.

Macrophages
≠ NO produc on B cells
Dendri c cells ≠
≠ Cathelicidin ≠ IgE produc on (invitro)
≠ Phagocytosis Matura on ≠
≠ plasma cell
≠ Chemotaxis Migra on differen a on

+
Vitamin D

+
+
T Regulatory
Th2 cells Th17 cells
Th1 cells ≠
IL-23 cells
≠ ≠ IL-4, IL-5, IL-10
IL-12 ≠
Produc on of Th17 ≠ Conversion of CD4+ T
≠ ≠ T helper cells skewed
Produc on of Th1 cells to Th2 response cells cells to T regulatory
cells

Figure 2 The impact of vitamin D on the immune system.

Co-repressors

VDR RXR No transcription

Inhibitory
VDRE

OR
Transcription
VDR RXR
RXR Activating
VDRE

Vitamin D Co-activators

VDR

Figure 3 Vitamin D and gene expression.

diseases. The first hypothesis suggests that high vitamin D newborns in order to prevent infantile rickets (30). A compet-
levels are responsible for the rise in prevalence of allergies ing hypothesis developed several years later postulated that
and asthma (30). This theory was initially based on the low vitamin D levels may contribute to the increase in allergy
observed increase in allergies coinciding with an increase prevalence (5). This theory was supported by an observed
in vitamin D supplementation for pregnant women and association between vitamin D deficiency/insufficiency and an

298 Allergy 67 (2012) 296–301 ª 2011 John Wiley & Sons A/S
Benson et al. The role of vitamin D in the immunopathogenesis

increased prevalence of allergic diseases, such as asthma (4, risk of AD at 6 years of age. These studies collectively sup-
6–12). port the theory that increased vitamin D may be tied to aller-
Due to the conflicting observations regarding vitamin D’s gic diseases, including AD.
impact on allergy, in vitro human and in vivo murine studies However, there are several studies that suggest that vita-
have been performed to assess whether vitamin D directly min D deficiency contributes to the development of AD.
affects serum levels of immunoglobulin E (IgE). In one study, Oren et al. (36) compared vitamin D deficient patients with
previously stimulated B cells showed markedly decreased pro- vitamin D sufficient patients, and assessed the prevalence of
duction of IgE following the administration of vitamin D atopic disorders. In these patients, there was an increased risk
(31). In a second study, calcitriol and VDR agonists led to of AD among those who were vitamin D deficient, although
suppressed IgE production by cultured human B cells (32). there was no significant difference in the risk of asthma or
Furthermore, calcitriol and VDR agonists also reduced IgE allergic rhinitis (36).
production in an allergy mouse model (32). As compared to AD, there are significantly fewer studies
that have evaluated the potential link between vitamin D and
urticaria. One study showed that vitamin D levels were signif-
Effects of vitamin D on atopic dermatitis and urticaria
icantly reduced in subjects with chronic urticaria as compared
As with many of the atopic diseases, there are conflicting to controls (40). Goetz et al. (41) conducted a chart review to
data surrounding the effect that vitamin D has on the devel- investigate the possible therapeutic benefit of vitamin D for
opment of allergic skin diseases (Table 1). Most of the studies idiopathic itch, rash, and urticaria symptoms. Baseline
to assess the impact of vitamin D on allergic skin diseases 25(OH)D levels were significantly lower in those patients who
focus on atopic dermatitis (AD). The first study that investi- were later responsive to vitamin D as compared to the
gated the possible connection between vitamin D and AD patients who were unresponsive to vitamin D (41). Further-
was a prospective study primarily conducted to assess the more, 70% of patients with cutaneous symptoms and concur-
risk of recurrent wheeze in children based on maternal vita- rent vitamin D deficiency showed resolution of symptoms
min D intake (5). While the authors found a decreased risk following vitamin D replacement (41).
of recurrent wheeze in children of mothers with higher intake
of vitamin D during pregnancy, there was no decreased risk
Effects of vitamin D on severity of atopic dermatitis
of AD in these same individuals (5). Another study prospec-
tively demonstrated that increased maternal serum levels of There are several studies that have linked vitamin D supple-
25(OH)D predisposed infants to AD at 9 months of age (33). mentation with either the decreased risk or clinical improve-
Along these lines, Back et al. (34) observed that increased ment of AD. Javanbahkt et al. (37) assessed the potential
vitamin D intake during infancy correlated with a heightened treatment benefit of vitamin D supplementation in improving

