Nutrition xxx (2010) 1–6

Contents lists available at ScienceDirect

Nutrition
journal homepage: www.nutritionjrnl.com

Review

Current perspectives on vitamin D, immune system, and chronic diseases

Maria C. Borges M.D., Lígia A. Martini Ph.D., Marcelo M. Rogero Ph.D. *
Department of Nutrition, School of Public Health–University of São Paulo, São Paulo, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: Accumulating data support that vitamin D possesses several biological and molecular actions apart
Received 11 May 2010 from its role in calcium homeostasis. Immune cells express vitamin D receptor and are capable of
Accepted 30 July 2010 metabolizing vitamin D. Within this context, experimental studies show that vitamin D modulates
immune and inflammatory responses. Epidemiologic evidence linking poor vitamin D status to
Keywords: autoimmune diseases, type 2 diabetes, and cardiovascular disease suggests that insufficient
Vitamin D
vitamin D may be involved in the etiology of such disorders. Given the impact of immune and
Immune diseases
inflammatory abnormalities in the development of chronic diseases, including autoimmune
Inflammation
Diabetes disorders, it is possible that vitamin D might reduce chronic disease risk by modulating the
Cardiovascular disease immune system.
Ó 2010 Elsevier Inc. All rights reserved.

Introduction evidence links poor vitamin D status to osteoporosis, several

Vitamin D derives from nutritional sources or is synthesized
in the skin under a photochemical reaction influenced by
ultraviolet-B light. The preformed vitamin D needs both 25- and
1a-hydroxylation to become the active hormone 1,25-dihy-
droxivitamin D [1,25(OH)2D3]. Microsomal cytochrome P450
(CYP) isoforms (CYP2DII, CYPD25, CYP3A4, and CYP2R1) can
accomplish the 25-hydroxylation of vitamin D in human liver
cells [1], which is the main circulating form of vitamin D [for
review, see [2]]. The second hydroxylation takes place mainly in
the kidney, but it also occurs in skin, bone, cartilage, and
macrophages [3]. In the kidney, as well as in monocytes,
macrophages, and dendritic cells, 25(OH)D3 is hydroxylated by
1a-hydroxylase (CYP27B1) and 1,25(OH)2D3 is formed. For
transport, vitamin D compounds are complexed to the vitamin D
binding protein.
Vitamin D is a secosteroid (steroid with an opened B-ring)
hormone that is not limited to its well-known role in calcium
homeostasis. The genomic action of this hormone, like other
steroid hormones, is mediated by a nuclear receptor: the vitamin D
nuclear receptor (VDR). VDR acts by binding to specific DNA
sequences as a heterodimer with retinoid X receptor and to the
basal transcription machinery in a ligand-independent (TFIIB) and
-dependent manner (TFIIA). Genes with vitamin D response
elements directly and indirectly influence cell cycling and prolif-
eration, differentiation, and apoptosis [4,5]. Epidemiologic
* Corresponding author. Tel.: þ55 11 3061-7850; fax: þ55 11 3061-7705.
E-mail address: mmrogero@usp.br (M. M. Rogero).
0899-9007/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.nut.2010.07.022
cancers, diabetes mellitus, multiple sclerosis, tuberculosis, as well
as susceptibility to infection and autoimmune diseases [5].
The present review focuses on the mechanistic evidence
regarding vitamin D regulation of the immune system and its
impact on chronic disease risk.
Vitamin D and immune system
Metabolism of vitamin D in immune cells
VDR is constitutively expressed by macrophages and
dendritic cells and inducibly expressed by lymphocytes
following activation, indicating an important role for vitamin D
in the modulation of immune and inflammatory responses. The
1,25(OH)2D3 can be synthesized by antigen-presenting cells, like
macrophages and dendritic cells, because they express the
enzymes 25-hydroxylase and 1a-hydroxylase, which enable the
production of 25(OH)D3 and 1,25(OH)2D3, respectively. Given
that lymphocytes can only express 1a-hydroxylase, these cells
are just capable of converting 25(OH)D3 into 1,25(OH)2D3 [6,7].
A relevant aspect of vitamin D metabolism in macrophages
and dendritic cells refers to the fact that the mechanisms regu-
lating 1a-hydroxylase in these cells differ from the mechanisms
that regulate this enzyme in the kidney. Although, in the kidneys,
1a-hydroxylase is mainly regulated by parathyroid hormone
(PTH), calcium, and 1,25(OH)2D3, it is observed that, in macro-
phages and dendritic cells, 1a-hydroxylase is predominantly
regulated by interferon (IFN)-g and lipopolysaccharides (LPS) [3].
In this context, it should be highlighted that alveolar

Please cite this article in press as: Borges MC, et al., Current perspectives on vitamin D, immune system, and chronic diseases, Nutrition
(2010), doi:10.1016/j.nut.2010.07.022
2 M. C. Borges et al. / Nutrition xxx (2010) 1–6
macrophages of sarcoidosis patients display a very high level of
1a-hydroxylase activity, leading to high concentrations of 1,25
(OH)2D3 and hypercalcemia. Therefore, high levels of calcium
and 1,25(OH)2D3 lead to the shut-down of 1a-hydroxylase
expression in kidney cells, whereas macrophages do not respond
to these signals [8,9].
