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Introduction Introdução
Multiple sclerosis (MS) is a slowly progressive, often disabling disease of the central nervous system (CNS), characterized by disseminated patches of demyelination in the brain and spinal cord. A esclerose múltipla (EM) é lentamente progressiva, muitas vezes incapacitantes doenças do sistema nervoso central (SNC), caracterizada por manchas disseminadas de desmielinização no cérebro e medula espinhal. This disease results in multiple and varied neurologic symptoms and signs, usually with exacerbations and remissions at the onset: relapsing-remitting (RR) MS, followed in later years by a more chronic progressive course: secondary progressive (SP) MS. Esta doença resulta em múltiplos e variados sintomas e sinais neurológicos, geralmente com exacerbações e remissões no início: remitente-recorrente (RR), MS, seguido nos últimos anos por um curso mais crônico e progressivo: secundária progressiva (SP) MS. A primary progressive form (PP) of MS is also recognized. A forma primária progressiva (PP) de MS é reconhecido também. Women are affected more often than men. As mulheres são mais afetadas que os homens. Age at onset of the clinical symptoms is typically between 20 and 40 y. A idade de início dos sintomas clínicos é tipicamente entre 20 e 40 y. It is uncertain whether MS is a single disease or whether the varying clinical patterns, for example, the relapsing and progressive forms, represent distinct entities ( Noseworthy, 1999 ). É incerto se o MS é uma única doença ou se os padrões variáveis clínicas, por exemplo, os surtos e formas progressivas, representam entidades distintas (Dixon, 1999). In some MS patients (10–20%), the course of the disease can be classified as benign as they do not develop the characteristic disabilities ( McAlpine, 1961 ; Ramsaransing et al , 2001 ). Em alguns pacientes com esclerose múltipla (10-20%), o curso da doença pode ser classificada como benigna, pois não desenvolver a deficiência característica (McAlpine, 1961; Ramsaransing et al, 2001). Plaques of demyelination, with perivascular inflammation and destruction of oligodendroglia, preceded by violation of the blood–brain barrier (BBB), are scattered throughout the white matter of the CNS. Placas de desmielinização, com inflamação perivascular e destruição de oligodendroglia, precedido por violação da barreira hemato-encefálica (BBB), estão espalhadas por toda a substância branca do SNC. Apart from demyelination, axonal damage occurs in early stages of MS ( Trapp et al , 1999 ; Bjartmar et al , 2003 ). Além de desmielinização, lesão axonal ocorre nas fases iniciais de MS (Trapp et al, 1999; Bjartmar et al, 2003). Within one person, recent inflamed and more chronic lesions may coexist. Dentro de uma pessoa, os recentes lesões inflamadas e mais crônicas podem coexistir. Between MS patients, four basic patterns of neuropathological lesion characteristics suggest distinct, divergent disease mechanisms ( Lucchinetti et al , 1996 ). Entre pacientes com esclerose múltipla, quatro padrões básicos de características da lesão neuropatológicas sugerem distintas, divergentes mecanismos da doença (Lucchinetti et al, 1996).
A role for vitamin D in MS has been suggested ( Goldberg, 1974a , 1974b ; Hayes et al , 1997 ; Hayes, 2000 ). Um papel para a vitamina D em MS tem sido sugerido (Goldberg, 1974a, 1974b; Hayes et al, 1997; Hayes, 2000). The key questions concerning vitamin D are, one: is MS prevented by an adequate supply of vitamin D 3 , two: is MS aggravated by vitamin D deficiency, three: is MS aggravated by a vitamin D metabolic disorder, including four: a genetic vitamin D-related disorder? As questões-chave sobre a vitamina D, uma: MS é impedido por um fornecimento adequado de vitamina D 3, dois: MS é agravada pela deficiência de vitamina D, três: MS é agravada por um distúrbio metabólico da vitamina D, incluindo quatro: a vitamina genética D-transtorno relacionado?
Etiological factors of MS Os fatores etiológicos da MS
The etiology of MS is unknown. A etiologia da EM é desconhecida. It is regarded as a complex multicausal disease. É considerada uma doença complexa multicausal. The etiological factors comprise (a) genetic factors, (b) dysfunction of the immune system (autoimmunity), and (c) environmental factors. Os fatores etiológicos incluem: (a) fatores genéticos, (b) disfunção do sistema imune (auto), e (c) fatores ambientais.
An increased family incidence and association with certain HLA allotypes suggests genetic susceptibility ( Ebers & Sadovnick, 1994 ). Uma incidência familiar aumentada e associação com HLA alotipos certos sugere susceptibilidade genética (Sadovnick & Ebers, 1994). The genetic epidemiology indicates that MS is not a single-gene disorder ( Ebers, 1994 ; Compston, 1997 ; Noseworthy, 1999 ). A epidemiologia genética indica que o MS não é um distúrbio único gene-(Ebers, 1994; Compston, 1997; Noseworthy, 1999).
Autoimmune responses to myelin components may play an important role in the initiation of MS. Respostas auto-imunes a mielina componentes podem desempenhar um papel importante na iniciação do MS. The autoimmune character of MS is supported by the presence of numerous T lymphocytes in MS lesions and various deviating immune parameters for MS patients ( Lucchinetti et al , 1996 ). O caráter auto-imune de MS é suportado pela presença de numerosos linfócitos T em lesões de MS e de vários parâmetros imunológicos desviando para pacientes com esclerose múltipla (Lucchinetti et al, 1996). Furthermore, the autoimmune animal model for MS, experimental allergic encephalomyelitis (EAE), has supported the role of autoimmunity in the pathogenesis of MS. Além disso, o modelo animal para o auto-MS, encefalomielite alérgica experimental (EAE), tem apoiado o papel da autoimunidade na patogênese da esclerose múltipla.
Among the postulated environmental etiological factors for MS is infection by a latent virus, possibly by a human herpes virus or retrovirus, in which viral activation and expression trigger a secondary response. Entre os postulados ambientais fatores etiológicos para o MS é a infecção por um vírus latente, possivelmente por um vírus herpes humano ou retrovírus, em que a ativação viral e de expressão desencadear uma resposta secundária. However, no virus has yet been identified that causes MS ( Genain & Hauser, 1997 ; Monteyne et al , 1998 ). No entanto, nenhum vírus ainda não foi identificado que as causas da EM (Genain & Hauser, 1997; Monteyne et al, 1998). Other environmental factors, possibly contributing to susceptibility for MS, are sunlight and nutrition ( Agranoff & Goldberg, 1974 ; Alter et al , 1974 ; Goldberg, 1974a , 1974b ; Murrell et al , 1991 ; Esparza et al , 1995 ; Hutter & Laing, 1996 ; Hayes et al , 1997 ; Lauer, 1997 ; Van Noort & Amor, 1998 ). Outros fatores ambientais, podendo contribuir para a susceptibilidade para o MS, são a luz solar e nutrição (Agranoff & Goldberg, 1974; Alter et al, 1974; Goldberg, 1974a, 1974b; Murrell et al, 1991; Esparza et al, 1995; Hutter & Laing, 1996, Hayes et al, 1997; Lauer, 1997; Van Noort & Amor, 1998). The vast amount of literature on nutrition and MS indicates that food intake may be an influencing factor determining the disease susceptibility. A grande quantidade de literatura sobre a nutrição e MS indica que a ingestão de alimentos pode ser um fator que influencia a determinação da susceptibilidade à doença. For example, the intake of grain (high in phytic acid) or meat, fat, and milk from animals correlated positively with the prevalence of MS ( Swank et al , 1952 ; Goldberg, 1974a ; Murrell et al , 1991 ; Esparza et al , 1995 ). Por exemplo, a ingestão de cereais (ricos em ácido fítico) ou a carne, gordura e leite de animais foi positivamente correlacionada com a prevalência de MS (Swank et al, 1952; Goldberg, 1974a; Murrell et al, 1991; Esparza et al, 1995). Conversely, the intake of rice (low in phytic acid), fish, oil, skim milk, vegetables, and fruit correlated negatively with the prevalence of MS ( Swank, 1953 ; Goldberg, 1974a ; Lauer, 1997 ). Em contrapartida, o consumo de arroz (pobre em ácido fítico), peixes, azeite, leite desnatado, verduras e frutas correlacionada negativamente com a prevalência de MS (Swank, 1953; Goldberg, 1974a; Lauer, 1997). Both phytic acid and fat may influence the bioavailability of vitamin D metabolites. O ácido fítico e gordura podem influenciar a biodisponibilidade dos metabólitos da vitamina D. Phytic acid may reduce the absorption of calcium in the gut ( Mellanby, 1950 ). O ácido fítico podem reduzir a absorção do cálcio no intestino (Mellanby, 1950). Obesity has been associated with vitamin D deficiency ( Wortsman et al , 2000 ). A obesidade tem sido associada com a deficiência de vitamina D (Wortsman et al, 2000). Unfortunately, conclusive studies on the bioavailability of vitamin D 3 are rare as no validated methods for assessing the bioavailability are available ( Van den Berg, 1997 ). Infelizmente, os estudos conclusivos sobre a biodisponibilidade da vitamina D 3 não são raras como os métodos validados para avaliar a biodisponibilidade estão disponíveis (Van den Berg, 1997). An association has been reported in Norway between the relatively low risk of MS along its Atlantic coast and the relatively high dietary intake of fish oil, a rich source of vitamin D 3 ( Swank et al , 1952 ; Goldberg, 1974a ; Hayes et al , 1997 ). Uma associação tem sido relatada na Noruega entre o risco relativamente baixo de MS ao longo da sua costa atlântica e da ingestão dietética relativamente elevada de óleo de peixe, uma rica fonte de vitamina D 3 (Swank et al, 1952; Goldberg, 1974a; Hayes et al, 1997).