Table 1 Studies assessing a link between allergic skin diseases and vitamin D

Study Conclusion

Atopic dermatitis
Camargo, C.A., et al. (2007) (5) Maternal intake of vitamin D not correlated with early childhood eczema
Sidbury, R., et al. (2008) (38) Beneficial, but no statistically significant different change in the mean AD clinical severity score of
those treated with vitamin D and placebo
Oren, E., et al. (2008) (36) Increased likelihood of AD in obese patients with vitamin D deficiency as compared to normal
vitamin D levels
Gale, C.R., et al., (2008) (33) Increased maternal serum levels of vitamin D predisposed to infant AD at nine months old
Back, O., et al. (2009) (34) Increased vitamin D intake during infancy correlated with a heightened risk of AD at six years of
age
Miyake, Y., et al. (2010) (39) Decreased risk of childhood AD above a threshold level of maternal vitamin D intake during
pregnancy
Peroni, D.G., et al. (2011) (35) In series of 37 Italian children, there was an inverse correlation between serum concentrations of
vitamin D and severity of AD
Javanbakht, M.H., et al. (2011) (37) Vitamin D alone or vitamin D with vitamin E showed a significant improvement in SCORAD index
as compared to placebo
Urticaria
Thorp, W.A., et al. (2010) (40) Vitamin D levels were significantly reduced in subjects with chronic urticaria compared to subjects
with allergic rhinitis
Goetz, D.W. (2011) (41) 70% vitamin D treatment success rate for patients with idiopathic itch, rash, and
urticaria/angioedema
Contact dermatitis
Malley, R.C., et al. (2009) (42) Vitamin D deficient male mice had an increased contact hypersensitivity response as compared to
those with normal vitamin D

Allergy 67 (2012) 296–301 ª 2011 John Wiley & Sons A/S 299
The role of vitamin D in the immunopathogenesis Benson et al.

AD symptoms, and found that administration of oral vitamin results among the studies and many of the studies have
D alone or vitamin D in combination with vitamin E showed significant limitations. The larger studies to assess the link
a significant improvement in SCORAD (‘SCORing AD’) between vitamin D and allergic skin diseases have focused on
index as compared to placebo. Sidbury et al. (38) evaluated the effects of maternal vitamin D intake during pregnancy on
the effect of vitamin D supplementation on AD improve- AD in children. Studies attempting to evaluate the treatment
ment, and randomly assigned vitamin D or placebo to eleven effect of vitamin D on allergic skin diseases have measured
children with AD. Although there was a beneficial effect in small sample sizes. Finally, a second limitation of most stud-
the treatment group, there was no statistically significant ies, especially the case-control and cross-sectional protocols,
change in the mean of either group’s AD clinical severity is that they did not ascertain a causal relationship between
score (38). A Japanese cohort of mothers and children dem- vitamin D deficiency and AD. In each study, it is difficult to
onstrated the decreased risk of childhood AD above a certain determine if the low serum vitamin D levels contributed to
threshold level of maternal vitamin D intake during preg- the development of AD, whether damage of skin from AD
nancy (39). led to low vitamin D absorption from the sun, or if the two
Peroni et al. (35) demonstrated an inverse association are unrelated.
between vitamin D levels and severity of AD. The study One potential reason for the inconsistent connection
determined serum 25(OH)D levels and SCORAD index levels between vitamin D and allergic skin diseases is that there
in 37 Italian children. There was an inverse correlation may be a bimodal and/or gender-specific association. Hypon-
between serum concentrations of 25(OH)D and clinical sever- nen et al. (43) demonstrated a statistically significant non-lin-
ity of AD (35). Mean serum levels of 25(OH)D were signifi- ear association between serum 25(OH)D and serum IgE. In
cantly higher in patients with mild disease (36.9 ± 17.7 ng/ this study, patients with both low and high levels of serum
ml) compared with those with moderate (27.5 ± 8.3 ng/ml) 25(OH)D exhibited increased levels of serum IgE (43).
or severe AD (20.5 ± 5.9 ng/ml) (35) Regarding the gender-specific differences in contact hypersen-
Although there are no clinical studies to evaluate a poten- sitivity responses in mice with regards to vitamin D status,
tial connection between vitamin D and contact dermatitis in one must wonder if these findings would similarly manifest in
humans, there is one murine study that assessed this potential humans. As is evident by the many studies reviewed in this
link. Malley et al. (42) compared the contact hypersensitivity paper, it is difficult to completely assess the role that vitamin
responses of mice with normal levels of vitamin D and mice D plays in the development of atopic diseases. In order to
with deficient vitamin D levels. Within the group of mice further delineate a possible correlation between vitamin D
with normal levels of vitamin D, female mice displayed a and allergic skin diseases, large and prospective studies need
higher response as compared to males. However, vitamin D to be conducted. Randomized controlled trials regarding
deficient males showed a significantly increased contact treatment with vitamin D in the context of allergic diseases
hypersensitivity response as compared to males with normal may also assist in determining a definitive link.
vitamin D levels. Interestingly, there were no significant dif-
ferences in contact hypersensitivity responses for the female
Conflict of interest
mice between the vitamin D deficient and sufficient groups
(42). Ariel A. Benson, MD, Jennifer A. Toh, MD, Natalia Vernon,
MD, and Sunit P. Jariwala, MD have no conflicts of interest.
Conclusion
Author contributions
While there is increasing evidence to show that vitamin D
plays a significant role in the immune system, and specifically Ariel A. Benson, MD, Jennifer A. Toh, MD, Natalia Vernon,
in allergic diseases, the extent of the impact has not been MD, and Sunit P. Jariwala, MD have (i) made substantial
fully elucidated. Although many studies have sought to deter- contributions to conception and design of, or acquisition of
mine the effect that vitamin D has on allergic diseases, and data or analysis and interpretation of data; (ii) drafted the
specifically allergic skin diseases, there have been no large- article and revised it critically for important intellectual con-
scale prospective studies. Furthermore, there are conflicting tent; and (iii) gave final approval of the version to be published.

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