Vitamin D and Th1/Th2 responses
The activation of naive CD4þ T helper (Th) lymphocytes leads
to its differentiation in Th1 or Th2 effector subsets. Th1 cells
preferentially produce interleukin (IL)-2 and IFN-g, which
promote cellular immune responses against intracellular path-
ogens, whereas Th2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13,
promoting humoral immunity by playing an important role in
the growth and differentiation of B cells. Among the cytokines
involved in the modulation of Th1/Th2 responses, it has been
demonstrated that IL-12 favors the differentiation of naive CD4þ
Th lymphocytes to Th1, whereas the presence of IL-4 induces the
Th2 phenotype. The Th1 response contributes to an increase in
IFN-g production, resulting in the activation of macrophages,
whereas cytokines produced by Th2 cells are responsible for high
IgE antibody production, mast cell degranulation, and eosinophil
activation. Also, Th2 response has a regulatory role in the
development of Th1 response and in macrophages activation
[10]. Thus, the balance between Th1/Th2 responses can deter-
mine the outcome of different immunologically mediated clin-
ical syndromes including infectious, autoimmune, and allergic
diseases.
In relation to the modulatory effect of vitamin D on the Th1
and Th2 responses, IFN-g and IL-2 production by T cells is
diminished by exposure to 1,25(OH)2D3, whereas IL-4, IL-5, and
IL-10 are increased, consistent with a shift toward a Th2
response. The reduction in IFN-g synthesis induced by 1,25
(OH)2D3 is related to the binding of VDR/retinoid X receptor to
a silencer region in the promoter region of IFN-g gene [11,12].
Besides, the upregulation of GATA3 (GATA binding protein 3)
transcription factor caused by 1,25(OH)2D3 favors the develop-
ment of Th2 response [13].
In T lymphocytes, Fas (APO-1/CD95) and its ligand (FasL/
CD95L) regulate activation-induced cell death, a fundamental
mechanism for negative selection of immature T cells in the
thymus and for maintenance of peripheral tolerance. Cippitelli
et al. [14] reported that 1,25(OH)2D3 inhibits activation-induced
cell death, fasL mRNA expression, and that 1,25(OH)2D3-
activated VDR represses fasL promoter activity by a mechanism
dependent on the presence of a functional VDR DNA-binding
domain and ligand-dependent transcriptional activation
domain (AF-2).
Vitamin D and innate immune system
Vitamin D modulates the function of cells participating in
innate immune response, because this vitamin inhibits the
differentiation, maturation, and immunostimulatory capacity of
dendritic cells by decreasing the expression of MHC class II
molecules and of CD40, CD80, and CD86. Furthermore, mono-
cytes exposed to 1,25(OH)2D3 increase proliferation in vitro,
phagocytic and chemotactic capacity, and phagosome matura-
tion, while macrophages increase the killing of Mycobacterium
tuberculosis (Fig. 1) [15,16].
The activation of Toll-like receptors (TLRs) increases macro-
phages microbicidal activity against intracellular bacteria. Liu
et al. [16] observed that TLR activation of human macrophages
Please cite this article in press as: Borges MC, et al., Current perspectives on vitamin D, immune system, and chronic diseases, Nutrition
(2010), doi:10.1016/j.nut.2010.07.022
up-regulated expression of VDR and vitamin D-1-hydroxylase
genes, leading to the induction of the antimicrobial peptide
cathelicidin and killing of intracellular M. tuberculosis. In the
same study, it was verified that sera from African-American
individuals, known to have increased susceptibility to tubercu-
losis, had low 25(OH)D3 levels and were inefficient in supporting
cathelicidin messenger RNA induction. This fact suggests that
decreased 25(OH)D3 serum concentration is associated with an
increased susceptibility to microbial infection.
Macrophages are cells with a large capacity for cytokine
production, in particular TNF-a, which is one of the most
important products released from these cells [17]. The promoter
region of the TNF-a gene contains a complex array of potential
regulatory elements. Transcriptional activation of the TNF-a gene
in macrophages has been demonstrated to be predominantly
dependent on the transcription factor nuclear factor-kB (NF-kB),
which has four binding sites in the TNF-a promoter, and is
a major regulator of gene transcription involved in immune,
inflammatory, and stress responses [18]. With the exception of
mature B cells, in which NF-kB is constitutively nuclear, in all
other cell types including macrophages, NF-kB is kept in the
cytoplasm through association with the inhibitor-kB (IkB), which
masks their nuclear localization sequence [19]. When cells are
activated by proinflammatory cytokines [20], oxidants [21], or
LPS [22], the IkBs are rapidly phosphorylated at two serines
within their amino-terminal regulatory domains [23]. Phos-
phorylation of these two sites triggers polyubiquitination of IkBs
and their subsequent degradation. Paralleling the loss of IkB in
the cytoplasm is the appearance of NF-kB in the nucleus. Acti-
vated NF-kB then binds to the cognate DNA binding sites and
induces gene transcription [23]. In macrophages incubated with
1,25(OH)2D3 and then stimulated with LPS, it has been shown
that vitamin D up-regulates IkB-a levels by increasing mRNA
stability and decreasing IkB-a phosphorylation. The increase in
IkB-a levels leads to a reduction in nuclear translocation of NF-
kB, thereby causing a decline in activity. In view of the key role of
NF-kB as a transcription factor of inflammatory mediators, it is
suggested that 1,25(OH)2D3 has anti-inflammatory action in
macrophages [24]. Furthermore, 1,25(OH)2D3 suppresses the
expression of TLR2 and TLR4 protein and mRNA in human
monocytes in a time- and dose-dependent fashion (Fig. 1) [25].