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Vitamin D metabolism Metabolismo da vitamina D
Vitamin D Vitamina D
Vitamin D 3 , a lipid-soluble vitamin, is produced by sunlight in the skin, and can also be provided by the diet. A vitamina D 3, uma vitamina solúvel em lipídios, é produzida pelo sol na pele, e também pode ser fornecido pela dieta. It is a precursor of the metabolic active hormone 1,25-(OH) 2 D. É um precursor do hormônio metabólico ativo 1,25 – (OH) 2 D. Sunlight has long been recognized as a major provider of vitamin D 3 for humans. Luz do Sol tem sido reconhecida como um importante fornecedor de vitamina D 3 para os humanos. Radiation in the UV-B (290–315 nm) portion of the solar spectrum photolyzes 7-dehydrocholesterol (provitamin D 3 ) in the skin to previtamin D 3 , which, in turn, is converted by a thermal process to vitamin D 3 ( Holick, 1987 ; Webb & Holick, 1988 ). Radiação no UV-B (290-315 nm) a porção do espectro solar photolyzes 7-dehidrocolesterol (pró-vitamina D 3) na pele a pré-vitamina D 3, que, por sua vez, é convertido por um processo térmico a vitamina D 3 ( Holick, 1987; Webb & Holick, 1988). The synthesis of vitamin D 3 in the skin is self-regulating ( Webb et al , 1989 ). A síntese da vitamina D 3 na pele é de auto-regulação (Webb et al, 1989). Excessive exposure to sunlight causes a photodegradation of previtamin D 3 and vitamin D 3 to prevent vitamin D 3 intoxication ( Clemens et al , 1982 ; Matsuoka et al , 1987 ). A exposição excessiva ao sol provoca uma fotodegradação de pré-vitamina D 3 e vitamina D 3 para evitar intoxicação por vitamina D 3 (Clemens et al, 1982; Matsuoka et al, 1987).
In addition to the production in the skin, vitamin D is supplied by food in two forms; vitamin D 2 (ergocalciferol, activated ergosterol), found in irradiated yeast, and vitamin D 3 (cholecalciferol), found in fish liver oils and fatty fish, including herring, mackerel, and sardines. Além da produção na pele, a vitamina D é fornecida pelos alimentos em duas formas, a vitamina D 2 (ergocalciferol, ativado ergosterol), encontrado no fermento irradiados e vitamina D 3 (colecalciferol), encontrada em óleos de fígado de peixe e peixes gordos , incluindo o arenque, cavala e sardinha. The natural human diet can only be considered as a secondary source of the vitamin, when there is enough exposure to sunlight ( Fraser, 1995 ; Vieth, 1999 ; Heaney et al , 2003a ). A dieta humana natural pode ser considerada apenas como uma fonte secundária de vitamina A, quando há bastante exposição à luz solar (Fraser, 1995; Vieth, 1999; Heaney et al, 2003a). However, in winter when UV-B in sunlight is limited, or when sunlight exposure is not adequate, dietary factors become of vital importance and dietary compensation should occur. No entanto, no inverno, quando a radiação UV-B na luz solar é limitada, ou quando a exposição solar não for adequada, fatores dietéticos se de vital importância e compensação alimentar deve ocorrer.
Vitamin D 3 is biologically inactive. A vitamina D 3 é biologicamente inativo. It is either stored in fat or converted by 25-hydroxylase (25-OHase) enzyme in the liver to 25OHD. Ou é armazenado na gordura ou convertida pela 25-hidroxilase (25-OHase) enzima no fígado a 25OHD. Interestingly, the presence of 25-OHase activity has also been demonstrated outside the liver in kidney, in keratinocytes in skin, and in parathyroid cells ( Lehmann et al , 1999 ; Gascon-Barre et al , 2001 ; Correa et al , 2002 ). Curiosamente, a presença de 25-atividade OHase demonstrou, também fora do fígado nos rins, nos queratinócitos na pele e nas células da paratireóide (Lehmann et al, 1999; Gascon-Barre et al, 2001; Correa et al, 2002).
25OHD 25OHD
25OHD is the major circulating form of vitamin D. The serum half-life of 25OHD is approximately 10 days to 3 weeks. 25OHD é a principal forma circulante da vitamina D. A meia-vida sérica de 25OHD é de aproximadamente 10 dias a 3 semanas. Serum 25OHD concentration is the indicator of the vitamin D status, and provides a good reflection of cumulative effects of exposure to sunlight and dietary intake of vitamin D ( Food and Nutrition Board (FNB), Institute of Medicine, 1997 ). A concentração sérica de 25OHD é o indicador do status da vitamina D, e fornece um bom reflexo do efeito cumulativo da exposição ao sol e ingestão de vitamina D (Food and Nutrition Board (FNB), Instituto de Medicina, 1997). Its concentration is used as a diagnostic criterion of vitamin D deficiency. Sua concentração é usado como critério de diagnóstico da deficiência de vitamina D. 25OHD is either stored in the liver or further converted by the enzyme 1 25OHD ou é armazenado no fígado ou ainda transformado pela enzima 1 
-hydroxylase (1 -hidroxilase (1 -OHase) to 1,25-(OH) 2 D in the kidney, as well as in extra-renal tissues, including the brain (cerebellum, cerebral cortex) and lymph nodes ( Hewison et al , 2000 ; Zehnder et al , 2001 ). -OHase) a 1,25 – (OH) 2 D no rim, bem como em tecidos extra-renais, incluindo o cérebro (cerebelo, córtex cerebral) e gânglios linfáticos (Hewison et al, 2000; Zehnder et al, 2001 ).
Renal 1,25-(OH) 2 D and extra-renal 1,25-(OH) 2 D Renal 1,25 – (OH) 2 D e extra-renal 1,25 – (OH) 2 D
1,25-(OH) 2 D is the hormonally active form of vitamin D. Accumulating reports have provided evidence that 1,25-(OH) 2 D is a pleiotropic hormone influencing a plethora of biological actions, including regulation of calcium homeostasis, control of cell differentiation and maturation, and modification of immune responses ( Casteels et al , 1995 ; Cantorna et al , 1996 ; Hayes et al , 1997 ; Verstuyf et al , 1998 ; Brown et al , 1999 ; Hewison et al , 2000 ; Hayes, 2000 ; Overbergh et al , 2000 ; Mathieu et al , 2001 ; Garcion et al , 2002 ). 1,25 – (OH) 2 D é a forma hormonal ativa da vitamina D. Acumulando relatórios forneceram provas de que 1,25 – (OH) 2 D é um hormônio pleiotrópicos influenciando um grande número de ações biológicas, incluindo a regulação da homeostase do cálcio, controle da diferenciação celular e na maturação, e modificação de respostas imunes (Casteels et al, 1995; Cantorna et al, 1996; Hayes et al, 1997; Verstuyf et al, 1998; Brown et al, 1999; Hewison et al, 2000; Hayes , 2000; Overbergh et al, 2000; Mathieu et al, 2001; Garcion et al, 2002). In addition, 1,25-(OH) 2 D induces cell death, making the hormone of potential interest in the management of breast, prostate, and colon cancer, including brain tumors ( Hewison et al , 2001 ; Garcion et al , 2002 ). Além disso, 1,25 – (OH) 2 D induz a morte celular, fazendo com que o hormônio de potencial interesse na gestão de mama, próstata e cancro do cólon, incluindo tumores cerebrais (Hewison et al, 2001; Garcion et al, 2002) . The serum half-life of 1,25-(OH) 2 D is 4–6 h ( Kumar, 1986 ). A meia-vida de 1,25 – (OH) 2 D é de 4-6 h (Kumar, 1986). The renal 1 O 1 renal -hydroxylation of 25OHD to 1,25-(OH) 2 D is highly regulated by the serum concentrations of parathyroid hormone (PTH), calcium, and phosphate ( Lips, 2001 ). -hidroxilação de 25OHD a 1,25 – (OH) 2 D é altamente regulada pelas concentrações séricas de hormônio da paratireóide (PTH), cálcio e fosfato (Lips, 2001). Owing to its relatively short serum half-life and the tight regulation of the production of 1,25-(OH) 2 D, it has not been proven to be a valuable marker for vitamin D deficiency, adequacy, or excess ( FNB, Institute of Medicine, 1997 ). Devido à sua meia soro-vida relativamente curta e uma regulamentação mais estrita da produção de 1,25 – (OH) 2 D, não foi provado ser um marcador valioso para a deficiência de vitamina D, a adequação ou excesso (FNB, Instituto de Medicina, 1997).
It is now acknowledged that a wide variety of extra-renal cells can produce 1,25-(OH) 2 D from 25OHD by the enzyme 1 É hoje reconhecido que uma ampla variedade de células extra-renal pode produzir 1,25 – (OH) 2 D a partir de 25OHD pela enzima 1 -OHase in vitro , including activated macrophages, keratinocytes, and CNS cells (neurons and microglial cells) ( Adams et al , 1985 ; Pillai et al , 1987 ; Neveu et al , 1994 ). -OHase in vitro, incluindo macrófagos ativados, queratinócitos e células do SNC (neurônios e células da microglia) (Adams et al, 1985; Pillai et al, 1987; Neveu et al, 1994). The extra-renal production of 1,25-(OH) 2 D is not regulated in the same way as its renal production. A produção extra-renal de 1,25 – (OH) 2 D não está regulamentada, da mesma forma como sua produção renal. The relationship between expression of 1 A relação entre a expressão de 1 -OHase activity by 1,25-(OH) 2 D in a particular tissue probably involves two specific mechanisms, the first of these being substrate access, and the second being auto-regulation of 1 -OHase atividade por 1,25 – (OH) 2 D em um tecido especial, provavelmente envolve dois mecanismos específicos, o primeiro deles sendo o acesso do substrato, ea segunda a ser auto-regulação de 1 -OHase activity by 1,25-(OH) 2 D itself ( Hewison et al , 2000 ). -OHase atividade por 1,25 – (OH) 2 D em si (Hewison et al, 2000).
