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Vitamin D in MS - 02

  1. A longitudinal study of Serum 25-HydroxyVitamin D and intact ParaThyroid Hormone levels indicate the importance of Vitamin D and Calcium homeostasis regulation in Multiple Sclerosis
    J Neurol NeuroSurg Psychiatry 2008 Feb;79(2):152-7

  2. Studies of associations between disability in Multiple Sclerosis, skin type, gender and ultraviolet radiation
    Mult Scler 2007 Apr;13(3):369-75

  3. 1,25-DihydroxyVitamin D3 reverses Experimental Autoimmune Encephalomyelitis by inhibiting Chemokine synthesis and Monocyte trafficking
    J NeuroSci Res 2007 Aug 15;85(11):2480-90

  4. Vitamin D levels in people with Multiple Sclerosis and community controls in Tasmania, Australia
    J Neurol 2007 May;254(5):581-90

  5. Assessment of 25-HydroxyVitamin-D and 1,25-DihydroxyVitamin-D3 concentrations in male and female Multiple Sclerosis patients and control volunteers
    Mult Scler 2007 Jun;13(5):670-2

  6. Expanding role for Vitamin-D in chronic Kidney Disease: importance of blood 25-OH-D levels and extra-renal 1alpha-Hydroxylase in the classical and nonclassical actions of 1alpha,25-DihydroxyVitamin-D(3)
    Semin Dial 2007 Jul-Aug;20(4):316-24

  7. IL-10 signaling is essential for 1,25-DihydroxyVitamin-D3-mediated inhibition of Experimental Autoimmune Encephalomyelitis
    J Immunol 2006 Nov 1;177(9):6030-7

  8. Vitamin-D physiology
    Prog Biophys Mol Biol 2006 Sep;92(1):4-8

  9. 1,25 DihydroxyVitamin-D3 modulates JAK-STAT pathway in IL-12/IFN-gamma axis leading to Th1 response in Experimental Allergic Encephalomyelitis
    J NeuroSci Res 2006 May 15;83(7):1299-309

  10. Vitamin-D and Autoimmune Disease--implications for practice from the Multiple Sclerosis literature
    J Am Diet Assoc 2006 Mar;106(3):418-24


A Longitudinal Study Of Serum 25-HydroxyVitamin D And Intact ParaThyroid Hormone Levels Indicate The Importance Of Vitamin D And Calcium Homeostasis Regulation In Multiple Sclerosis

Soilu-Hänninen M, Laaksonen M, Laitinen I, Erälinna JP, Lilius EM, Mononen I
J Neurol NeuroSurg Psychiatry 2008 Feb;79(2):152-7
University of Turku, Department of Neurology, Kiinamyllynkatu 4-8, PL52, FIN-20521, Turku, Finland
PMID# 17578859

Past sun exposure and Vitamin D3 supplementation have been associated with a reduced risk of Multiple Sclerosis (MS). There are no previous longitudinal studies of Vitamin D in MS.

To compare regulation of Vitamin D and Calcium homeostasis between patients with MS and healthy controls. To study the correlation of parameters of Vitamin D metabolism with MS activity.

We measured 25-HydroxyVitamin D (25(OH)D), ParaThyroid Hormone (PTH), Calcium, Phosphate, Magnesium, Chloride, Alkaline Phosphatase, Albumin and Thyroid Stimulating Hormone in Serum every 3 months.

And at the time of relapse over 1 year in 23 patients with MS and in 23 healthy controls. MRI burden of disease and T2 activity were assessed every 6 months.

Vitamin D deficiency (S-25(OH)D < or = 37 nmol/l) was common, affecting half of the patients and controls at some time in the year.

Seasonal variation of 25(OH)D was similar in patients and controls, but 25(OH)D Serum levels were lower and intact PTH (iPTH) Serum levels were higher during MS relapses than in remission.

All 21 relapses during the study occurred at Serum iPTH levels > 20 ng/l (2.2 pmol/l), whereas 38% of patients in remission had iPTH levels < or = 20 ng/l.

Patients with MS had a relative HypoCalcaemia and a blunted PTH response in the winter. There was no correlation between Serum 25(OH)D and MRI parameters.