Vitamin D and diseases
Vitamin D and diabetes
Type 1 diabetes
Observational data have described a higher occurrence of
type 1 diabetes mellitus (T1DM) during winter than during
summer, suggesting an inverse correlation between the inci-
dence of the disease and the exposure to sunlight [26,27], which
might be related to a role of endogenous synthesis of vitamin D
in T1DM risk reduction, because vitamin D acts as an immuno-
suppressive agent and T1DM is believed to be an autoimmune
disease [28]. In addition, there is evidence from case-control
studies that vitamin D intake during infancy, through either
vitamin D supplementation or cod liver oil use, is associated with
decreased T1DM incidence [29,30]. Within this context, in
a birth-cohort study, vitamin D supplementation (2000 IU/d)
during the first year of life reduced the risk of developing T1DM
by about 80%, whereas the incidence of the disease was three
times higher in children with suspected rickets [31].
Vitamin D deficiency results in an earlier onset and greater
overall incidence of diabetes in non-obese diabetic (NOD) mice,
 M. C. Borges et al. / Nutrition xxx (2010) 1–6
Fig. 1. Vitamin D modulates the function of macrophages, monocytes, and dendritic cells (DC). IKK: IkB kinase; IkB: inhibitor of NF-kB; LPS: lipopolysaccharides; TLR: Toll-like
receptors; VDR: vitamin D nuclear receptor.
a murine model of human T1DM [32–35]. Furthermore, the
addition of 50 ng 1,25(OH)2D3/d to the diet or its analogs represses
the development of insulitis and prevents disease onset [32–35].
The protective effect of vitamin D on T1DM development has been
associated with its modulation of the immune system. T1DM is an
autoimmune disorder, characterized by infiltration of the
pancreatic islets by mononuclear cells, mainly cytotoxic CD8þ
lymphocytes, which are regulated by IL-12-dependent Th1 cells,
leading to b-cell destruction [36–38]. Treatment of NOD mice
with the 1,25(OH)2D3 analog 1a,25-dihydroxy-16,23Z-diene-26,
27-hexafluoro-19-nor vitamin D3 (Ro 26-2198) inhibits IL-12
production and pancreatic infiltration of Th1 cells while
increasing the frequency of CD4þCD25þ regulatory T cells in
pancreatic lymph nodes [38,39].
Type 2 diabetes
Cross-sectional and case-control studies suggest an inverse
association between vitamin D status and glucose intolerance,
type 2 diabetes mellitus (T2DM), or metabolic syndrome [40–43].
However, definite conclusions are limited because vitamin D
status was measured in patients with glucose intolerance or
established diabetes, which might not reflect vitamin D status
prior to diagnosis [44]. In this context, a double-blind, random-
ized, controlled trial assessed the effect of combined calcium (500
mg/d) and vitamin D (700 IU/d) supplementation for 3 y on
glucose homeostasis in 314 Caucasian non-diabetic adults aged
65 y [45]. In a post-hoc analysis, the intake of calcium-vitamin D
supplements lowered the increase in fasting plasma glucose and
in insulin resistance (estimated by homeostasis model assess-
ment of insulin resistance) during the study period only in
participants with impaired fasting glucose at baseline. On the
other hand, calcium (1000 mg/d) plus vitamin D3 (400 IU)
supplementation did not reduce the risk of developing diabetes
over 7 y of follow-up in healthy postmenopausal women from The
Please cite this article in press as: Borges MC, et al., Current perspectives on vitamin D, immune system, and chronic diseases, Nutrition
(2010), doi:10.1016/j.nut.2010.07.022
3
Women’s Health Initiative double-blind, randomized, controlled
trial. Nevertheless, it should be emphasized that the dose of
vitamin D prescribed was low and higher doses might be required
to improve glucose metabolism and reduce diabetes risk.
Vitamin D status could affect glucose homeostasis and T2DM
risk through modulation of insulin secretion or insulin sensi-
tivity. Vitamin D deficiency impairs insulin secretion and induces
glucose intolerance in animal models [46,47], whereas repletion
of vitamin D status is associated with improvements in insulin
secretion and glucose homeostasis [48,49]. Furthermore, there
are some reports that mice expressing a functionally inactive
mutant VDR show reduced insulin and insulin mRNA levels [50].