Exceptional levels of circulating 1,25-(OH) 2 D are found in several clinical conditions. Níveis excepcionais de circulação de 1,25 – (OH) 2 D são encontrados em várias condições clínicas. Lower levels have been found in severe vitamin D deficiency ( Lips et al , 1982 , 1988 ; Bouillon et al , 1987 ), as well as in inherited vitamin D metabolic disorders and chronic renal failure. Os níveis mais baixos foram encontrados em situação de grave deficiência de vitamina D (Lips et al, 1982, 1988; Bouillon et al, 1987), bem como em distúrbios metabólicos da vitamina D herdado e insuficiência renal crônica. Higher levels, caused by excessive extra-renal production, have been observed in sarcoidosis, tuberculosis, or malignant lymphoproliferation ( Hewison et al , 2001 ). Níveis mais altos, causada pelo excesso de produção extra-renal, foram observados na sarcoidose, tuberculose, ou Linfoproliferação (Hewison et al, 2001). The gene encoding 1 O gene que codifica 1 -OHase is located on chromosome 12q13 and abnormal gene expression is the cause of hereditary pseudovitamin D-deficiency rickets (PDDR) ( St-Arnaud et al , 1997 ). -OHase está localizado no cromossomo 12q13 e expressão do gene anormal é a causa hereditária pseudovitamin D-raquitismo (deficiência PDDR) (St-Arnaud et al, 1997).
Vitamin D catabolism Catabolismo da vitamina D
Ultimately, 25OHD and 1,25-(OH) 2 D are metabolized by 24-hydroxylase (24-OHase), an enzyme induced by 1,25-(OH) 2 D itself to control its own levels in circulation ( Brown et al , 1999 ). Em última análise, 25OHD e 1,25 – (OH) 2 D são metabolizados pelo 24-hidroxilase (24-OHase), uma enzima induzida por 1,25 – (OH) 2 D-se a controlar os seus próprios níveis em circulação (Brown et al , 1999). Finally, calcitroic acid is the major excretory form ( Esvelt and De Luca, 1981 ). Finalmente, o ácido calcitroic é a principal forma de excreção (Esvelt e De Luca, 1981).
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Vitamin D transport and function A vitamina D de transportes e na função
Vitamin D-binding protein (DBP) A vitamina D-binding protein (DBP)
Vitamin D-binding protein (DBP) is a serum globulin, which is mainly produced in the liver. A vitamina D-binding protein (DBP) é uma globulina do soro, que é produzido principalmente no fígado. DBP transports vitamin D metabolites to a large number of target organs. PAD transporta metabólitos da vitamina D para um grande número de órgãos-alvo. Under normal physiological conditions, most of the circulating vitamin D metabolites are bound to DBP and albumin. Sob condições fisiológicas normais, a maioria dos metabolitos circulantes de vitamina D são obrigados a PAD e albumina. DBP helps to regulate the bioavailability of 1,25-(OH) 2 D, as it buffers the levels of the free metabolites and thus affords a degree of protection against short-term seasonally or dietary induced fluctuations ( White & Cooke, 2000 ). PAD ajuda a regular a biodisponibilidade de 1,25 – (OH) 2 D, como ele protege os níveis de metabólitos livres e, portanto, proporciona um grau de proteção contra curto prazo, as flutuações sazonais ou de dieta induzida (White & Cooke, 2000). The DBP gene locus 4q12 is among the most polymorphic known. O gene DBP locus 4q12 está entre os mais polimórfico conhecido.
Vitamin D receptor (VDR) Receptor da vitamina D (VDR)
When entering a target cell, 1,25-(OH) 2 D dissociates from DBP, diffuses across the plasma membrane, connects to the vitamin D receptor (VDR) and shuttles between the cytoplasm and the nucleus (nuclear VDR, nVDR). Ao entrar em uma célula-alvo, 1,25 – (OH) 2 D dissocia da PAD, difunde através da membrana plasmática, conecta-se ao receptor da vitamina D (VDR) e de ônibus entre o citoplasma eo núcleo (VDR nuclear, nVDR). Cellular action only follows after binding of 1,25-(OH) 2 D by the nVDR in the target cell. Ação celular só segue após a ligação de 1,25 – (OH) 2 D pelo nVDR na célula-alvo. The gene encoding the VDR is located on chromosome 12q14 and has several common allelic variants ( Zmuda et al , 2000 ). O gene que codifica o VDR está localizado no cromossomo 12q14 e tem diversas variantes alélicas comum (Zmuda et al, 2000).
The nVDR is a member of the nuclear steroid, retinoid, and thyroid hormone receptor superfamily, acts as a ligand-activated transcription regulator, and 1,25-(OH) 2 D is a ligand. O nVDR é um membro do esteróide nuclear, retinóide e superfamília do receptor da hormona tiroideia, age como um ligante ativado regulador de transcrição, e 1,25 – (OH) 2 D é um ligante. The activated VDR dimerizes with another nuclear receptor, the retinoic acid receptor (RXR). O activado dimerizes VDR com outro receptor nuclear, o receptor do ácido retinóico (RXR). The heterodimer RXR/VDR/1,25-(OH) 2 D binds to a vitamin D responsive element (VDRE), a specific sequence of DNA, in the promoter region of target genes, regulated by 1,25-(OH) 2 D. O RXR/VDR/1 heterodímero, 25 – (OH) 2 D se liga a um elemento responsivo da vitamina D (VDRE), uma seqüência específica de DNA, na região promotora dos genes-alvo, regulamentada por 1,25 – (OH) 2 D. Upon binding to the VDRE, the heterodimer RXR/VDR/1,25-(OH) 2 D activates or suppresses gene transcription, whereby synthesis of proteins is induced or repressed. Após a ligação para o VDRE, o RXR/VDR/1 heterodímero, 25 – (OH) 2 D ativa ou reprime a transcrição de genes, por meio da síntese de proteínas é induzida ou reprimida. 1,25-(OH) 2 D thus exerts biological actions through VDR-mediated gene expression dependent on the target cell ( Brown et al , 1999 ). 1,25 – (OH) 2 D, assim, exerce ações biológicas através da expressão do gene VDR-mediada dependentes da célula-alvo (Brown et al, 1999). VDR can also form homodimers, of which the functional significance is unknown ( Issa et al , 1998 ). VDR também pode formar homodímeros, do qual o significado funcional é desconhecido (Issa et al, 1998). Efficient transcription requires co-activator or co-repressor proteins ( Brown et al , 1999 ). Transcrição eficiente requer co-ativador ou co-repressor proteínas (Brown et al, 1999). For instance, Smad3, a downstream component of the transforming growth factor (TGF)- Por exemplo, Smad3, um componente a jusante do fator de crescimento transformador (TGF) — 
signaling pathway, acts as a co-activator of VDR, by potentiating ligand-induced transactivation of the VDR ( Yanagisawa et al , 1999 ). via de sinalização, atua como um co-ativador da VDR, por potencialização ligand-induced transativação do VDR (Yanagisawa et al, 1999). On the other hand, Smad-7 abrogates this Smad3-mediated VDR potentiation by inhibiting the Smad3–VDR complex. Por outro lado, Smad-7 revoga este Smad3 potenciação VDR mediada através da inibição da Smad3 complexo VDR. Thus, the interplay between the TGF- Assim, a interação entre o TGF – and vitamin D pathways can modulate the VDR transactivation both positively and negatively by involving different Smad proteins ( Yanagi et al , 1999 ). e vias de vitamina D pode modular a transativação VDR positivamente e negativamente, envolvendo diferentes proteínas Smad (Yanagi et al, 1999). 1,25-(OH) 2 D also mediates rapid responses via a putative membrane-bound receptor of the hormone ( Norman et al , 1992 ). 1,25 – (OH) 2 D é um mediador de resposta rápida através de uma membrana putative receptor do hormônio ligado (Norman et al, 1992).
Serum 1,25-(OH) 2 D concentration influences the number of VDR in the cells. Soro 1,25 – (OH) 2 D influencia a concentração do número de VDR em células. VDR in cells bind 1,25-(OH) 2 D and buffer 1,25-(OH) 2 D concentration in serum. VDR em células ligam 1,25 – (OH) 2 D e tampão 1,25 – (OH) 2 D concentração no soro. Action of 1,25-(OH) 2 D through the VDR can be hindered by low 1,25-(OH) 2 D levels, or by VDR underexpression, abnormal binding functions, and aberrant transcription ( Pike, 1991 ). Ação da 1,25 – (OH) 2 D através do VDR pode ser prejudicada pela baixa 1,25 – (OH) 2 níveis D, ou pelo VDR underexpression anormal, as funções de ligação, ea transcrição aberrante (Pike, 1991). The VDR has been identified in most nucleated cells of the body, involved in countless physiological functions ( Walters, 1992 ). O VDR tem sido identificado na maioria das células nucleadas do corpo, envolvido em inúmeras funções fisiológicas (Walters, 1992). VDR-containing cells, in autoimmune diseases, include VDR-células contendo, em doenças auto-imunes, incluem -cells in the pancreas in insulin-dependent diabetes mellitus (IDDM), chondrocytes in the joints in rheumatoid arthritis (RA), and oligodendrocytes in the brain in MS ( Casteels et al , 1995 ; Baas et al , 2000 ; DeLuca & Cantorna, 2001 ). As células do pâncreas no diabetes mellitus insulino-dependente (DMID), condrócitos nas articulações na artrite reumatóide (AR) e oligodendrócitos no cérebro em MS (Casteels et al, 1995; Baas et al, 2000; DeLuca & Cantorna, 2001). In parallel to oligodendrocytes, other CNS constituent cells (microglia, neurons, and astrocytes) are VDR-expressing cells responding directly to the hormone ( Garcion et al , 2002 ). Em paralelo com oligodendrócitos, CNS outras células constituintes microglia (, neurônios e astrócitos) são VDR-células que expressam a responder diretamente ao hormônio (Garcion et al, 2002). The VDR has also been identified in immune-competent cells, including macrophages and activated T-lymphocytes, which implies that 1,25-(OH) 2 D can exert effects on immune functions carried out by these cells ( Bhalla et al , 1983 ; Provvedini et al , 1983 ). O VDR também foi identificada em células imunes competentes, incluindo macrófagos e linfócitos T activados, o que significa que 1,25 – (OH) 2 D pode exercer efeitos sobre as funções imunológicas realizadas por essas células (Bhalla et al, 1983; Provvedini et al, 1983).
