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PNEC-1608; No of Pages 13
Please cite this article in press as: Fernandes de Abreu, D.A., et al., Vitamin D, a neuro-immunomodulator: Implications for
neurodegenerative and autoimmune diseases. Psychoneuroendocrinology (2009), doi:10.1016/j.psyneuen.2009.05.023
Vitamin D, a neuro-immunomodulator: Implications
for neurodegenerative and autoimmune diseases
D.A. Fernandes de Abreu
a
, D. Eyles
b
,F.Fe
´ron
a,
*
a
Institut Jean Roche, NICN, CNRS UMR 6184, Faculte
´de Me
´decine, Universite
´Aix-Marseille, France
b
Queensland Centre for Mental Health Research, Queensland Brain Institute, The University of Queensland,
Brisbane, Qld 4072, Australia
Received 27 March 2009; received in revised form 20 May 2009; accepted 20 May 2009
1. Introduction
Vitamin D was first discovered during the industrial revolu-
tion, when England was struck by an unprecedented epi-
demic of rickets. In 1918, Sir Edward Mellanby demonstrated
Psychoneuroendocrinology (2009) xxx, xxx—xxx
* Corresponding author at: CNRS UMR 6184, Faculte
´de Me
´decine,
Universite
´Aix-Marseille, CS811, Bd Pierre Dramard, 13344 Marseille
cedex 15, France. Tel.: +33 491698770; fax: +33 491258970.
E-mail address: francois.feron@univmed.fr (F. Fe
´ron).
KEYWORDS
Vitamin D;
Steroid hormone;
Nervous system;
Immune system;
Multiple sclerosis
Summary It has been known for more than 20 years that vitamin D exerts marked effects on
immune and neural cells. These non-classical actions of vitamin D have recently gained a renewed
attention since it has been shown that diminished levels of vitamin D induce immune-mediated
symptoms in animal models of autoimmune diseases and is a risk factor for various brain diseases.
For example, it has been demonstrated that vitamin D (i) modulates the production of several
neurotrophins, (ii) up-regulates Interleukin-4 and (iii) inhibits the differentiation and survival of
dendritic cells, resulting in impaired allo-reactive T cell activation. Not surprisingly, vitamin D has
been found to be a strong candidate risk-modifying factor for Multiple Sclerosis (MS), the most
prevalent neurological and inflammatory disease in the young adult population.
Vitamin D is a seco-steroid hormone, produced photochemically in the animal epidermis. The
action of ultraviolet light (UVB) on 7-dehydrocholesterol results in the production of pre-vitamin
D which, after thermo-conversion and two separate hydroxylations, gives rise to the active 1,25-
dihydroxyvitamin D. Vitamin D acts through two types of receptors: (i) the vitamin D receptor
(VDR), a member of the steroid/thyroid hormone superfamily of transcription factors, and (ii) the
MARRS (membrane associated, rapid response steroid binding) receptor, also known as Erp57/
Grp58.
In this article, we review some of the mechanisms that may underlie the role of vitamin D in
various brain diseases. We then assess how vitamin D imbalance may lay the foundation for a
range of adult disorders, including brain pathologies (Parkinson’s disease, epilepsy, depression)
and immune-mediated disorders (rheumatoid arthritis, type I diabetes mellitus, systemic lupus
erythematosus or inflammatory bowel diseases). Multidisciplinary scientific collaborations are
now required to fully appreciate the complex role of vitamin D in mammal metabolism.
#2009 Elsevier Ltd. All rights reserved.
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doi:10.1016/j.psyneuen.2009.05.023
that the disease was caused by a nutritional deficiency and,
soon after, rachitic infants were cured with cod liver oil.
1,25-(OH)
2
D (1,25-dihydroxyvitamin D), the active com-
pound, was isolated for the first time, in 1922, by McCollum
and was named vitamin D. Two years later, researchers from
three universities discovered simultaneously that sunlight
was a source of vitamin D (Hess, 1924; Hume and Smith,
1924; Steenbock, 1924). In 1965, R.B. Woodward was
awarded a Nobel Price for having synthesised vitamin D
and vitamin B12.
For historical and epidemiological reasons, vitamin D has
been classified as a vitamin. However its synthesis from
precursor molecules actually begins in skin cells. Vitamin D
is now being reconsidered as a genuine steroid hormone with
a multifaceted function.
2. The steroid hormone of sunlight
Vitamin D is a steroid with a broken ring and, as such, is
named a seco-steroid. Vitamin D
2
(ergocalciferol) and vita-
min D
3
(cholecalciferol) are the two major forms of vitamin
D. Vitamin D
2
is derived from plants while vitamin D
3
is
produced photochemically in the animal epidermis. The
action of UVB radiation (295—310 nM) on 7-dehydrocholes-
terol results in the production of pre-vitamin D which, after
thermo-conversion and two separate hydroxylations (per-
formed by the P450 enzymes 25-hydroxylase and 1a-hydro-
xylase, respectively), gives rise to the active 1,25-(OH)
2
D.
Vitamin D synthesis peaks at wavelengths between 295 and
297 nm (UV index greater than 3) and satisfactory amounts of
vitamin D are produced after 15 min of sun exposure, at least
twice a week. When exposed to UVB rays during a longer
period, the body degrades pre-vitamin D as fast as it gen-
erates it and equilibrium is achieved.