This effect of vitamin D on insulin secretion may be mediated by
changes in intracellular calcium concentration in pancreatic
b cells [51,52]. In addition, there is some evidence that vitamin D
improves insulin sensitivity by its anti-inflammatory activity.
Incubation of isolated monocytes with 1,25(OH)2D3 attenuates
the expression of proinflammatory cytokines involved in insulin
resistance such as IL-1, IL-6, and TNF-a in T2DM patients [53],
which may be related to the down-regulation of NF-kB activity
[54]. Another mechanism by which vitamin D could interfere
with insulin sensitivity is through modulation of PTH levels.
Increased PTH can impair insulin sensitivity, and hyperparathy-
roidism is associated with a greater prevalence of glucose
intolerance and T2DM [55,56]. Therefore, vitamin D may
improve insulin action by reducing PTH levels [57].
Vitamin D and cardiovascular disease
Evolving data indicate that vitamin D deficiency plays an
important role in the genesis of coronary risk factors and
cardiovascular disease [58]. Epidemiologic studies support the
protective effect of vitamin D on incident cardiovascular events
4 M. C. Borges et al. / Nutrition xxx (2010) 1–6
[59,60]. Also, results of a meta-analysis of randomized controlled
trials suggest that intake of vitamin D supplements (300 to 2000
IU) decreased total mortality by 7%, which was in part due to the
decrease in cardiovascular mortality [61].
Individuals with deficient or insufficient serum 25(OH)D
levels have a greater prevalence of myocardial infarction, stroke,
peripheral arterial disease, and extended coronary artery calci-
fication [58,62-65]. Besides, vitamin D status is negatively asso-
ciated with several known cardiovascular risk factors such as
hypertension, diabetes mellitus, hypertriglyceridemia, and
obesity [66]. Additionally, Talmor et al. [67] showed that calci-
triol counteracted the in vitro deleterious actions of advanced
glycation end products on endothelial cells, which could
contribute to the prevention of cardiovascular complications.
Vitamin D and autoimmunity
As for the general population, hypovitaminosis D is highly
prevalent in patients with autoimmune disorders [2,68,69].
Epidemiological data indicate that >60% of patients with rheu-
matoid arthritis (RA) have 25(OH)D3 levels <50 nmol/L, and 16%
have levels in the range of vitamin D deficiency (<12.5 nmol/L),
which may have relevant implications in bone metabolism and
in the inflammatory status of these patients [70].
A number of recent studies have highlighted the association
between autoimmunity and vitamin D deficiency [71–74]. For
example, treatment of NOD mice with 1,25(OH)2D3 has been
proven effective in preventing disease, whereas 1,25(OH)2D3
deficiency in early life worsen it. The risk of developing multiple
sclerosis is 40% lower in women with the highest vitamin D
intakes (as supplements) [75]. In this context, the use of 1,25
(OH)2D3 analogs prevents experimental autoimmune encepha-
lomyelitis, a model for multiple sclerosis [76]. Also, it is impor-
tant to emphasize that 1,25(OH)2D3 suppresses experimental
inflammatory bowel disease, given that this vitamin inhibits
TNF-a production and other TNF-a-activated downstream
genes [77].
Despite the limited number of prospective studies of vitamin D
in systemic lupus erythematosus, the majority of cross-sectional
studies have shown an inverse relationship between levels of
vitamin D and disease activity. The addition of vitamin D to
peripheral blood mononuclear cells of patients with systemic
lupus erythematosus causes a significant reduction in both
spontaneous polyclonal antibody production and anti-dsDNA
autoantibody production from B lymphocytes [78].
Vitamin D receptor and inflammatory conditions
The VDR is a type 1 nuclear receptor, a transcription factor that
forms homodimers and heterodimers active in the transcription
and transrepression of about 900 genes [79]. VDR is expressed in
most cells of the immune system, including activated CD4 and
CD8 T lymphocytes, macrophages, and dendritic cells, leading to
the recognition that 1,25(OH)2D3 has a central immunomodula-
tory role [1]. In this context, it should be highlighted that the VDR/
1,25(OH)_2 D_3 complex dose-dependently interfaces with the
signaling of transcription factors such as NFkB, activating
protein 1, and nuclear factor of activated T cells (a family of five
proteins that are evolutionarily related to the REL– NFkB family of
transcription factors), all of which play a role in regulating
immunomodulatory genes and whose dysregulation could be
related to pathogenesis of autoimmune diseases [80].
Recently, 25-OHD, 1,25(OH)2D3, and the inflammatory
biomarkers, C-reactive protein and creatine kinase, were
Please cite this article in press as: Borges MC, et al., Current perspectives on vitamin D, immune system, and chronic diseases, Nutrition
(2010), doi:10.1016/j.nut.2010.07.022
measured in patients with autoimmune and chronic conditions.