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Sunlight and vitamin D metabolism Luz solar e metabolismo da vitamina D
Sunlight and vitamin D 3 production in skin Luz solar e vitamina D na pele de produção 3
The production of vitamin D 3 in the skin depends on exposure to sunlight. A produção de vitamina D 3 na pele depende da exposição à luz solar. Yet, not all sunlight is intense enough to produce vitamin D 3 in the skin. Porém, nem toda a luz solar é intensa o suficiente para produzir a vitamina D 3 na pele. UV-B irradiance is the result of solar elevation, which in turn relies on three factors — latitude, time of year, and time of day. Irradiância UV-B é o resultado de elevação solar, que por sua vez, depende de três fatores – latitude, época do ano e hora do dia. UV-B irradiance, necessary for vitamin D 3 production, is less when the sun is lower and its path length through the atmosphere becomes longer; additional factors influencing its intensity include cloud cover, the amount of ozone, altitude, reflectivity of the earth’s surface, haze (aerosols), and other pollutions. Irradiância UV-B, necessárias para a produção de vitamina D 3, é menor quando o sol está mais baixo e seu comprimento do caminho através da atmosfera torna-se mais; fatores adicionais que influenciam a sua intensidade incluem cobertura de nuvens, a quantidade de ozônio, altitude, reflexibilidade da superfície da Terra , neblina (aerossóis), e outras poluições. In the tropics, sunlight is able to produce vitamin D 3 in the skin all year round. Nos trópicos, a luz solar é capaz de produzir a vitamina D 3 na pele durante todo o ano. Outside the tropics at latitudes between 23:5°, the sun is never at right angles relative to the earth’s surface and the seasonal influence becomes greater. Fora dos trópicos, em latitudes entre 23:5 °, o sol nunca se perpendicularmente em relação à superfície da terra e da influência sazonal torna-se maior. At latitudes higher than around 35°, sunlight is not able to produce previtamin D 3 in vitro all year round ( Holick, 2002 ). Em latitudes mais elevadas do que em torno de 35 °, a luz solar não é capaz de produzir pré-vitamina D 3, in vitro, durante todo o ano (Holick, 2002). In winter, the sun is not only weaker as its elevation is lower, but people also spend less time outdoors and cover their skin with clothing ( Webb & Holick, 1988 ). No inverno, o sol não é apenas mais fraca, pois sua elevação é menor, mas as pessoas também gastam menos tempo ao ar livre e cobrir sua pele com roupa (Webb & Holick, 1988). If one strives to achieve and maintain an optimal serum 25OHD concentration throughout the year, it is important to know when sunlight is able to produce vitamin D 3 in the skin and how long one needs to stay outdoors to produce a sufficient amount. Se alguém se esforça para alcançar e manter uma ótima 25OHD sérica concentração durante todo o ano, é importante saber quando a luz solar é capaz de produzir a vitamina D 3 na pele e em quanto tempo é necessário para ficar ao ar livre para produzir uma quantidade suficiente. Matters are being complicated, as UV-B irradiance has become a topic of increasing concern, because of its potential negative effects, including sunburn and skin cancer. Questões são complicadas, como irradiância UV-B tornou-se um tema de crescente preocupação, por causa de seus potenciais efeitos negativos, incluindo queimaduras solares e cancro da pele. Excessive UV-B irradiance needs to be avoided, without losing sight of its positive effect. Excesso irradiância UV-B deve ser evitado, sem perder de vista o seu efeito positivo.
The ability to synthesize previtamin D 3 in vitro has been published for a number of cities in the world ( Figure 1 ). A capacidade de sintetizar D previtamin 3 in vitro tem sido publicado por várias cidades do mundo (Figura 1). In Los Angeles, USA, at latitude 33:56°NL with an altitude (alt.) at 38 m above sea level, sunlight can produce previtamin D 3 in vitro all year round. Em Los Angeles, E.U.A., na latitude 33:56 ° NL com uma altitude (alt.) em 38 m acima do nível do mar, a luz solar pode produzir pré-vitamina D 3, in vitro, durante todo o ano. In Boston, USA (42:22° NL, alt. 6 m), little if any cutaneous vitamin D 3 production occurs in the four winter months from November to February, no matter how long one stays outdoors and in Edmonton, Canada (53:19° NL, alt. 715 m) the equivalent ‘vitamin D winter’ lasts 6 months, from October to March ( Webb & Holick, 1988 ). The influence of season and latitude on the synthesis of previtamin D 3 in vitro in the southern hemisphere was measured in Buenos Aires (34:50 SL°, alt. 20 m), Cape Town (33:58 SL°, alt. 42 m), Johannesburg (26:08° SL, alt. 1694 m) and Ushuaoa (54:48° SL, alt. 16 m) ( Holick, 2002 ). Only in Ushuaoa (54:48° SL, alt. 16 m) no previtamin D 3 was formed in the 6 winter months April–September. For Europe, no comparable data on cutaneous vitamin D 3 production have been reported, except for Bergen in Norway (60:17° NL, alt. 50 m). In Bergen the ‘vitamin D winter’ lasted 6 months, from October to March, but in the other months of the year the previtamin D 3 formation per month is less than in Edmonton and the hours of UV-B per day are also fewer ( Holick, 2002 ).
Cities of the world, red dots, where the length of the ‘vitamin D winter’ has been measured: Bergen in Norway (60:17° NL, alt. 50 m), Boston (44:22° NL, alt. 6 m), Buenos Aires (34:50 SL°, alt. 20 m), Edmonton (59:19 NL°, alt. 715 m), Cape Town (33:58 SL°, alt. 42 m), Johannesburg (26:08° SL, alt. 1694 m), Ushuaoa (54:48° SL, alt. 16 m). Note: At latitudes higher than around 35°, sunlight is unable to produce previtamin D 3 in vitro all year round.
Full figure and legend (178 K )
In the United States the vitamin D intake is much higher than in Europe, due to fortification of milk with 10 Nos Estados Unidos, a ingestão de vitamina D é muito maior do que na Europa, devido à fortificação do leite com 10 
g (400 IU) vitamin D per quart ( Norman, 2000 ). g (400 UI) de vitamina D por litro (Norman, 2000). Currently, in Europe, which is, by the way, much further away from the equator than the United States, milk is not fortified with vitamin D and recommended nutritional supplementation with vitamin D differs from country to country. Atualmente, na Europa, que é, aliás, muito mais longe do equador do que nos Estados Unidos, o leite não é fortificado com vitamina D e suplementação nutricional recomendada de vitamina D difere de país para país.
During the ‘vitamin D winter’, the body is dependent on its vitamin D 3 stores or on dietary intake from natural sources, food fortified with vitamin D, or supplements. Durante o “inverno vitamina D”, o corpo é dependente de sua vitamina D 3 lojas ou na ingestão de fontes naturais, alimentos fortificados com vitamina D ou suplementos. As vitamin D 3 barely occurs naturally in food, and food in most countries is not fortified with vitamin D, dietary supplementation with the vitamin may be necessary for certain groups in the ‘vitamin D winter’ to maintain an optimal 25OHD serum level throughout the year. Como a vitamina D 3 mal ocorre naturalmente nos alimentos, e alimentos, na maioria dos países não são fortificados com vitamina D, a suplementação com vitamina A pode ser necessário para certos grupos no ‘inverno vitamina D “para manter um nível sérico ideal 25OHD durante todo o ano .
Sunlight and 25OHD Luz solar e 25OHD
The approximate normal range for serum 25OHD values is 25–130 nmol/l ( Feldman et al , 1997 ). O intervalo de aproximadamente normal para soro 25OHD valores é 25-130 nmol / l (Feldman et al, 1997). Currently, there is no consensus on what represents an optimal serum 25OHD concentration. Atualmente, não há consenso sobre o que representa um ótimo soro 25OHD concentração. An increasing number of reports is available on 25OHD serum levels both in healthy and unhealthy populations, from which it has become apparent that serum 25OHD levels vary from winter to summer, with lower levels in winter ( Stamp, 1975 ; Bouillon et al , 1987 ; Lips et al , 1988 : McKenna, 1992 ; Scharla et al , 1996 ; Scharla, 1998 ). Um número crescente de relatórios está disponível em ambos os níveis séricos de 25OHD em populações saudáveis e insalubres, da qual tornou-se evidente que os níveis séricos de 25OHD variam de inverno a verão, com níveis mais baixos no inverno (Stamp, 1975; Bouillon et al, 1987; Lips et al, 1988: McKenna, 1992; Scharla et al, 1996; Scharla, 1998). Here we focus on two of these reports ( Bouillon et al , 1987 ; Scharla, 1998 ). Aqui nos concentramos em dois desses relatórios (Bouillon et al, 1987; Scharla, 1998).