1,25-(OH)
2
D can be considered as an hormone which is
released into the circulation and, with the assistance of
vitamin D binding protein (VDBP), is transported to various
target organs. It is generally appropriate to consider this
molecule as a vitamin since, in temperate regions, UVB radia-
tion fail to provide adequate amounts of vitamin D synthesis
from mid-Autumnto mid-Spring. Worldwide, a high prevalence
of hypovitaminosis D among apparently healthy children,
adolescents and adults has been observed (Gordon et al.,
2004; Holick, 2006; Huh and Gordon, 2008; Looker et al.,
2002; Rajakumar et al., 2007) and it is suggested that up to
1 billion people may have vitamin D deficiency or insufficiency
(Holick, 2007). Accordingly, hypovitaminosis D is relatively
common in developed countries, such as the US and the UK
(Compston and Coles, 2008; Lawson et al., 1999; Thomas
et al., 1998; Utiger, 1998). A large epidemiologically based
US study reported that, of the women aged 20—39 (peak ages
for child-bearing), 12% had low serum 25-hydroxyvitamin D
levels (Looker and Gunter, 1998). In France, it has been
observed that, between November and April, diet failed to
provide an adequate amount of vitamin D to normal adults
living in an urban environment with a lack of direct exposure to
sunshine (Chapuy et al., 1997). Pregnant women are at risk of
hypovitaminosis D, especially those wearing concealing
clothes (Belaid et al., 2008), because of the increased needs
of the foetus and thepotential for these women to reduce their
outdoor activity, leading to a diminished supply of vitamin D
(Hillman and Haddad, 1976; Markestad et al., 1983). Of great
concern is the observation that at the end of spring, one baby
out of four shows signs of hypovitaminosis D (Zeghoud et al.,
1997).
Initially, it was thought that liver and kidneys were the
only organs responsible for the production of 1,25-(OH)
2
D.
However, it is now clearly established that many tissues,
including the brain (Eyles et al., 2005), express vitamin D 1a-
hydroxylase, the limiting enzyme responsible for the forma-
tion of 1,25-(OH)
2
D. 1,25-(OH)
2
D receptors are also found
throughout the whole body including the CNS.
Like other neurosteroids (i.e. oestrogen) 1,25-(OH)
2
Dis
believed to act via two types of receptors: (i) the nuclear
vitamin D receptor (VDR), a member of the steroid/thyroid
hormone super-family of transcription regulation factors,
and (ii) the putative membrane receptor–—MARRS (membrane
associated, rapid response steroid binding), also known as
Erp57/Grp58. The classical actions of vitamin D start with
binding to the VDR which, in turn, hetero-dimerises with
nuclear receptors of the retinoic X receptor (RXR) family
binding to vitamin D responsive elements (VDRE), located in
the promoter regions of hundreds of target genes (Wang
et al., 2005). The more rapid non-classical actions of 1,25-
(OH)
2
D are believed to involve binding to the MARRS receptor,
located at the cell surface, initiating non-genomic effects
such as the rapid stimulation of calcium and phosphorus
uptake (Khanal and Nemere, 2007).
2.1. Genomic effects: the vitamin D receptor, a
transcription factor
Upon 1,25-(OH)
2
D binding, the VDR is phosphorylated and
recruits one of the three 9-cis retinoid X receptors (RXR).
Modulation of gene expression is then dependent of the
ability of these hetero-dimers to recruit co-regulatory pro-
teins complexes including the steroid receptor co-activators
(SRCs) and the vitamin D receptor interacting protein (DRIP).
These complexes bind to specific genomic sequences named
vitamin D responsive elements (VDRE). The VDR not only
directly activates gene transcription but also directly
down-regulates the transcription of several genes such as
those encoding PTH or CYP27B1 (for reviews, see Bouillon
et al., 2008; Kato et al., 2007; McDonald, 1984)(Fig. 1).
2.2. Rapid non-genomic effects
In addition to genomic effects, 1,25-(OH)
2
Dlikeother
neurosteroid hormones mediates these effects through
rapid non-genomic actions. Thus, 1,25-(OH)
2
Dactivates
a variety of signal transduction systems including Ca
2+
influx, release of Ca
2+
from intracellular stores, modula-
tion of adenylate cyclase, PLC and protein kinases C and D
as well as MAP and Raf kinase pathways. These activities
have been observed in many cells including enterocytes,
keratinocytes, muscle cells, osteoblasts, chondrocytes and
are cell type dependent (for reviews see Falkenstein et al.,
2000). VDR is necessary for some of these non-genomic
pathways, however another protein named 1,25-(OH)
2
D-
MARRS is also involved in these rapid non-genomic actions
(Khanal et al., 2008; Nemere et al., 2004; Rohe et al.,
2005; Teillaud et al., 2005)(Fig. 1).
+ Models
PNEC-1608; No of Pages 13
Please cite this article in press as: Fernandes de Abreu, D.A., et al., Vitamin D, a neuro-immunomodulator: Implications for
neurodegenerative and autoimmune diseases. Psychoneuroendocrinology (2009), doi:10.1016/j.psyneuen.2009.05.023
2 D.A. Fernandes de Abreu et al.
3. A neuro-immuno-modulator
Over the past 15 years accumulating data have provided
evidence that targets of 1,25-(OH)
2
D are multiple (Holick,
2006; Szodoray et al., 2008) and include nervous system
tissues (Buell and Dawson-Hughes, 2008; Cherniack et al.,
2009; Garcion et al., 2002; Kalueff and Tuohimaa, 2007;
Kiraly et al., 2006; McCann and Ames, 2008).