Results showed a positive association between autoimmune
conditions and levels of 1,25(OH)2D3, and a slight association
with vitamin D deficiency (25-OHD 50 nmol/L) or the inflam-
matory markers [81]. Furthermore, in patients with RA, 1,25
(OH)2D3 can suppress interleukin-1b stimulation of matrix
metalloproteinases and prostaglandin E2, two important regu-
lators of inflammatory process, in synovial fibroblasts, suggest-
ing that VDR-mediated biological process are important in
controlling RA [82].
Because immune effects of 1,25(OH)2D3 are mediated through
VDR, the immune system of VDR null mice became a focus of
interest. Gysemans et al. [83] analyzed the effects of lack of
functional VDR in NOD mice. Severe immune defects were
observed, but the VDR null NOD mice, when fed a normal diet,
did not display an enhanced susceptibility to diabetes. In fact,
Bouillon et al. [1] described the discrepancies between conse-
quences of absence of VDR and vitamin D in the immune system.
It appears that vitamin D deficient animals and humans have
increased susceptibility to mycobacteria, probably due to a defi-
cient macrophage function, whereas in VDR null NOD mice
macrophage chemotaxis, phagocytosis, and respiratory burst
were normal.
Conclusion
Immune cells are capable of producing 1,25(OH)2D3. This
active form of vitamin D modulates leukocytes’ gene expression
through VDR, impacting on the function of these cells and, as
a consequence, on immune and inflammatory responses. Obser-
vational data support an association between poor vitamin D
status and chronic diseases such as diabetes and autoimmune and
cardiovascular diseases, all of which involve immune and/or
inflammatory abnormalities. However, a causal relationship has
not been established because few controlled well-designed
clinical trials have been performed. In addition, further studies
concerning the interaction of VDR gene polymorphisms and
immune/inflammatory responses could shed new light on the
understanding of the influence of vitamin D on health and disease.
References
[1] Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF,
et al. Vitamin D and human health: lessons from vitamin D receptor null
mice. Endocrine Rev 2008;29:726–76.
[2] Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81.
[3] van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D3:
basic concepts. J Steroid Biochem Mol Biol 2005;97:93–101.
[4] Samuel S, Sitrin MD. Vitamin D’s role in cell proliferation and differentia-
tion. Nutr Rev 2008;66:S116–24.
[5] Prentice A, Goldberg GR, Schoenmakers I. Vitamin D across the lifecycle:
physiology and biomarkers. Am J Clin Nutr 2008;88:500S–6S.
[6] Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A, Soler D, et al. DCs
metabolize sunlight-induced vitamin D3 to ‘program’ T cell attraction to
the epidermal chemokine CCL27. Nat Immunol 2007;8:285–93.
[7] Fritsche J, Mondal K, Ehrnsperger A, Andreesen R, Kreutz M. Regulation of
25-hydroxyvitamin D3–1a-hydroxylase and production of 1a, 25-
dihydroxyvitamin D3 by human dendritic cells. Blood 2003;102:3314–6.
[8] Rosenbaum JT, Pasadhika S, Crouser ED, Choi D, Harrington CA, Lewis JA,
et al. Hypothesis: sarcoidosis is a STAT1-mediated disease. Clin Immunol
2009;132:174–83.
[9] Dusso AS, Kamimura S, Gallieni M, Zhong M, Negrea L, Shapiro S, et al.
Gamma-interferon-induced resistance to 1,25-(OH)2D3 in human mono-
cytes and macrophages: a mechanism for the hypercalcemia of various
granulomatoses. J Clin Endocrinol Metab 1997;82:2222–32.
[10] Bowen H, Kelly A, Lee T, Lavender P. Control of cytokine gene transcription
in Th1 and Th2 cells. Clin Exp Allergy 2008;38:1422–31.
[11] Alroy I, Towers TL, Freedman LP. Transcriptional repression of the
interleukin-2 gene by vitamin D3: direct inhibition of NFATp/AP-1 complex
formation by a nuclear hormone receptor. Mol Cell Biol 1995;15:5789–99.
 M. C. Borges et al. / Nutrition xxx (2010) 1–6
[12] Cippitelli M, Santoni A. Vitamin D3: a transcriptional modulator of the
interferon-gamma gene. Eur J Immunol 1998;28:3017–30.
[13] Zhu J, Yamane H, Cote-Sierra J, Guo L, Paul WE. GATA-3 promotes Th2
responses through three different mechanisms: induction of Th2 cytokine
production, selective growth of Th2 cells and inhibition of Th1 cell-specific
factors. Cell Res 2006;16:3–10.
[14] Cippitelli M, Fionda C, Di Bona D, Di Rosa F, Lupo A, Piccoli M, et al. Negative
regulation of CD95 ligand gene expression by vitamin D3 in T lymphocytes.
J Immunol 2002;168:1154–66.
[15] Xu H, Soruri A, Gieseler RK, Peters JH. 1,25-Dihydroxyvitamin D3 exerts
opposing effects to IL-4 on MHC class-II antigen expression, accessory
activity, and phagocytosis of human monocytes. Scand J Immunol
1993;38:535–40.