In an age- and sex-stratified population-based sample of a normal population living in South Germany ( n =415, 206 women and 209 men, ranging from 50 to 80 y), serum 25OHD reached its nadir of 42.5 Em uma idade e sexo da população estratificada baseada em amostras de uma população que vive no sul da Alemanha normal (n = 415, 206 mulheres e 209 homens, variando de 50 a 80 y), 25OHD sérica atingiu seu ponto mais baixo de 42,5 
22.5 nmol/l in January, and its zenith of 67.5 22,5 nmol / l, em janeiro, e seu apogeu de 67,5 25 nmol/l in the months August and September ( Scharla et al , 1996 ). 25 nmol / l no mês de agosto e setembro (Scharla et al, 1996). Of the women, 40% had a subclinical vitamin D deficiency in winter, defined as < 30 nmol/l 25OHD ( Scharla, 1998 ). Das mulheres, 40% tinham uma deficiência subclínica de vitamina D no inverno, definidas como <30 nmol / l 25OHD (Scharla, 1998). The serum 25OHD concentration of elderly subjects living in Belgium, who were consecutively admitted to one of the geriatric wards in Leuven ( n =240, 137 women and 103 men, ranging from 55 to 99 y), reached its nadir of 18 nmol/l in February. O soro 25OHD concentração de idosos residentes na Bélgica, que foram, consecutivamente admitidas em uma das enfermarias de geriatria em Leuven (n = 240, 137 mulheres e 103 homens, variando de 55 a 99 y), atingiu seu nadir de 18 nmol / l em fevereiro. The lowest levels were recorded in the 4 months from January to April (mean < 25 nmol/l), and its zenith of 30 nmol/l in July ( Bouillon et al , 1987 ). Os níveis mais baixos foram registrados nos 4 meses de janeiro a abril (média <25 nmol / l), e seu auge de 30 nmol / l em julho (Bouillon et al, 1987). It was found that the frequency of very low levels of 25OHD (< 12.5 nmol/l) was more pronounced in wheelchair-bound or institutionalized elderly subjects ( Bouillon et al , 1987 ). Verificou-se que a freqüência de níveis muito baixos de 25OHD (<12,5 nmol / l) foi mais pronunciada em cadeira de rodas ou idosos institucionalizados (Bouillon et al, 1987). From these reports, it could be concluded that the unhealthy elderly living in Belgium had lower 25OHD levels in winter than in summer. A partir destes relatórios, pode-se concluir que a vida não saudáveis idosos na Bélgica tinham níveis de 25OHD menores no inverno que no verão. Their monthly and yearly 25OHD levels were significantly lower than those of their healthy younger control subjects. Sua mensal e anual 25OHD níveis foram significativamente inferiores aos dos seus indivíduos saudáveis jovens controle. The unhealthy elderly living in Belgium also had lower monthly 25OHD levels than the healthy elderly living in South Germany. Os idosos saudáveis que vivem na Bélgica também tinham níveis de 25OHD mensal menor do que os idosos saudáveis que vivem no sul da Alemanha. Not only in unhealthy elderly, but also in young subjects a significant difference between winter and summer 25OHD has been found ( Guillemant et al , 1995 , 1999 ; Docio et al , 1998 ; Zittermann et al , 1999 ). Não só em idosos saudáveis, mas também em indivíduos jovens, uma diferença significativa entre o inverno eo verão 25OHD foi encontrado (Guillemant et al, 1995, 1999; Docio et al, 1998; Zittermann et al, 1999). Taken together, these results emphasize a widespread seasonal variation in 25OHD levels, with low 25OHD levels in winter. Em conjunto, estes resultados enfatizam uma ampla variação sazonal em níveis de 25OHD, com baixos níveis de 25OHD no inverno. This seasonal variation is reflected in the approximate normal range for serum 25OHD values 25–130 nmol/l. Esta variação sazonal é refletido no intervalo de aproximadamente normal para soro 25OHD valores de 25-130 nmol / l. This wide range is used to classify individuals in vitamin D deficient and sufficient. Esta gama é usada para classificar os indivíduos deficientes em vitamina D e suficiente.
The Royal Dutch Meteorological Institute (KNMI) publishes the monthly and yearly mean duration of sunlight in hours of different cities in the world ( Nellestijn & Dekker, 1998 ). O Instituto Meteorológico Real Holandês (KNMI) publica a duração mensal e anual médio de horas de luz solar em diferentes cidades do mundo (Nellestijn & Dekker, 1998). The monthly mean duration of sunlight in hours in Munich in south Germany (48:21° NL, alt. 527 m) and Brussels in Belgium (50:54° NL, alt. 55 m) published by Nellestijn and Dekker (1998) , as well as the monthly mean serum 25OHD concentration of healthy elderly in south Germany reported by Scharla (1998) and that of unhealthy elderly in Belgium reported by Bouillon et al (1987) , were used to calculate the correlations. A duração média mensal da luz do sol nas horas em Munique, no sul da Alemanha (48:21 ° NL, alt. 527 m) e Bruxelas, na Bélgica (50:54 ° NL, alt. 55 m), publicado pela Nellestijn e Dekker (1998), bem como o valor médio mensal do soro 25OHD concentração de idosos saudáveis no sul da Alemanha relatado por Scharla (1998) e de idosos saudáveis na Bélgica relatado por Bouillon et al (1987), foram utilizados para calcular as correlações. The author of the present paper compared 12 consecutive months of the year and found a significant correlation between sunlight and 25OHD, 2 months later, in healthy elderly in south Germany r =0.86 ( P < 0.001, n =12) and in unhealthy elderly in Belgium r =0.90 ( P < 0.001, n =12). O autor do presente trabalho em comparação de 12 meses consecutivos do ano e encontraram uma correlação significativa entre a luz solar e 25OHD, 2 meses depois, em idosos saudáveis no sul da Alemanha r = 0,86 (P <0,001, n = 12) e em idosos saudáveis em Bélgica r = 0,90 (P <0,001, n = 12). This finding is in line with the time lag of 2 months between sunlight and 25OHD reported in other studies ( Hine & Roberts, 1994 ; Need et al , 2000 ). Esta constatação está em consonância com o lapso de tempo de 2 meses entre a luz solar e 25OHD relatado em outros estudos (Hine & Roberts, 1994; Need et al, 2000). It has been stated that the concentration as found in healthy individuals at the end of summer or as found in healthy individuals in the tropics provides a physiological indication of what might be optimal to maintain throughout the year ( Vieth, 1999 ). Tem sido afirmado que a concentração, tal como encontrados em indivíduos saudáveis no fim do verão ou como encontrados em indivíduos saudáveis nos trópicos fornece uma indicação fisiológica do que poderia ser ideal para manter durante todo o ano (Vieth, 1999).
The approximate normal range for serum 1,25-(OH) 2 D values is 36–144 pmol/l ( Feldman et al , 1997 ). O intervalo de aproximadamente normal para soro 1,25 – (OH) 2 D é valores 36-144 pmol / l (Feldman et al, 1997). No seasonal variation in 1,25-(OH) 2 D levels was observed in healthy adults ( Chesney et al , 1981 ; Bouillon et al , 1987 ). Não houve variação sazonal em 1,25 – (OH) 2 níveis D foi observada em adultos saudáveis (Chesney et al, 1981; Bouillon et al, 1987). No association between 25OHD and concentrations of 1,25-(OH) 2 D was found in euthyroid patients, who previously had low 25OHD (<50 nmol/l) levels, but had been advised to take 25 Não houve associação entre 25OHD e as concentrações de 1,25 – (OH) 2 D foi encontrada em pacientes euthyroid, que anteriormente tinha 25OHD baixa (<50 nmol / l) níveis, mas tinham sido aconselhados a tomar 25 g (1000 IU)/day vitamin D 3 ( Vieth et al , 2003 ). g (1000 UI) / dia de vitamina D 3 (Vieth et al, 2003).
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Vitamin D nutrition Vitamina D nutrição
Dietary compensation should occur to overcome low 25OHD levels when cutaneous production of vitamin D 3 is inadequate. Dietary compensação deve ocorrer de baixo para superar os níveis de 25OHD, quando a produção cutânea de vitamina D 3 é inadequada. For their recommendations of vitamin D 3 intake, National Councils on Food and Nutrition have abandoned the older criterion of absence of disease as the definition of adequacy. Para que as suas recomendações de ingestão de vitamina D 3, Conselhos Nacionais de Alimentação e Nutrição, ter abandonado o antigo critério de ausência de doenças como a definição de adequação. Now they are confronted with two new questions, one: what concentration of serum 25OHD is adequate, and two: how much vitamin D 3 is needed each day to meet or sustain that concentration. Agora, eles são confrontados com duas novas perguntas, uma: que a concentração sérica de 25OHD é adequado, e dois: o quanto de vitamina D 3 é necessária a cada dia para atingir ou manter a concentração. The border between a vitamin D-deficient and -sufficient state is represented by reported cutoff levels for the 25OHD concentration which rang widely from 12.5 to 140 nmol/l, but seem to increase over the years ( Bouillon et al , 1987 ; Chapuy et al , 1997 ; Dawson-Hughes et al , 1997 ; Barger-Lux et al , 1998 ; Malabanan et al , 1998 ; Scharla, 1998 ; Thomas et al , 1998 ; Vieth, 1999 ; Need et al , 2000 ; Lips, 2001 ; Heaney et al , 2003a ). A fronteira entre uma deficiência de vitamina D e estado-suficiente é representada por níveis de corte relatado para a concentração 25OHD que tocou amplamente 12,5-140 nmol / l, mas parece aumentar ao longo dos anos (Bouillon et al, 1987; Chapuy et al , 1997; Dawson-Hughes et al, 1997; Barger-Lux et al, 1998; Malabanan et al, 1998; Scharla, 1998, Thomas et al, 1998; Vieth, 1999; Need et al, 2000; Lips, 2001; Heaney et al, 2003a). Serum levels of 25OHD between 30 and 100 nmol/l have been mentioned as necessary to ensure vitamin D sufficiency ( Barger-Lux et al , 1998 ; Lips, 2001 ; Heaney, 2003b ; Vieth et al , 2003 ). Os níveis séricos de 25OHD entre 30 e 100 nmol / l foram mencionadas como necessárias para garantir a suficiência de vitamina D (Barger-Lux et al, 1998; Lips, 2001; Heaney, 2003b; Vieth et al, 2003). In elderly nursing home residents, vitamin D 3 10 Em residentes de asilos de idosos, a vitamina D 3 10 g (400 IU)/day increased serum 25OHD from 22 to 62 nmol/l in 12 weeks ( Chel et al , 1998 ). g (400 UI) / dia 25OHD sérica de 22-62 nmol / l em 12 semanas (Chel et al, 1998). Others have observed higher doses to ensure adequate serum 25OHD levels ( Barger-Lux et al , 1998 ; Heaney et al , 2003a ; Vieth et al , 2003 ). Outros têm observado altas doses de soro adequada para assegurar níveis de 25OHD (Barger-Lux et al, 1998; Heaney et al, 2003a; Vieth et al, 2003). Recently, a daily supplement of 25 Recentemente, um suplemento diário de 25 g (1000 IU) vitamin D 3 has been advocated for all adults to ensure a serum 25OHD level of at least 40 nmol/l ( Vieth et al , 2001 , 2003 ). g (1000 UI) de vitamina D 3 tem sido defendida por todos os adultos para garantir um nível de 25OHD sérica de pelo menos 40 nmol / l (Vieth et al, 2001, 2003). There is no consensus on this, but this dose is well below the Tolerable Upper Intake Level (UL) of vitamin D for adults of 50 Não há consenso sobre isso, mas esta dose for bem abaixo do tolerável Upper Intake Level (UL) de vitamina D para adultos de 50 g (2000 IU)/day set by the FNB of the Institute of Medicine for the USA, as well as by the Scientific Committee on Food of the European Commission (SCF) for the European Union ( FNB, Institute of Medicine, 1997 ; SCF, 2002 ). g (2000 UI) / dia fixado pela FNB, do Instituto de Medicina para a E.U.A., bem como pelo Comité Científico da Alimentação Humana da Comissão Européia (SCF) para a União Europeia (FNB, Instituto de Medicina, 1997; SCF , 2002).