3.1. Vitamin D and the nervous system
Vitamin D receptors (VDR) are widely distributed throughout
the embryonic brain prominently in the neuro-epithelium and
proliferating zones (Stumpf et al., 1982). Expression is not
confined to these regions; VDR is expressed widely in the
adult brain in temporal, orbital and cingulate cortex, in the
thalamus, in the accumbens nuclei, parts of the stria termi-
nalis and amygdala and widely throughout the olfactory
system. It is also expressed in pyramidal neurons of the
hippocampal regions CA1, CA2, CA3, CA4, in rats (Stumpf
et al., 1982) as well as in humans (Eyles et al., 2005). In
parallel, it has been shown that (i) 1,25-(OH)
2
D is present in
the cerebrospinal fluid (Balabanova et al., 1984) and (ii)
genes coding for the enzymes involved in the biosynthesis/
catabolism of this hormone are expressed in the brain (Eyles
et al., 2005; Naveilhan et al., 1993; Neveu et al., 1994b).
Local synthesis of 1,25-(OH)
2
D is performed by 1a-hydroxy-
lase-expressing neurons and microglia. Altogether, these
findings suggest that 1,25-(OH)
2
D could act in a paracrine/
autocrine fashion in nervous system (for review see Garcion
et al., 2002; Kalueff and Tuohimaa, 2007).
Vitamin D has also been shown to regulate important
neurotrophic factors in the brain such as nerve growth factor
(NGF) (Wion et al., 1991). This finding has been replicated by
several groups (Cornet et al., 1998; Neveu et al., 1994a;
Saporito et al., 1994). Vitamin D has also been shown to up-
regulate neurotrophin 3 (NT3) (Neveu et al., 1994b) and glial
+ Models
PNEC-1608; No of Pages 13
Please cite this article in press as: Fernandes de Abreu, D.A., et al., Vitamin D, a neuro-immunomodulator: Implications for
neurodegenerative and autoimmune diseases. Psychoneuroendocrinology (2009), doi:10.1016/j.psyneuen.2009.05.023
Fig. 1 Vitamin D genomic and non-genomic signaling pathways. 1,25-(OH)
2
D binds to its nuclear receptor (VDR) which, after hetero-
dimerisation with RXR, induces genomic responses. The 1,25D/VDR/RXR complex recognises vitamin D responsive elements (VDRE)
within the promoter region of hundreds of genes. Upon binding, co-repressive factors (CoRe) or co-activator factors (CoAc) are
recruited. Genes whose expression is repressed by 1,25-(OH)
2
D comprise parathyroid hormone (PTH) and 1-a-hydroxylase. Within the
immune and the nervous systems, genes with an enhanced expression include (i) osteopontin, cathelicidin, TNF alpha, HLA DRB 15* and
(ii) NGF, p75NTR, TGF beta, calbindin, respectively. 1,25-(OH)
2
D can also bind to its membrane receptor (MARRS) and induce rapid non-
genomic responses. 1,25-(OH)
2
D regulates the activity of adenylate cyclase, phospholipase C (PLC), protein kinase C (PKC), Src
proteins. 1,25-(OH)
2
D induces the release of Ca
2+
from intracellular stores as well as the recruitment of extracellular Ca
2+
through store
operated channels (SOC). 1,25-(OH)
2
D also modulates the cell cycle via TGF and EGF receptors. When located in the endoplasmic
reticulum, MARRS is involved in MHC1 assembly. VDR: Vitamin D Receptor; RXR: Retinoic acid X Receptor; MARRS: membrane
associated, rapid response steroid binding; TNF: Tumour Necrosis Factor; NGF: Nerve Growth Factor; p75
NTR
: low affinity neurotrophin
receptor; TGF: Transforming Growth Factor; EGF: Epidermal Growth Factor; MHC I: major histocompatibility complex class I.
Vitamin D : a neuro-immunomodulator 3
cell line-derived neurotrophic factor (GDNF) (Naveilhan
et al., 1993) whereas neurotrophin 4 (NT4) was down-regu-
lated (Neveu et al., 1994b) in glioma cell lines. In addition,
vitamin D increases neurite outgrowth, when added to cul-
tured hippocampal cells (Brown et al., 2003). Conversely,
when vitamin D is removed from the diet of pregnant rat
females, decreased expression of NGF is observed in the
brains of both, neonates (Eyles et al., 2003) and adult off-
spring (Feron et al., 2005).
Vitamin D may also affect neuronal plasticity processes
such as axogenesis. It has been shown that vitamin D up-
regulates the expression of microtubule-associated protein-2
(MAP2), growth-associated protein-43 (GAP43) and synapsin-
1 in cultured rat cortical neurons (Taniura et al., 2006). In
parallel, using a rat model of maternal hypovitaminosis D, we
demonstrated a robust and consistent down-regulation of
transcripts and proteins involved in cytoskeleton mainte-
nance (neurofilament, tubulin, actin, MAP2, glial fibrillary
acidic protein ...), molecular transport of organelles (crea-
tine kinase b, kinesin, RhoA, dynactin) and synaptic plasticity
(drebrin, GAP43, connexin 43) (Almeras et al., 2007; Eyles
et al., 2007).
Finally, vitamin D has been shown to be neuro-protective,
notably by inducing the synthesis of Ca
2+
-binding proteins,
such as parvalbumin (de Viragh et al., 1989). Vitamin D has
also been reported to inhibit the synthesis of inducible nitric
oxide synthase (Garcion et al., 1997, 1998), an enzyme
induced in neurons and non-neuronal cells during ischemia
or in the neurodegenerative conditions Alzheimer’s disease,
Parkinson’s disease, AIDS, infections, multiple sclerosis).
These actions are summarised in Fig. 2.