[16] Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, et al. Toll-like receptor
triggering of a vitamin D-mediated human antimicrobial response. Science
2006;311:1770–3.
[17] Murphy C, Newsholme P. Macrophage-mediated lysis of a beta-cell line,
tumour necrosis factor-alpha release from bacillus Calmette-Guérin (BCG)-
activated murine macrophages and interleukin-8 release from human
monocytes are dependent on extracellular glutamine concentration and
glutamine metabolism. Clin Sci 1999;96:89–97.
[18] Ghosh S, Hayden MS. New regulators of NF-kappaB in inflammation. Nat
Rev Immunol 2008;8:837–48.
[19] Vallabhapurapu S, Karin M. Regulation and function of NF-kappaB tran-
scription factors in the immune system. Ann Rev Immunol 2009;27:693–733.
[20] Osborn L, Kunkel S, Nabel GJ. Tumor necrosis factor alpha and interleukin 1
stimulate the human immunodeficiency virus enhancer by activation of
the nuclear factor kappa B. Proc Natl Acad Sci USA 1989;86:2336–40.
[21] Cooke CL, Davidge ST. Peroxynitrite increases iNOS through NF-kappaB and
decreases prostacyclin synthase in endothelial cells. Am J Physiol Cell
Physiol 2002;282:C395–402.
[22] Sen R, Baltimore D. Inducibility of kappa immunoglobulin enhancer-
binding protein NF-kB by a posttranslational mechanism. Cell
1986;47:921–8.
[23] Perkins ND. Integrating cell-signalling pathways with NF-kappaB and IKK
function. Nat Rev Mol Cell Biol 2007;8:49–62.
[24] Cohen-Lahav M, Shany S, Tobvin D, Chaimovitz C, Douvdevani A. Vitamin D
decreases NFkappaB activity by increasing IkappaBalpha levels. Nephrol
Dial Transplant 2006;21:889–97.
[25] Sadeghi K, Wessner B, Laggner U, Ploder M, Tamandl D, Friedl J, et al.
Vitamin D3 down-regulates monocyte TLR expression and triggers hypo-
responsiveness to pathogen-associated molecular patterns. Eur J Immunol
2006;36:361–70.
[26] Karvonen M, Jäntti V, Muntoni S, Stabilini M, Stabilini L, Muntoni S, et al.
Comparison of the seasonal pattern in the clinical onset of IDDM in Finland
and Sardinia. Diabetes Care 1998;21:1101–9.
[27] Ponsonby AL, Pezic A, Ellis J, Morley R, Cameron F, Carlin J, et al. Variation
in associations between allelic variants of the vitamin D receptor gene and
onset of type 1 diabetes mellitus by ambient winter ultraviolet radiation
levels: a meta-regression analysis. Am J Epidemiol 2008;168:358–65.
[28] Bach JF. Insulin-dependent diabetes mellitus as an autoimmune disease.
Endocr Rev 1994;15:516–42.
[29] The EURODIAB Substudy 2 Study Group. Vitamin D supplement in early
childhood and risk for Type I (insulin-dependent) diabetes mellitus. Dia-
betologia 1999;42:51–4.
[30] Stene LC, Joner G, for the Norwegian Childhood Diabetes Study Group. Use
of cod liver oil during the first year of life is associated with lower risk of
childhood-onset type 1 diabetes: a large, population-based, case-control
study. Am J Clin Nutr 2003;78:1128–34.
[31] Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM. Intake of
vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet
2001;358:1500–3.
[32] Mathieu C, Waer M, Laureys J, Rutgeerts O, Bouillon R. Prevention of
autoimmune diabetes in NOD mice by 1,25 dihydroxyvitamin D3. Dia-
betologia 1994;37:552–8.
[33] Mathieu C, Waer M, Casteels K, Laureys J, Bouillon R. Prevention of type I
diabetes in NOD mice by nonhypercalcemic doses of a new structural
analog of 1,25-dihydroxyvitamin D3, KH1060. Endocrinology
1995;136:866–72.
[34] Zella JB, McCary LC, DeLuca HF. Oral administration of 1,25-dihydroxy-
vitamin D3 completely protects NOD mice from insulin-dependent
diabetes mellitus. Arch Biochem Biophys 2003;417:77–80.
[35] Giulietti A, Gysemans C, Stoffels K, van Etten E, Decallonne B, Overbergh L,
et al. Vitamin D deficiency in early life accelerates Type 1 diabetes in non-
obese diabetic mice. Diabetologia 2004;47:451–62.
[36] Trembleau S, Penna G, Bosi E, Mortara A, Gately MK, Adorini L. Interleukin
12 administration induces T helper type 1 cells and accelerates autoim-
mune diabetes in NOD mice. J Exp Med 1995;181:817–21.
[37] Mathis D, Vence L, Benoist C. Beta-cell death during progression to dia-
betes. Nature 2001;414:792–8.
[38] Gregori S, Giarratana N, Smiroldo S, Uskokovic M, Adorini LA. 1alpha,25-
dihydroxyvitamin D(3) analog enhances regulatory T-cells and arrests
autoimmune diabetes in NOD mice. Diabetes 2002;51:1367–74.