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MS and vitamin D MS e de vitamina D
MS prevalence and sunlight Prevalência e da luz solar
MS is more common in temperate climates than in the tropics, with a prevalence of 100/100 000 and 10/100 000, respectively ( Martyn, 1991 ; Gale & Martyn, 1995 ). MS é mais comum em climas temperados que nos trópicos, com uma prevalência de 100/100 000 e 10/100 000, respectivamente (Martyn, 1991; Gale & Martyn, 1995). Of all the climatic variables analyzed, insolation, in terms of annual and winter hours of sunlight, exhibited the strongest negative correlation with the prevalence of MS ( Acheson et al , 1960 ; Norman et al , 1983 ). De todas as variáveis climáticas analisadas, insolação, em termos de horas anuais de inverno e de luz solar, apresentaram a maior correlação negativa com a prevalência de MS (Acheson et al, 1960; Norman et al, 1983). The incidence of MS is low in areas with at least 3000 h sunlight annually or with sufficient vitamin D 3 intake ( Goldberg, 1974a ). A incidência de MS é baixa em áreas com luz solar, no mínimo, 3000 h anualmente ou com um número suficiente de vitamina D 3 de admissão (Goldberg, 1974a). Unlike mortality from skin cancer, mortality from MS was negatively associated with residential exposure to sunlight ( Freedman et al , 2000 ). Ao contrário da mortalidade por câncer de pele, a mortalidade de MS foi negativamente associado com a exposição à luz solar residencial (Freedman et al, 2000). A negative correlation between ultraviolet radiation (UVR) and MS prevalence was found in Australia ( Van der Mei et al , 2001 ). A correlação negativa entre a radiação ultravioleta (RUV) ea prevalência de SM foi encontrado na Austrália (Van der Mei et al, 2001). The suggestion that the risk of developing MS is largely determined before the age of 15 y has been questioned by Australian epidemiological data. A sugestão de que o risco de desenvolver esclerose múltipla é largamente determinado antes da idade de 15 y tem sido questionada pelo australiano dados epidemiológicos. The prevalence in the migrant population from the UK and Ireland in the different regions in Australia showed a significant correlation with latitude and was considerably less than in their countries of origin ( Hammond et al , 2000 ). A prevalência na população de migrantes provenientes do Reino Unido e na Irlanda em diferentes regiões da Austrália mostrou uma correlação significativa com a latitude e foi consideravelmente menor do que nos seus países de origem (Hammond et al, 2000). The epidemiological evidence suggests that UVR may play a protective role in three autoimmune diseases: MS, insulin-dependent diabetes mellitus, and rheumatoid arthritis has been reviewed ( Ponsonby et al , 2002 ). A evidência epidemiológica sugere que a RUV pode desempenhar um papel protetor em três doenças autoimunes: esclerose múltipla, diabetes mellitus insulino-dependente, e artrite reumatóide foi comentado (Ponsonby et al, 2002). New evidence has been reported that increased sun exposure during ages 6–15 y is associated with a decreased risk of multiple sclerosis ( Van der Mei et al , 2003 ). Novas evidências tem sido relatado que a exposição ao sol aumentou durante as idades 6-15 y está associado com um risco menor de esclerose múltipla (Van der Mei et al, 2003). Interestingly, the prevalence of MS among Sardinians presents evidence against the latitude gradient theory ( Pugliatti et al , 2001 ) and could be explained by a high susceptibility of the population to MS ( Montomoli et al , 2002 ). Curiosamente, a prevalência de SM entre Sardinians apresenta provas contra a teoria do gradiente de latitude (Pugliatti et al, 2001) e poderia ser explicada por uma alta suscetibilidade da população de MS (Montomoli et al, 2002).
MS and 25OHD serum concentration MS e da concentração de 25OHD sérica
Only a few reports have investigated the association between MS and 25OHD serum concentration. Somente alguns relatórios têm investigado a associação entre MS e concentração sérica de 25OHD. Vitamin D deficiency was detected in a group of female MS patients who were subjects of a study on osteoporosis. A deficiência de vitamina D foi detectado em um grupo de pacientes do sexo feminino de MS que participaram de um estudo sobre a osteoporose. Of these patients ( n =52), 70% had a subclinical vitamin D deficiency, defined as serum 25OHD <50 nmol/l ( Nieves et al , 1994 ). Destes pacientes (n = 52), 70% tinham uma deficiência subclínica de vitamina D, definida como 25OHD sérica <50 nmol / l (Nieves et al, 1994). This study consecutively recruited female MS patients who were admitted to a tertiary care hospital because of deterioration in their clinical status, and there was no appropriate control group. Este estudo consecutivamente recrutados pacientes do sexo feminino de MS que foram internados em um hospital terciário por causa da deterioração do seu estado clínico, e não havia um grupo controle adequado. Results suggested that low circulating 25OHD levels contributed to low bone mineral density (BMD) ( Nieves et al , 1994 ). Os resultados sugerem que baixos níveis circulantes 25OHD contribuiu para a baixa densidade mineral óssea (DMO) (Nieves et al, 1994).
Another group of MS patients ( n =54), of whom 64% had a subclinical vitamin D deficiency, defined as serum 25OHD < 50 nmol/l, had more rapid bone loss and more frequent fractures than healthy age- and gender-matched controls ( Cosman et al , 1998 ). Outro grupo de pacientes com esclerose múltipla (n = 54), dos quais 64% tinham uma deficiência subclínica de vitamina D, definida como 25OHD sérica <50 nmol / l apresentaram perda óssea mais rápida e mais freqüente de fraturas que a idade saudáveis e de sexo, controles pareados (Cosman et al, 1998). Levels of 25OHD were on average 20–37.5 nmol/l lower in MS patients than they were in the three control groups: men, pre- and postmenopausal women. Níveis de 25OHD foram, em média 20-37,5 nmol / l menor em pacientes com EM do que eram em três grupos de controle: homens, pré e pós-menopausa. In the analyses, lack of sunlight exposure, a vitamin D-deficient diet, immobility, and corticosteroid treatment contributed to the low 25OHD serum concentrations ( Cosman et al , 1998 ). Nas análises, a falta de exposição à luz solar, a vitamina D, dieta deficiente, imobilidade, uso de corticóide e contribuiu para a baixa concentrações séricas de 25OHD (Cosman et al, 1998). However, in this study, it was not clear whether the vitamin D deficiency was merely a result of immobility, as it has been reported that immobility may be the strongest risk factor for vitamin D deficiency ( Gloth et al , 1995 ). No entanto, neste estudo, ficou claro se a deficiência da vitamina D foi apenas uma conseqüência da imobilidade, como tem sido relatado que a imobilidade pode ser o maior factor de risco para a deficiência de vitamina D (Gloth et al, 1995).
Mahon et al (2003) reported that 48% of MS patients ( n =39) had a subclinical vitamin D deficiency at baseline, defined as serum 25OHD <50 nmol/l. Mahon et al (2003) relataram que 48% dos pacientes com EM (n = 39) tinha uma deficiência subclínica de vitamina D na linha de base, definido como 25OHD sérica <50 nmol / l.
No reports have been found on the 1,25-(OH) 2 D serum concentration in MS patients. Não foram encontrados relatos sobre a 1,25 – (OH) 2 D concentração do soro em pacientes com EM. Case–control studies with sufficient power on patients with MS with respect to serum 25OHD and 1,25-(OH) 2 D concentration are lacking. Estudos de caso-controle com potência suficiente em pacientes com EM com relação ao soro 25OHD e 1,25 – (OH) 2 D concentração estão faltando. Moreover, seasonal variation of 25OHD serum concentration has not yet been established in MS patients. Além disso, a variação sazonal da concentração sérica de 25OHD ainda não foi estabelecida em pacientes com EM.
MRI and season RM e temporada
Various studies have investigated the association between number of active magnetic resonance imaging (MRI) lesions and season ( Auer et al , 2000 ; Embry et al , 2000 ; Rovaris et al , 2001 ; Killestein et al , 2002 ). Vários estudos têm investigado a associação entre o número de imagens de ressonância magnética ativa (MRI) e lesões temporada (Auer et al, 2000; Embry et al, 2000; Rovaris et al, 2001; Killestein et al, 2002). Active MRI lesions are the gadolinium-enhancing lesions on MRI scans, which reflect subclinical disease activity. Lesões ativas são a ressonância magnética gadolínio-realçando lesões em varreduras de MRI, que refletem a atividade da doença subclínica. A statistical significant seasonal fluctuation, measured as active MRI lesions, has been demonstrated in MS patients ( n =53) living in south Germany. A flutuação estatística significativa sazonal, medido como lesões ativas de ressonância magnética, tem sido demonstrada em pacientes com EM (n = 53) que vivem no sul da Alemanha. The number of active MRI lesions was the highest in April and lowest in October ( Auer et al , 2000 ). O número de lesões ativas de ressonância magnética foi o maior em abril e menor em outubro (Auer et al, 2000). The seasonal variation of active MRI lesions in MS patients has since been re-addressed in other studies. A variação sazonal de lesões ativas de ressonância magnética em pacientes do MS, desde então, sido re-abordados em outros estudos. The monthly mean number of MRI lesions was pooled in four seasons: spring (March, April, May), summer (June, July, August), autumn (September, October, November), and winter (December, January, February). O número médio mensal de lesões de RM foi agrupada em quatro estações: primavera (março, abril, maio), verão (junho, julho, agosto), Outono (Setembro, Outubro, Novembro), e no inverno (dezembro, janeiro, fevereiro). No statistical significant difference could be detected between the number of active MRI lesions in these four seasons ( Rovaris et al , 2001 ; Killestein et al , 2002 ). Não houve diferença estatística significativa poderia ser detectada entre o número de lesões ativas de ressonância magnética nestes quatro temporadas (Rovaris et al, 2001; Killestein et al, 2002). However, these calendar months do not necessarily correspond with the ‘vitamin D winter’ and more importantly do not necessarily represent the circulating 25OHD levels of the individuals under investigation. No entanto, estes meses de calendário não corresponde necessariamente com a ‘Winter vitamina D “e, mais importante, não representam necessariamente a 25OHD níveis circulantes dos indivíduos sob investigação. In addition, Rovaris et al (2001) used data from MS patients living in different parts of the world. Além disso, Rovaris et al (2001) utilizou dados de pacientes com esclerose múltipla que vivem em diferentes partes do mundo.