3.2. Vitamin D and the immune system
It has been known for more than 20 years that vitamin D
exerts marked effects on immune cells (Lemire et al., 1984;
Rigby et al., 1984). However, this non-classical action of
vitamin D has recently gained a renewed attention since it
has been shown that diminished vitamin D (i) induces
immune-mediated symptoms in animal models of auto-
immune diseases such as rheumatoid arthritis, type I diabetes
mellitus, systemic lupus erythematosus or inflammatory
bowel diseases (for a review Szodoray et al., 2008) and (ii)
is a risk factor for viral infections, including tuberculosis (Liu
et al., 2006) and possibly influenza (Cannell et al., 2006). It
has also been demonstrated that vitamin D reverses age-
related inflammatory changes in the rat hippocampus (Moore
et al., 2005).
Macrophages and some dendritic cells express the VDR as
well as the two cytochrome P450 enzymes required to produce
vitamin D. Activated Tcells and, possibly, B cells express 1a-
hydroxylase and VDR only after activation (Moro et al., 2008).
CD4-positive T lymphocytes (Th1, Th2, Th17) have been shown
to be the preferential target of vitamin D. 1,25-(OH)
2
D inhibits
+ Models
PNEC-1608; No of Pages 13
Please cite this article in press as: Fernandes de Abreu, D.A., et al., Vitamin D, a neuro-immunomodulator: Implications for
neurodegenerative and autoimmune diseases. Psychoneuroendocrinology (2009), doi:10.1016/j.psyneuen.2009.05.023
Fig. 2 Vitamin D and CNS Cells. VDR and MARRS are expressed by all neural cells while 1-a-hydroxylase is found only in neurons and
astrocytes. 1,25-(OH)
2
D stimulates the expression of choline acetyl transferase (ChAT) and tyrosine hydroxylase (TH) in dopaminergic
neurons. 1,25-(OH)
2
D is a potent modulator of neurotrophin expression: in astrocytes, NGF, NT-3 and GDNF are up-regulated while NT-4
is down-regulated. In neurons, 1,25-(OH)
2
D modulates the activity of L-type calcium channels (L-Ca
2+
). It also plays a protective role by
stimulating the production of g-glutamyl transpeptidase (g-GT) and decreasing the synthesis of Inducible Nitric Oxide Synthase (iNOS)
in the astrocytes. VDR: vitamin D receptor; MARRS: membrane associated, rapid response steroid binding; NGF: neuron growth factor;
NT-3: neurotrophine-3; GDNF: glial cell line-derived neurotrophic factor; NT-4: neurotrophine-4.
4 D.A. Fernandes de Abreu et al.
Th1 cells and the production of Th1 cytokines like IL-2, IFN-g,
and TNF-a(Lemire and Archer, 1991).
Vitamin D affects the differentiation and function of cells
in the immune system. CD4-positive T lymphocytes have been
shown to be the preferential target of vitamin D. The three
distinct functional CD4 cell types are Th1, Th2 and Th17 cells.
Th1 cells preferentially produce IL-2, IFN-g, and TNF-aand
stimulate the cellular immune system. Th2 cells principally
secrete IL-4 and IL-10 and inhibit Th1 function. Th17 cells
predominantly express IL-17. Th1 cells are the main effector
cells of a number of autoimmune diseases and of organ
rejection (Liblau et al., 1995). It has been demonstrated
that vitamin D inhibits Th1 cells and the production of Th1
cytokines like IL-2, IFN-g, and TNF-a(Lemire and Archer,
1991). It has been previously observed that the mechanism
involves a VDR mediated inhibition of gene transcription
(Alroy et al., 1995; Cippitelli and Santoni, 1998). Vitamin
D has also been reported to (i) up-regulate IL-4 (Cantorna
et al., 1998) and IL-10 (Correale et al., 2009) and (ii) inhibit
the production of IL-6 and IL-17 (Correale et al., 2009) as well
as the differentiation and survival of dendritic cells, resulting
in impaired allo-reactive T cell activation (Cantorna, 2006;
Griffin et al., 2001; Mathieu and Adorini, 2002).
Vitamin D has long been known as a preventive factor for
experimental autoimmune encephalomyelitis (EAE) (Lemire
and Archer, 1991), an animal model of multiple sclerosis.
Vitamin D reversibly blocks the progression of EAE when
administered after the onset of clinical signs in both rats
(Nataf et al., 1996) and mice (Cantorna et al., 1996). In these
models, the beneficial effect of vitamin D treatment is
accompanied by an inhibition of (i) CD4 antigen expression
(Nataf et al., 1996), (ii) interleukin 12 (IL-12)-dependent T
helper type 1 cell development (Mattner et al., 2000;
Muthian et al., 2006), (iii) iNOS synthesis within the CNS
(Garcion et al., 1997) and by enhancing (i) an IL-10-depen-
dent anti-inflammatory loop (Spach et al., 2006) and (ii)
apoptotic death of inflammatory CD4+ T cells (Pedersen
et al., 2007). Similarly, a down-regulation of mRNA encoding
iNOS and the protein itself by vitamin D was demonstrated in
a rat model of hippocampal inflammation (Garcion et al.,
1998). Furthermore, after vitamin D curative treatment of
EAE, levels of the anti-inflammatory cytokines TGF-band IL-4
were increased in the mouse model (Cantorna et al., 1998).
Cells of the immune system patrolling the CNS might repre-
sent potential targets for vitamin D in immune or inflamma-
tory diseases of the brain, but microglial cells and astrocytes
also respond to the hormone during EAE or brain inflamma-
tion (Garcion et al., 1997, 1998; Nataf et al., 1996). The
immuno-modulatory properties of vitamin D are summarised
in Fig. 3.