Please cite this article in press as: Borges MC, et al., Current perspectives on vitamin D, immune system, and chronic diseases, Nutrition
(2010), doi:10.1016/j.nut.2010.07.022
5
[39] Adorini L. Tolerogenic dendritic cells induced by vitamin D receptor ligands
enhance regulatory T cells inhibiting autoimmune diabetes. Ann NY Acad
Sci 2003;987:258–61.
[40] Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with
insulin resistance and beta cell dysfunction. Am J Clin Nutr 2004;79:820–5.
[41] Scragg R, Sowers M, Bell C. Third National Health and Nutrition Examina-
tion Survey. Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the
Third National Health and Nutrition Examination Survey. Diabetes Care
2004;27:2813–8.
[42] Ford ES, Ajani UA, McGuire LC, Liu S. Concentrations of serum vitamin D
and the metabolic syndrome among U.S. adults. Diabetes Care
2005;28:1228–30.
[43] Cigolini M, Iagulli MP, Miconi V, Galiotto M, Lombardi S, Targher G. Serum
25-hydroxyvitamin D3 concentrations and prevalence of cardiovascular
disease among type 2 diabetic patients. Diabetes Care 2006;29:722–4.
[44] Pittas AG, Lau J, Hu FB, Dawson-Hughes B. The role of vitamin D and
calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin
Endocrinol Metab 2007;92:2017–29.
[45] Pittas AG, Harris SS, Stark PC, Dawson-Hughes B. The effects of calcium and
vitamin D supplementation on blood glucose and markers of inflammation
in nondiabetic adults. Diabetes Care 2007;30:980–6.
[46] Norman AW, Frankel JB, Heldt AM, Grodsky GM. Vitamin D deficiency
inhibits pancreatic secretion of insulin. Science 1980;209:823–5.
[47] Cade C, Norman AW. Vitamin D3 improves impaired glucose tolerance and
insulin secretion in the vitamin D-deficient rat in vivo. Endocrinology
1986;119:84–90.
[48] Kadowaki S, Norman AW. Dietary vitamin D is essential for normal insulin
secretion from the perfused rat pancreas. J Clin Invest 1984;73:759–66.
[49] Nyomba BL, Bouillon R, De Moor P. Influence of vitamin D status on
insulin secretion and glucose tolerance in the rabbit. Endocrinology
1984;115:191–7.
[50] Zeitz U, Weber K, Soegiarto DW, Wolf E, Balling R, Erben RG. Impaired
insulin secretory capacity in mice lacking a functional vitamin D receptor.
FASEB J 2003;17:509–11.
[51] Billaudel BJ, Faure AG, Sutter BC. Effect of 1,25 dihydroxyvitamin D3 on
isolated islets from vitamin D3-deprived rats. Am J Physiol
1990;258:E643–8.
[52] Danescu LG, Levy S, Levy J. Vitamin D and diabetes mellitus. Endocrine
2009;35:11–7.
[53] Giulietti A, van Etten E, Overbergh L, Stoffels K, Bouillon R, Mathieu C.
Monocytes from type 2 diabetic patients have a pro-inflammatory profile.
1,25-Dihydroxyvitamin D(3) works as anti-inflammatory. Diabetes Res Clin
Pract 2007;77:47–57.
[54] Cohen-Lahav M, Douvdevani A, Chaimovitz C, Shany S. The anti-
inflammatory activity of 1,25-dihydroxyvitamin D3 in macrophages. J
Steroid Biochem Mol Biol 2007;103:558–62.
[55] Saxe AW, Gibson G, Gingerich RL, Levy J. Parathyroid hormone decreases in
vivo insulin effect on glucose utilization. Calcif Tissue Int 1995;57:127–32.
[56] Procopio M, Magro G, Cesario F, Piovesan A, Pia A, Molineri N, et al. The oral
glucose tolerance test reveals a high frequency of both impaired glucose
tolerance and undiagnosed Type 2 diabetes mellitus in primary hyper-
parathyroidism. Diabet Med 2002;19:958–61.
[57] Teegarden D, Donkin SS, Vitamin D. emerging new roles in insulin sensi-
tivity. Nutr Res Rev 2009;22:82–92.
[58] Lee JH, O’Keefe JH, Bell D, Hensrud DD, Holick MF. Vitamin D deficiency an
important, common, and easily treatable cardiovascular risk factor? J Am
Coll Cardiol 2008;52:1949–56.
[59] Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-hydroxyvitamin D and risk of
myocardial infarction in men: a prospective study. Arch Intern Med
2008;168:1174–80.
[60] Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, et al.
Vitamin D deficiency and risk of cardiovascular disease. Circulation
2008;117:503–11.
[61] Autier P, Gandini S. Vitamin D supplementation and total mortality:
a meta-analysis of randomized controlled trials. Arch Intern Med
2007;167:1730–7.
[62] Scragg R, Jackson R, Holdaway IM, Lim T, Beaglehole R. Myocardial
infarction is inversely associated with plasma 25-hydroxyvitamin D3
levels: a community-based study. Int J Epidemiol 1990;19:559–63.