Embry et al (2000) have graphically combined two separate studies and showed close correspondence between the curve representing monthly mean serum 25OHD concentrations in the group of non-MS individuals provided by Scharla and the curve representing the monthly number of MRI lesions, 2 months later, in MS patients provided by Auer ( Scharla, 1998 ; Auer et al , 2000 ). Of course, there exists an inherent weakness in combining data from different studies to reach a new conclusion. In this case, the 25OHD serum levels were measured in a group of non-MS individuals. These levels may not be representative of a cohort of MS patients, whose vitamin D metabolite levels may be influenced by their MS.
The monthly mean duration of sunlight in hours in Munich published by Nellestijn and Dekker (1998) and the monthly mean number of active MRI lesions reported by Auer et al (2000) were used to calculate the correlation. The author of the present paper compared the 12 consecutive months of the year and found a statistical significant inverse correlation between sunlight and active MRI lesions, 4 months later, r =-0.90 ( P <0.001, n =12).
Further research is required; currently no reports are available on mean serum 25OHD concentrations, and active MRI lesions by months of the year in patients with MS living in the same area.
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Neuro-immunology and vitamin D metabolites
The CNS as a target tissue for vitamin D metabolites is supported by discovery of VDR in the rat forebrain, hippocampus, cerebellum, brainstem, spinal cord, and perivascular tissue and the discovery of 1 
-OHase in cerebellum and cerebral cortex ( Neveu et al , 1994 , Issa et al , 1998 , Hewison et al , 2000 ; Zehnder et al , 2001 ). In addition, the possibility of a local synthesis of 1,25-(OH) 2 D in brain has been postulated ( Garcion et al , 2002 ). Profound alterations in the brain at birth have been demonstrated in rats born to vitamin D 3 -deficient mothers ( Eyles et al , 2003 ).
The influences of 1,25-(OH) 2 D on cells of the nervous system were recently reviewed by Garcion ( Garcion et al , 2002 ). It appeared that 1,25-(OH) 2 D had effects on neurons, oligodendrocytes, as well as astrocytes, but the exact pathways of these effects remain to be established. In general, the influences of 1,25-(OH) 2 D on these cells seem to be neuroprotective and anti-inflammatory ( Garcion et al , 2002 ).
Immune system and 1,25-(OH) 2 D
The active form of vitamin D, 1,25-(OH) 2 D, is a potent regulator of the immune system ( Bouillon et al , 1995 ; Casteels et al , 1995 ; Cantorna et al , 1996 , 1998 , 1999 ; Hayes et al , 1997 ; Nashold et al , 2000 , 2001 ; Gregori et al , 2001 ; Griffin et al , 2001 ). Here we focus on the autoimmune animal model for MS EAE. The preventive and curative effects of vitamin D-related treatment on the clinical course of EAE are described ( Table 1 ). The effects on the cellular level, which are relevant for EAE, and may have implications for MS and other autoimmune diseases, are summarized. The possible actions of vitamin D metabolites on immune cells relevant for EAE are portrayed in Figure 2 . Finally, the influences of vitamin D metabolites on the production of cytokines and nitric oxide (NO), and on the BBB are described.
Downregulation by 1,25-(OH) 2 D of pro-inflammatory dendritic cell and T-cell function and macrophage activity and migration, in experimental allergic encephalomyelitis (EAE, an animal model of MS). Effects on the CNS-constituting cells are not incorporated in this figure, but are reviewed in Garcion et al (2002) . The effect of 1,25-(OH) 2 D on the cells of the BBB is unknown, but EAE data suggest that cellular infiltration is inhibited ( Nashold et al , 2000 ). Further references on which this figure is based are mentioned in the text under Neuro-immunology and vitamin D metabolites. Dendritic cell, DC; monocyte, MO; T helper 1 lymphocyte, Th1; T helper 2 lymphocyte, Th2; interferon gamma, IFN 
; interleukin, IL; nitric oxide, NO; transforming growth factor , TGF , TGF ; tumor necrosis factor alpha, TNF . .
Full figure and legend (198 K )
Experimental autoimmune encephalomyelitis (EAE)
EAE is a useful (although not perfect) animal model of human MS ( Van Etten et al , 2003 ). EAE is induced by immunization of rodents or primates with myelin or myelin components. This results in the generation of autoreactive, myelin-specific T lymphocytes. In the CNS of EAE animals perivascular inflammatory lesions are present and, depending on the immunization protocol, a variable degree of demyelination is observed. The lesions in the brain and spinal cord are accompanied by transient clinical signs such as paralysis of the tail and hind limbs. EAE can also be induced by transferring T lymphocytes from rats immunized with myelin components into naïve rats, indicating the crucial role of T lymphocytes in this model ( Paterson & Hanson, 1969 ). In particular, the interferon-gamma (IFN- )-producing T helper 1 (Th1) lymphocytes are required for induction of EAE. Macrophages are crucial for the effector phase of EAE, the phase in which actual tissue damage is caused by an immune response. In EAE, macrophage depletion leads to complete suppression of clinical signs ( Huitinga et al , 1990 ; Tran et al , 1998 ).
EAE and vitamin D-related treatment
Table 1 summarizes the observed effects of vitamin D-related treatment on EAE. Exposure of mice to whole body (full spectrum) UV was effective in preventing EAE when administered before immunization, but was ineffective in modifying ongoing EAE or in preventing relapses of EAE induced by re-immunization ( Hauser et al , 1984 ). However, this report does not mention vitamin D metabolites at all. The first study on 1,25-(OH) 2 D treatment of EAE was by Lemire and Archer (1991) and showed that administration of 1,25-(OH) 2 D during the immunization phase in mice significantly prevented the onset and development of EAE. The preventive effect of 1,25-(OH) 2 D on EAE in mice given before EAE induction was complete ( Cantorna et al , 1996 ). When treatment with 1,25-(OH) 2 D on EAE was started after the appearance of clinical signs, progression and severity was decreased in mice ( Cantorna et al , 1996 ) and rats ( Nataf et al , 1996 ). A vitamin D-deficient diet resulted in an increased susceptibility to EAE, an accelerated onset of paralytic symptoms and aggravated clinical symptoms ( Cantorna et al , 1996 ). In rats deprived of vitamin D, the clinical signs of EAE increased ( Garcion et al , 2003 ). Withdrawal of 1,25-(OH) 2 D after EAE induction resulted in a resumption of clinical signs ( Cantorna et al , 1996 ). The effect of 1,25-(OH) 2 D can be potentiated by cyclosporine, sirolimus (Rapamycin, RAP), and calcium ( Branisteanu et al , 1995 , 1997 ; Cantorna et al , 1999 ). In EAE in mice, calcium was required in addition to 1,25-(OH) 2 D to prevent the appearance of this disease, and the higher the calcium intake the lower the 1,25-(OH) 2 D dose needed ( Cantorna et al , 1999 ). These results suggest that 1,25-(OH) 2 D and dietary calcium are both involved in the prevention of symptomatic EAE ( Cantorna et al , 1999 ; DeLuca & Cantorna, 2001 ). Interestingly, changes in dietary calcium and phosphate levels resulted in changes in target tissue VDR expression ( Issa et al , 1998 ). VDR itself is essential for the immunosuppressive ability of 1,25-(OH) 2 D during EAE ( Meehan & DeLuca, 2002 ). From studies on vitamin D deficiency in the elderly, it is understood that a low calcium intake causes secondary hyperparathyroidism, which increases vitamin D turnover and aggravates vitamin D deficiency and its consequences, while high calcium intake may reduce vitamin D requirement ( Lips, 2001 ).
Treatment with synthetic 1,25-(OH) 2 D analogs has also been reported ( Lemire et al , 1994 ; Mattner et al , 2000 ; Van Etten et al , 2000 , 2003 ; Garcion et al , 2003 ). Curative treatment of vitamin D-deprived rats with the nontoxic-1,25-(OH) 2 D analog MC1288 strongly inhibited EAE symptoms, thus suggesting that these compounds may be a suitable treatment for MS ( Garcion et al , 2003 ). The 1,25-(OH) 2 D analog TX527 decreased disease severity and postponed onset in mice with EAE, and adding the bisphosphonate pamidronate prevented the side effects of this analog ( Van Etten et al , 2003 ).