4. Vitamin D and multiple sclerosis
Multiple Sclerosis (MS), the most prevalent neurological dis-
order in the young adult population, is an inflammatory
disease in which the immune system attacks the central
+ Models
PNEC-1608; No of Pages 13
Please cite this article in press as: Fernandes de Abreu, D.A., et al., Vitamin D, a neuro-immunomodulator: Implications for
neurodegenerative and autoimmune diseases. Psychoneuroendocrinology (2009), doi:10.1016/j.psyneuen.2009.05.023
Fig. 3 Vitamin D and the immune system. VDR and the converting enzyme, 1-a-hydroxylase, are expressed in monocytes,
macrophages, CD4+ cells, activated B cells (Act B) and dendritic cells (DC) while MARRS is ubiquitously produced. In macrophages
and monocytes (Mw/Mono) 1,25-(OH)
2
D induces the production of the antibiotic cathelicidin upon Toll-like receptor1/2 (TLR1/2)
activation. 1,25-(OH)
2
D arrests the recruitment of CD4+ lymphocytes by inhibiting the production of IL-12 by Mw/Mono and DCs and the
presentation of co-stimulatory receptors (CD40, CD80, CD86). In parallel, 1,25-(OH)
2
D stimulates the maturation of Natural Killer (NK)
T lymphocytes via the activation of T-bet factor (T-bet) which, in turn, stimulates Natural-Killer cell-associated antigen (NK1.1), a
marker for NK cells maturation. Furthermore, 1,25-(OH)
2
D plays a role in the Th1/Th2/Th17 balance by increasing the expression of
anti-inflammatory cytokines (IL-4, IL-5, IL-10, FoxP3) and reducing the production of pro-inflammatory cytokines (Il-2, IL-16, IL-23,
IFN-g).
Vitamin D : a neuro-immunomodulator 5
nervous system, provoking demyelination and axon degen-
eration (Compston and Coles, 2008). Approximately 15—20%
of MS patients have a family history of MS and studies in twins
(Ebers et al., 1986; Heltberg et al., 1985; Kinnunen et al.,
1987; Mackay and Myrianthopoulos, 1966; Mumford et al.,
1994; Williams et al., 1980) and conjugal pairs (Robertson
et al., 1997) indicate that much of this familial clustering is
the result of shared genetic risk factors. To date, the Major
Histocompatibility Complex (MHC) gene region is the pre-
ponderant area of the human genome associated with the
disease. MS is also prompted by environmental exposure.
Goldberg was the first to link sunlight, dietary factors and
epidemiology of MS (Goldberg et al., 1986). He surmised that
MS could result from an inadequate supply of vitamin D and
calcium at times of rapid myelination, mainly in adolescence.
Thirty-five years later, epidemiological, animal and in vitro
data are compelling and indicate that low vitamin D is a
candidate risk-modifying factor for MS.
1. Latitude variations. The disease is virtually unknown in
equatorial regions and there is an inverse correlation
between latitude (a proxy marker for vitamin D levels)
and disease prevalence (Esparza et al., 1995; Giovannoni
and Ebers, 2007; Hammond et al., 2000; Hernan et al.,
1999; Kurtzke et al., 1997; McGuigan et al., 2004; Nor-
man et al., 1983; Weinshenker, 1996). This inverse cor-
relation with latitude is also present within countries
being observed in Australia (Hammond et al., 2000;
McLeod et al., 1994), Canada (Willer et al., 2005), France
(Vukusic et al., 2007), New Zealand (Fawcett and Skegg,
1988) and the USA (Templer et al., 1992).
2. Ultraviolet B radiation (UVB). MS prevalence increases
with decreasing solar radiation, suggesting a protective
effect of sunlight. A reduced risk of MS was associated
with (i) higher sun exposure when aged 6—15 years in
Tasmania (van der Mei et al., 2003), (ii) summer outdoor
activities in childhood and adolescence in Norway (Kamp-
man et al., 2007) and (iii) sun sensitive skin types 1 and 2
in the UK (Woolmore et al., 2007). In the USA, a pro-
spective study among more than 7 million military per-
sonnel suggest that high circulating levels of vitamin D is
correlated to a lower risk of MS (Munger et al., 2006).
Furthermore, incidence of demyelination in MS parallels
seasonal fluctuations in vitamin D levels (Auer et al.,
2000).
3. Season of birth. There is evidence in many areas that MS
has seasonality of birth (Acheson et al., 1960; Fernandes
de Abreu et al., in press; Leibowitz et al., 1968; Suther-
land et al., 1962; Templer et al., 1992; Torrey et al.,
2000).
4. Oral vitamin D intake. Areas with diets rich in fish oil (a
major source of vitamin D) have lower incidence of MS
(Agranoff and Goldberg, 1974; Hayes et al., 1997). A
protective effect of vitamin D intake on risk of developing
MS has been reported in a cohort of nearly 200,000
women (Munger et al., 2006).
5. In vitro and animal experiments. As previously stated,
vitamin D and analogues ameliorate the clinical outcome
in EAE animal model of MS. When administered during the
immunisation phase, vitamin D prevents clinical signs of
EAE. When vitamin D is given after the beginning of
clinical signs, a significant improvement is observed
(Cantorna et al., 1996; Garcion et al., 2003; Meehan
and DeLuca, 2002; Nashold et al., 2001, 2000; Nataf
et al., 1996; Spach and Hayes, 2005; Spach et al.,
2006, 2004). It has been observed that vitamin D reverses
EAE by inhibiting chemokine synthesis and monocyte
trafficking (Pedersen et al., 2007). Conversely, a post-
natal vitamin D deficiency induces an earlier onset of the
EAE symptoms (Cantorna et al., 1996; Garcion et al.,
2003) and an amplified severity of the symptoms, includ-
ing a second paralytic attack with a noticeable ataxia
(Garcion et al., 2003).