[63] Poole KE, Loveridge N, Barker PJ, Halsall DJ, Rose C, Reeve J, et al. Reduced
vitamin D in acute stroke. Stroke 2006;37:243–5.
[64] Melamed ML, Muntner P, Michos ED, Uribarri J, Weber C, Sharma J, et al.
Serum 25-hydroxyvitamin D levels and the prevalence of peripheral
arterial disease: results from NHANES 2001 to 2004. Arterioscler Thromb
Vasc Biol 2008;28:1179–85.
[65] Watson KE, Abrolat ML, Malone LL, Hoeg JM, Doherty T, Detrano R, et al.
Active serum vitamin D levels are inversely correlated with coronary
calcification. Circulation 1997;96:1755–60.
[66] Martins D, Wolf M, Pan D, Zadshir A, Tareen N, Thadhani R, et al. Prev-
alence of cardiovascular risk factors and the serum levels of 25-hydrox-
yvitamin D in the United States: data from the Third National Health
and Nutrition Examination Survey. Arch Intern Med 2007;167:
1159–65.
6 M. C. Borges et al. / Nutrition xxx (2010) 1–6
[67] Talmor Y, Golan E, Benchetrit S, Bernheim J, Klein O, Green J, et al. Calcitriol
blunts the deleterious impact of advanced glycation end products on
endothelial cells. Am J Physiol Renal Physiol 2008;294:F1059–64.
[68] Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-
hydroxyvitamin D levels and risk of multiple sclerosis. JAMA
2006;296:2832–8.
[69] Craig SM, Yu F, Curtis JR, Alarcón GS, Conn DL, Jonas B, et al. Vitamin D status
and its associations with disease activity and severity in African Americans
with recent-onset rheumatoid arthritis. J Rheumatol 2010;37:275–81.
[70] Orbach H, Zandman-Goddard G, Amital H, Barak V, Szekanecz Z, Szucs G, et al.
Novel biomarkers in autoimmune diseases: prolactin, ferritin, vitamin D, and
TPA levels in autoimmune diseases. Ann NY Acad Sci 2007;1109:385–400.
[71] Lips P. Vitamin D physiology. Prog Biophys Mol Biol 2006;92:4–8.
[72] Hayes CE. Vitamin D: a natural inhibitor of multiple sclerosis. Proc Nutr Soc
2000;59:531–5.
[73] Simmons JD, Mullighan C, Welsh KI, Jewell DP. Vitamin D receptor gene
polymorphism: association with Crohn’s disease susceptibility. Gut
2000;47:211–4.
[74] Cutolo M, Otsa K, Uprus M, Paolino S, Seriolo B. Vitamin D in rheumatoid
arthritis. Autoimmun Rev 2007;7:59–64.
[75] Munger KL, Zhang SM, O’Reilly E, Hernán MA, Olek MJ, Willett WC, et al.
Vitamin D intake and incidence of multiple sclerosis. Neurology 2004;13
(62):60–5.
Please cite this article in press as: Borges MC, et al., Current perspectives on vitamin D, immune system, and chronic diseases, Nutrition
(2010), doi:10.1016/j.nut.2010.07.022
[76] Meehan TF, DeLuca HF. The vitamin D receptor is necessary for
1alpha,25-dihydroxyvitamin D(3) to suppress experimental autoimmune
encephalomyelitis in mice. Arch Biochem Biophys 2002;408:200–4.
[77] Zhu Y, Mahon BD, Froicu M, Cantorna MT. Calcium and 1alpha,25-
dihydroxyvitamin D3 target the TNF-alpha pathway to suppress experi-
mental inflammatory bowel disease. Eur J Immunol 2005;35:217–24.
[78] Kamen D, Aranow C. Vitamin D in systemic lupus erythematosus. Curr Opin
Rheumatol 2008;20:532–7.
[79] Wang TT, Tavera-Mendonza LE, Laperriere D, Libby E, MacLeod NB, Nagai Y,
et al. Large-scale in silico and microarray-based identification of direct
1,25-dihydroxivitamin D3 target genes. Mol Endocrinol 2005;19:
2685–95.
[80] Eggert M, Klutter A, Zettl UK, Neeck G. Transcription factors in autoimmune
diseases. Curr Pharm Des 2004;10:2787–896.
[81] Blaney GP, Albert PJ, Proal AD. Vitamin D metabolites as clinical markers
in autoimmune and chronic disease. Ann NY Acad Sci 2009;1173:
384–90.
[82] Tebtlow LC, Wooley DE. The effects of 1,25 dihydroxivitamin D3 on matriz
metalloproteinase and prostaglandinE (2) production by cells of the reu-
mathoid lesion. Arthritis Res 1999;1:63–70.
[83] Gysemans C, Van Etten E, Overbergh L, Giulietti A, Eelen G, Waer M, et al.
Unaltered diabetes presentation in NOD mice lacking the vitamin D
receptor. Diabetes 2008;57:269–75.