Cellular effects
T lymphocytes and dendritic cells
The effect of 1,25-(OH) 2 D on the acquired, antigen-specific immune response is initiated by exposure of antigen in the groove of MHC class II molecules to T lymphocytes. This so-called antigen presentation results in proliferation and cytokine production by antigen-specific T lymphocytes. Based on the cytokine production profile, two populations of T lymphocytes can be distinguished. Th1 cells produce IFN- , a pro-inflammatory cytokine that promotes macrophage activation and MHC class II expression. T helper 2 (Th2) cells produce interleukin (IL)-4 and IL-5, promoting antibody production in particular IgE. Antigen-presenting cells can influence the cytokine production profile of T lymphocytes upon antigen recognition. By production of the cytokine IL-12, antigen-presenting cells can induce a shift towards the Th1 cytokine profile. Classical antigen-presenting cells are the so-called dendritic cells, which are derived from monocytes. They occur in almost all tissues of the body and in large numbers in lymphoid organs where they present antigen to T lymphocytes. 1,25-(OH) 2 D inhibits antigen-induced T-lymphocyte proliferation ( Bhalla et al , 1984 ; Lemire & Adams, 1992 ) and prevents Th1 development in EAE ( Mattner et al , 2000 ). Various reports have shown that 1,25-(OH) 2 D exerts major effects on dendritic cells (DC), by inhibition of DC maturation ( Penna & Adorini, 2000 ; Griffin et al , 2001 ). Accordingly, DC of VDR-deficient mice fail to respond to maturational stimuli ( Griffin et al , 2001 ). Mature DC are required for the induction of an efficient Th1 response, in particular by their production of the pro-inflammatory cytokine IL-12. The production of IL-12 by DC is downregulated by 1,25-(OH) 2 D, whereas the production of the anti-inflammatory cytokines IL-10 is enhanced ( Penna & Adorini, 2000 ) and the production of TGF- is unaffected ( Griffin et al , 2001 ). Thus, by reduction of IL-12 production by DC, 1,25-(OH) 2 D may inhibit the development of pro-inflammatory Th1 cells.
Furthermore, 1,25-(OH) 2 D treatment results, alone or when combined with the selective inhibitor of lymphocyte proliferation mycophenolate mofetil (MMF), in the generation of a population of CD4+CD25-regulatory T cells ( Gregori et al , 2001 ). The potency of this effect of 1,25-(OH) 2 D is illustrated by the fact that tolerance is induced by 1,25-(OH) 2 D/MMF treatment to fully mismatched pancreatic islet allografts in mice ( Gregori et al , 2001 ). Altogether, these data show that 1,25-(OH) 2 D inhibits DC maturation and inhibits the induction of pro-inflammatory Th1 cells. In addition, the formation of tolerogenic T cells, an active mechanism for natural immune suppression, and the production of anti-inflammatory cytokine IL-10 are promoted by 1,25-(OH) 2 D.
Macrophages Macrófagos
In addition to its effect on T lymphocytes, the effect of 1,25-(OH) 2 D on macrophages contributes to its immunomodulatory potential. Almost two decades ago, it has been reported that 1,25-(OH) 2 D promoted the induction of (pro)monocytic differentiation to macrophages ( Koeffler et al , 1984 ). 1,25-(OH) 2 D increases the antigen-presenting activity of macrophages and enhances the phagocytic activity of macrophages ( Goldman, 1984 ; Amento & Cotter, 1988 ).
Cytokines and nitric oxide (NO)
The cellular effects of 1,25-(OH) 2 D include effects on production of immunoregulatory molecules such as cytokines and NO. 1,25-(OH) 2 D decreases the production of pro-inflammatory cytokines IL-2, IFN- and TNF- in vitro and in vivo ( Manolagas et al , 1985 ; Reichel et al , 1989 ; Lemire & Adams, 1992 ), and IL-12 in vivo ( Lemire et al , 1994 ; D’Ambrosio et al , 1998 ; Mattner et al , 2000 ). On the other hand, it promotes the in vivo production of anti-inflammatory cytokines such as IL-4 and TGF- ( Cantorna et al , 1998 ). An increase of TGF- 1 expression in lymph nodes at the periphery may explain the beneficial effect of 1,25-(OH) 2 D in EAE and has been re-emphasized in MS ( Cantorna et al , 1998 ; Mahon et al , 2003 ). In contrast, TGF- 1 increase was not found in the rat CNS ( Garcion et al , 2003 ), suggesting that the effects of 1,25-(OH) 2 D in EAE are due to effects on the peripheral immune system rather than on local immune suppression. 1,25-(OH) 2 D triggers the production of inducible nitric oxide synthase (iNOS) by a human macrophage cell line in vitro ( Figure 2 ) ( Rockett et al , 1998 ), but decreases iNOS expression during rat EAE ( Garcion et al , 1997 , 1998 , 2003 ). The macrophage enzyme iNOS is required for the inducible production of NO by macrophages. The role of NO in EAE and MS is not yet fully clarified, but several studies indicate a worsening effect due to NO production in the brain ( Cross et al , 1994 , 2000 ; Zhao et al , 1996 ). Others indicate that NO has an immune-downregulating effect in EAE ( Ruuls et al , 1996 ; Willenborg et al , 1999 ).
Blood–brain barrier (BBB)
Inflammatory cells can only cause damage in the CNS after they have migrated from the peripheral blood into the CNS parenchyma. This involves passage of these cells across the BBB. A direct effect of 1,25-(OH) 2 D on the BBB has, to our knowledge, not been described thus far. In 1,25-(OH) 2 D-treated EAE rats, a reduced number of infiltrated macrophages in the CNS was observed ( Nataf et al , 1996 , Nashold et al , 2000 ), suggesting that 1,25-(OH) 2 D suppresses the transendothelial migration of monocytes ( Nashold et al , 2000 ).
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Future prospects: MS and 1,25-(OH) 2 D treatment
Given its immune-modulatory and anti-inflammatory effects, treatment with 1,25-(OH) 2 D, or its analogs, may be valuable in the management of MS ( Cantorna et al , 1996 ; Hayes et al , 1997 ; Verstuyf et al , 1998 ; Mathieu et al , 2001 ; Mathieu & Adorini, 2002 ). The calcemic side effects of 1,25-(OH) 2 D make its use in high doses, needed for immunomodulation, unattractive. 1,25-(OH) 2 D analogs, which might block MS without affecting the blood calcium level, have been identified and synthesized ( DeLuca et al , 2000 ). Until now, only one of these 1,25-(OH) 2 D analogs, 19-nor-1,25-dihydroxyvitamin D 2 (19-nor), was given in an oral dose for more than 9 months to 11 newly diagnosed MS patients with RRMS. This analog, however, did not reduce the number of active MRI lesions ( Flemming et al , 2000 ). More research and clinical trials are needed to assess the usefulness of vitamin D compounds for the treatment of MS.
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Conclusion Conclusão
This review provides some epidemiological and ecological evidence for the preventive role that vitamin D nutrition may play in decreasing susceptibility to MS. The putative preventive effect of adequate supply of vitamin D 3 is supported by results obtained in EAE. In EAE 1,25-(OH) 2 D prevents the onset when administered before EAE induction and ameliorates the severity and duration of EAE when given after EAE induction ( Table 1 ).
Widespread seasonal variation in serum 25OHD levels has been reported especially in temperate climates, with low 25OHD levels in winter. A vitamin D-deficient diet in mice and rats resulted in an increased susceptibility to EAE, and 1,25-(OH) 2 D deprivation aggravated the clinical signs of EAE ( Cantorna et al , 1996 ; Garcion et al , 2003 ). Likewise, once MS is apparent, low 25OHD levels may aggravate its severity. Living in a temperate climate may cause annually recurring seasonal low serum 25OHD concentrations in MS patients. Low serum 25OHD concentrations may be responsible for upsetting the balance in the neuro-immune system of MS patients, causing reversible and irreversible neuro-immunological damage aggravating RRMS. The cumulative negative effects over the years may contribute to the secondary progressive course of MS. Further studies are required to establish the seasonal fluctuations in serum concentrations of vitamin D metabolites in MS patients. The effects of sunlight on the clinical manifestations of MS may be influenced by the fact that this may not be a direct effect, but indirect. There might be a time lag of 2 months between sunlight and 25OHD and a time lag of 4 months between sunlight and MRI lesions. A 25OHD reference interval may need to be determined to distinguish inadequate from adequate levels. The quantitative relation between vitamin D 3 input and the resulting serum 25OHD concentration needs to be investigated, as it has been speculated that patients with MS may have a higher vitamin D requirement ( Goldberg, 1974a ; Cantorna et al , 1996 ; Hayes et al , 1997 ; Hayes, 2000 ; Vieth, 1999 ; DeLuca & Cantorna, 2001 ; Holick, 2002 ; Mahon et al , 2003 ). More research is also needed to address the question if MS might be aggravated by a vitamin D-related metabolic or genetic disorder. It is hypothesized that vitamin D deficiency might only lead to MS in susceptible individuals, and a poor vitamin D status might expose an unknown, possibly gene-related, etiology.
Finally, we need to answer the question: ‘Do we need 1,25-(OH) 2 D analogs for the treatment of MS, as pharmacological doses of 1,25-(OH) 2 D are accompanied by adverse side effects, or is it simply a matter of enough vitamin D 3 all year round and enough time for it to take effect?’
Until more evidence is provided, it is suggested that MS patients living in temperate climates should have their serum 25OHD concentration checked in winter, January–March in the northern and July–September in the southern hemisphere, respectively, or use a vitamin D 3 supplement and follow the recommendations for vitamin D 3 and calcium published by their National Council on Food and Nutrition. The dietary reference intakes on vitamin D and calcium for the USA and Europe have been published by the FNB, Institute of Medicine in 1997 and by the SCF of the European Commission in 2002, respectively, and have since been updated ( FNB, Institute of Medicine, 1997 ; SCF, 2002 ; Heaney et al , 2003a ). Alternatively, the reader is referred to the most recent recommendations for the required daily intake of vitamin D 3 and calcium given for bone loss, osteoporosis, and fractures ( Chapuy et al , 1992 ; Lips, 2001 ). For the moment, it would be wise to aim at a serum 25OHD level >50 nmol/l either by augmenting sunlight exposure or by a vitamin D 3 supplement of 10 g (400 IU) per day. Such a dose is safe, and side effects are virtually nonexistent ( Lips, 2001 ). Further studies should be done to evaluate if higher levels of 25OHD are necessary in the management of MS to prevent exacerbations. In contrast, the use of the active metabolite 1,25-(OH) 2 D carries the danger of hypercalcemia, hypercalciuria, and renal failure, and should be restricted to clinical investigational use under close supervision.
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Acknowledgements Agradecimentos
The authors thank Jolijn Kragt, Arie van Nieuw Amerongen, Michael Eddleston, Pat Lee and I-Jin Chew for reading and commenting on draft versions and Adriana Dusso for always answering vitamin D queries.
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Cristiane Rozicki
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