So far, very few clinical trials in MS patients have been
conducted. Dietary supplementation with vitamin D and
other nutrients was found to decrease relapse rate in two
small groups of young MS patients but methodological biases
cast a doubt on the conclusions (Goldberg et al., 1986;
Nordvik et al., 2000). More recently, a small safety study
in 12 patients, supplemented with vitamin D, reported a
decline in the number of demyelinating plaques but without
any observed symptom improvement (Kimball et al., 2007).
Larger well-controlled trials are needed.
5. Mechanisms of action for vitamin D and
multiple sclerosis
No undisputed molecular mechanism underlying the role of
vitamin D in MS has been unveiled so far. However, several
metabolic pathways, possibly complementary, can be pro-
posed.
1. Vitamin D induces naı¨ve CD4+ T to differentiate into
regulatory T cells producing IL-10. These cells are able
to prevent CNS inflammation when they are targeted to
the site of inflammation (O’Garra and Barrat, 2003).
Accordingly, it has been found that IL-10 is essential
for vitamin D-mediated inhibition of EAE (Spach et al.,
2006). In addition, vitamin D stimulates NK cells that are
known to play an immuno-regulatory role in the preven-
tion of autoimmune diseases (Baxter and Smyth, 2002).
Deficiencies in NK cells are described in patients with MS
(Takahashi et al., 2004, 2001), or other autoimmune
diseases such as systemic lupus erythematosus and type
1 diabetes mellitus.
2. Vitamin D is a tissue-specific stimulator or inhibitor of
osteopontin, a molecule named due to its role in ossifica-
tion (Broess et al., 1995; Reinholt et al., 1990; Yoon et al.,
1987). However, osteopontin is also a pro-inflammatory
cytokine, with a pleiotropic action on the immune sys-
tem. Osteopontin (i) increases IL-12 production by
macrophages; (ii) enhances interferon gamma and TNF
expression by T cells; (iii) blocks IL-10 production by B
cells and Treg cells and (iv) augments survival of acti-
vated T cells (Stromnes and Goverman, 2007). Interest-
ingly, osteopontin-deficient mice are resistant to EAE and
have frequent remissions (Chabas et al., 2001). Moreover,
an increased number of osteopontin transcripts are also
found in the brain of MS patients (Chabas et al., 2001).
3. In one of our previous studies, we demonstrated that a
prenatal vitamin D deficiency led to a permanent dysre-
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neurodegenerative and autoimmune diseases. Psychoneuroendocrinology (2009), doi:10.1016/j.psyneuen.2009.05.023
6 D.A. Fernandes de Abreu et al.
gulation of many transcripts, including calcineurin and
one of the FK506 binding proteins (FKBP) (Eyles et al.,
2007) in brain tissue of offspring. These two molecules
play a pivotal role in immuno-suppression by limiting the
production of IL-2, which is necessary for full T-cell
activation. When bound to its ligand, FKBP blocks the
function of the enzyme calcineurin and, as a conse-
quence, inhibits the activation of the cytoplasmic com-
ponent of the nuclear factor of activated Tcells (NF-ATc),
preventing its entrance into the nucleus (Stepkowski,
2000).
4. We also observed that a prenatal vitamin D deficiency
induced an altered expression of transcripts and proteins
such as catalase, calnexin, various Heat Shock Proteins
(HSP) and GRP58/ERp57, which is also known as MARSS,
the putative membrane vitamin D receptor (Almeras
et al., 2007; Eyles et al., 2007). Interestingly, these
molecules are involved in antigen presentation and the
transport of steroid receptor from the cytoplasm to the
nucleus (Desjardins, 2003). In addition, GRP58/ERp57/
MARRS interacts with MHC I molecules and therefore may
play an unrecognized role in adaptive immunity.
5. The Major Histocompatibility Complex (MHC) gene region
is the preponderant area of the human genome asso-
ciated with multiple sclerosis. Within this region, HLA-
DRB1*1501 is the major locus determining genetic sus-
ceptibility for MS (ref). Attractively, it has been shown
very recently that vitamin D directly regulates the
expression of this gene (Ramagopalan et al., 2009).
6. It has been proposed that inadequate supply of vitamin D
during developmental myelination, mainly in adoles-
cence, is a risk factor for MS (Goldberg, 1974). This theory
is partly substantiated by a study showing that oligoden-
drocytes express VDR and respond to 1,25-(OH)
2
D(Baas
et al., 2000). In addition, we have shown that a prenatal
vitamin D deficiency induces a permanent down-regula-
tion of Myelin-associated oligodendrocytic basic protein
(MOBP) mRNA within the cerebrum of the adult offspring
(Eyles et al., 2007). However, it remains to be demon-
strated that vitamin D regulates the expression of myelin
proteins.
6. Implications for other brain diseases
The widespread expression of the receptor for vitamin D and
enzymes responsible for its synthesis in the CNS suggest that
reductions in this hormone production may be relevant for a
number of neurodegenerative or psychiatric pathologies.
6.1. Parkinson’s disease
The substantia nigra (the portion of the brain that degen-
erates in Parkinson’s disease) represents the area of the
human brain where the VDR is most highly expressed (Eyles
et al., 2005). Vitamin D also (i) protects in vitro mesence-
phalic neurons from Parkinson-like insults (Shinpo et al.,
2000) and (ii) reduces the lesion induced by injection of 6-
hydroxy-dopamine (Smith et al., 2006; Wang et al., 2001).
Vitamin D Responsive Elements (VDRE) have been identified
in silico in the promoter regions of GDNFR-a, ret, and neur-
turin, three genes strongly linked to Parkinson’s disease
((Wang et al., 2005) supplementary materials) and it has
been demonstrated that vitamin D positively regulates the
expression of GDNF (Sanchez et al., 2002) and tyrosine
hydroxylase (Puchacz et al., 1996). Furthermore, a perma-
nent down-regulation of Park 7 expression has been
described in the hippocampus of adult rats born to vitamin
D-deficient mothers (Eyles et al., 2007).
Confirmatively, a significant higher prevalence of hypovi-
taminosis D was observed in patients with Parkinson’s dis-
ease, when compared to both healthy controls and patients
with Alzheimer’s disease (Evatt et al., 2008). In addition, a
positive association between VDR gene polymorphism and
Parkinson’s disease has been reported (Kim et al., 2005).
Finally the vitamin D binding protein (VDBP) has been
recently shown to be one of eight cerebrospinal fluid bio-
markers in Parkinson’s disease (Zhang et al., 2008).
6.2. Epilepsy
A neuro-protective effect of vitamin D in a rodent model of
epilepsy was unveiled in 1984. When vitamin D is delivered
within the hippocampus, the threshold for provoked seizures
is reduced (Siegel et al., 1984). More recently, Kalueff’s team
has demonstrated that vitamin D plays an anti-convulsive role
in an epilepsy animal model, triggered by pentylenetetrazole
chloride (PTZ). Injection of vitamin D, 30—180 min before
seizure induction, reduces the deleterious effect of PTZ
(Kalueff et al., 2005). Similarly, administration of PTZ to
VDR KO mice induces shorter latencies to the onset and
increased mortality rates (Kalueff et al., 2006).
An increased expression of VDR within the hippocampus
has been observed in rats after pilocarpine-induced seizures
(Janjoppi et al., 2008). In parallel, proteomic analysis of
cerebrospinal fluid (CSF) from patients with temporal lobe
epilepsy (TLE) and controls indicated an elevated expression
of vitamin D-binding protein (DBP) (Xiao et al., 2009).
6.3. Depression
Vitamin D Responsive Elements have been identified in silico
in the promoter regions of serotonin receptors and trypto-
phan hydroxylase, two genes associated with depression
((Wang et al., 2005) supplementary materials). It is also
known that vitamin D protects against serotonin-depleting
effects of neurotoxic doses of methamphetamine (Cass et al.,
2006). Finally, in a very large study involving more than 1000
older adults, mean levels of 25-hydroxyvitamin D were found
significantly lower in those with minor depression and major
depression when compared to controls (Hoogendijk et al.,
2008).
6.4. Schizophrenia
The idea that low prenatal vitamin D could be a risk factor for
the adult onset of schizophrenia was first proposed in 1999
(McGrath, 1999). Many studies have shown that those born in
winter and spring have a significantly increased risk of
developing schizophrenia (Torrey and Miller, 1997). This risk
is magnified with increasing latitude (Davies et al., 2003).
The incidence and prevalence of schizophrenia is also
greater from sites at higher latitudes (Saha et al., 2006).
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neurodegenerative and autoimmune diseases. Psychoneuroendocrinology (2009), doi:10.1016/j.psyneuen.2009.05.023
Vitamin D : a neuro-immunomodulator 7
The incidence of schizophrenia is also significantly higher in
dark-skinned migrants to cold countries compared to the
native born (Cantor-Graae and Selten, 2005). Given that
hypovitaminosis D is more common (a) during winter and
spring, (b) at high latitudes, and (c) in dark-skinned indivi-
duals (Holick, 2005), low prenatal vitamin D ‘fits’ these key
environmental features. Preliminary evidence from analy-
tical epidemiology studies also suggests that prenatal vita-
min D warrants closer attention as a candidate risk factor.
For example, vitamin D supplements in the first year of life
significantly reduced the risk of schizophrenia in males from
a large Finnish birth cohort (McGrath et al., 2004). In addi-
tion, a pilot study found that 25-hydroxyvitamin D
3
serum
levels in 26 mothers whose children developed schizophre-
nia were lower than that of 51 control mothers whose
children did not develop the disease, but this group differ-
ence was more prominent in mothers with dark skin
(McGrath et al., 2003). A model of developmental vitamin
D deficiency to test this hypothesis has been developed in
rodents (Eyles et al., 2003; Feron et al., 2005)andisthe
subject of another article in this issue.
7. Implications for immune-mediated
disorders
For many years, exposure to sunlight has been advocated as a
mean to fight immune-mediated disorders. However, in most
cases, evidence was lacking. Now, convergent studies pro-
vide a more solid background for this kind of treatment or the
oral delivery of vitamin D.
7.1. Tuberculosis
In 1895, Niels Finsen was the first to expose individuals with
tuberculosis — lupus vulgaris — to the rays of a mercury lamp.
This simple method was efficient in curing 95% of the patients
(Zasloff, 2006). ‘‘In recognition of his contribution to the
treatment of diseases, especially lupus vulgaris, with con-
centrated light radiation’’, he was awarded the Nobel Prize
in Medicine and Physiology in 1903. However, this technique
has not been extensively used and it is only recently that it
was shown that (i) Mycobacterium tuberculosis activates the
production of VDR and 1-hydroxylase (Schauber et al., 2007)
and (ii) many patients with lupus vulgaris are vitamin D-
deficient (Chan, 2000).
The pathogenic agent, Mycobacterium tuberculosis, binds
to the Toll like receptor1/2 (TLR), expressed by monocytes
and macrophages (Liu et al., 2007). When vitamin D is added
to the culture medium of monocytes and macrophages
infested with Mycobacterium tuberculosis, the intracellular
bacterium replication is strongly reduced (Crowle et al.,
1987; Rook et al., 1986). Vitamin D acts via cathelicidin,
an antibiotic compound that exhibit a VDRE in its promoter
region (Gombart et al., 2005). Conversely, when infested
monocytes are cultivated with a VDR antagonist or in a
vitamin D-free medium, cathelicidin is not expressed any-
more (Liu et al., 2006).
In mice, a different response to Mycobacterium tubercu-
losis is at play. The activation of TLR1/2 induces an increased
production of inducible nitric oxyde synthase (iNOS), which
also displays a VDRE in its promoter region (Liu et al., 2007).
Moreover, the anti-microbial action of vitamin D on infested
monocytes and macrophages entails the regulation of phos-
phatidylinositol-3 kinase (PI3-K) (Sly et al., 2001). The latter
mechanism is mediated by a non-genomic vitamin D receptor.
7.2. Immunosuppression
Heterologous grafting of organs requires the use of immuno-
suppressants. These agents work by either reducing the
number of lymphocytes or blocking their metabolism. Several
steroids are currently used as immuno-suppressive molecules
(Hale, 2004). Among them, vitamin D stands as a strong
contender. A therapeutic benefit has been observed after
transplantation of (i) hearts, (ii) small intestines, (iii) livers,
(iv) Langerhans islets, (v) bone marrows, (vi) skins and (vii)
kidneys (Baeke et al., 2008). Vitamin D immuno-modulatory
properties are mediated by T lymphocytes and dendritic
cells.
7.3. Autoimmune diseases
Hypovitaminosis D is associated to a higher prevalence for a
very large number of autoimmune diseases (Szodoray et al.,
2008). Numerous epidemiological and animal studies indicate
that, in addition to multiple sclerosis, a dysregulated vitamin
D metabolism is involved in (i) diabetes mellitus type 1, (ii)
inflammatory bowel diseases, (iii) rheumatoid arthritis and
(iv) systemic lupus erythematosus.
7.4. Diabetes mellitus type 1
Like for multiple sclerosis, an inverse correlation between
latitude and disease incidence is found for diabetes mellitus
type 1 (Pozzilli et al., 2005; Svoren et al., 2009). Children
with rickets have a three fold increased risk of developing
diabetes mellitus type 1 (Mathieu and Adorini, 2002). Con-
versely, a vitamin D supplementation during childhood
reduces the chance of being diabetic as an adult (The EURO-
DIAB Substudy 2 Study Group, 1999). The animal model for
this disease, named Non Obese Diabetes (NOD), mimics the
main symptoms around Week 8. A peri-natal vitamin D defi-
ciency induces an increased prevalence with an earlier onset
and more severe symptoms while a postnatal vitamin D
supplementation reduces Langerhans islet apoptosis and
limits symptom severity (Bouillon et al., 2008).
7.5. Inflammatory bowel diseases
The main forms of inflammatory bowel diseases are Crohn’s
disease and ulcerative colitis. Once again, a latitude gradient
is observed for these diseases and most patients are vitamin
D-deficient (Cantorna and Mahon, 2004). Interleukin-10
knockout mice exhibit most of the attached symptoms
between Week 9 and Week 12 (Kuhn et al., 1993). Vitamin
D-deficient IL-10 KO mice start dying at Week 6 and, at Week
9, half of them are dead (Cantorna, 2000).
7.6. Rheumatoid arthritis
A higher prevalence for this disease is associated to hypovi-
taminosis D (Merlino et al., 2004) and the use of alfacalcidiol,
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Please cite this article in press as: Fernandes de Abreu, D.A., et al., Vitamin D, a neuro-immunomodulator: Implications for
neurodegenerative and autoimmune diseases. Psychoneuroendocrinology (2009), doi:10.1016/j.psyneuen.2009.05.023
8 D.A. Fernandes de Abreu et al.
a vitamin D analogue, improves the symptoms in most (89%)
patients (Andjelkovic et al., 1999). One animal model is
based on mouse immunisation with type II collagen. When
administered during the immunisation phase, vitamin D pre-
vents clinical signs of rheumatoid arthritis (Cantorna et al.,
1998). When vitamin D is given after the beginning of clinical
signs, the progression of the disease is blocked (Larsson
et al., 1998).
7.7. Systemic lupus erythematosus
Vitamin D and some of its analogues reduce the symptoms
observed in lpr/lpr knockout mice, the animal model for this
disease (Abe et al., 1990). Furthermore, it has been demon-
strated that vitamin D inhibits induced mitosis of B cells in
asymptomatic patients but not spontaneous mitosis of B cells
in symptomatic patients (Chong et al., 1989).
8. Conclusions
Vitamin D exhibits all the main characteristics of a true
neuroactive steroid. We highlighted how deficiencies, pre-
valent all around the world, may contribute to a previously
unrecognized diverse range of adverse CNS outcomes, includ-
ing autoimmune and neurodegenerative diseases. It is our
wish that this review will inspire clinical and basic research-
ers to collaborate in an effort to understand the pleiotropic
roles of vitamin D in brain function.
Conflict of interest
None declared.
Acknowledgments
We gratefully acknowledge Alarme, ARSEP, Demain Debout
Foundations, Fondation de l’Avenir and IRME (Institut pour la
Recherche sur la Moelle e
´pinie
`re et l’Ence
´phale) and the
National Health and Medical Research Council of Australia for
their financial support.
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Please cite this article in press as: Fernandes de Abreu, D.A., et al., Vitamin D, a neuro-immunomodulator: Implications for
neurodegenerative and autoimmune diseases. Psychoneuroendocrinology (2009), doi:10.1016/j.psyneuen.2009.05.023
Vitamin D : a neuro-immunomodulator 13