The Endocrine circuitry regulating Serum Calcium may be altered in MS.

There is an inverse relationship between Serum Vitamin D level and MS clinical activity. The role of Vitamin D in MS must be explored further.


Studies Of Associations Between Disability In Multiple Sclerosis, Skin Type, Gender And Ultraviolet Radiation

Woolmore JA, Stone M, Pye EM, Partridge JM, Boggild M, Young C, Jones PW, Fryer AA, Hawkins CP, Strange RC
Mult Scler 2007 Apr;13(3):369-75
Keele University Medical School, University Hospital of North Staffordshire, Keele Multiple Sclerosis Research, Human Genomics Research Group, Institute of Science and Technology in Medicine, Stoke on Trent, Staffordshire, UK
PMID# 17439906

Recent studies suggest UltraViolet Radiation (UVR)/Vitamin D is protective against the development of Multiple Sclerosis (MS).

We determined if outcome in MS is associated with the surrogate for host pigmentation, skin type, and parameters of UVR exposure.

We used a validated questionnaire to determine skin type and UVR exposure during childhood (0-16 years), and early adult life (17-40 years), in 448 Caucasians with MS.

Outcome was assessed using the Kurtzke Expanded Disability Status Score (EDSS) and Multiple Sclerosis Severity Scale (MSSS).

We studied the association of skin type and exposure with dichotomized values of EDSS (< and > or = 6) and MSSS (continuous variable) using logistic and linear regression analyses, respectively.

Sex, onset age and MS duration were significantly associated with outcome in all patients.

In 169 females with established disease (> or = 10 years), sun sensitive skin types 1 and 2 were associated with reduced risk of EDSS > or = 6 (odds ratio = 0.50; 95% CI = 0.26-0.97), and higher MSSS values (coefficient = -0.86; 95% CI = -1.67 to -0.05).

Parameters of UVR exposure were not significantly associated with outcome. These preliminary data show an association between skin type and disability in female MS patients.

They are compatible with independent studies suggesting that exposure mediates MS pathogenesis via Vitamin D. Further studies are required to properly assess these potentially important findings.


1,25-DihydroxyVitamin D3 Reverses Experimental Autoimmune Encephalomyelitis By Inhibiting Chemokine Synthesis And Monocyte Trafficking

Pedersen LB, Nashold FE, Spach KM, Hayes CE
J NeuroSci Res 2007 Aug 15;85(11):2480-90
University of Wisconsin-Madison, Department of BioChemistry, College of Agricultural and Life Sciences, Madison, Wisconsin, USA
PMID# 17600374

Multiple Sclerosis (MS) is a complex NeuroDegenerative Disease whose pathogenesis involves genetic and environmental risk factors leading to an aberrant, NeuroAntigen-specific, CD4+ T Cell-mediated Autoimmune Response.

In support of the hypothesis that Vitamin-D3 may reduce MS risk and severity, we found that Vitamin-D3 and 1,25-DihydroxyVitamin D3 (1,25-(OH)2D3) inhibited induction of Experimental Autoimmune Encephalomyelitis (EAE), an MS model.

To investigate how 1,25-(OH)2D3 could carry out anti-inflammatory functions, we administered 1,25-(OH)2D3 or a placebo to mice with EAE.

And subsequently analyzed clinical disease, Chemokines, Inducible Nitric Oxide Synthase (iNOS), and recruitment of dye-labeled Monocytes.

The 1,25-(OH)2D3 treatment significantly reduced clinical EAE severity within 3 days.

Sharp declines in Chemokines, inducible iNOS, and CD11b+ Monocyte recruitment into the Central Nervous System (CNS) preceded this clinical disease abatement in the 1,25-(OH)2D3-treated animals.

The 1,25-(OH)2D3 did not directly and rapidly inhibit Chemokine synthesis in vivo or in vitro.

Rather, the 1,25-(OH)2D3 rapidly stimulated activated CD4+ T-Cell Apoptosis in the CNS and Spleen. Collectively, these results support a model wherein inflammation stimulates a natural anti-inflammatory feedback loop.

The activated inflammatory cells produce 1,25-(OH)2D3, and this hormone subsequently enhances the Apoptotic death of inflammatory CD4+ T-Cells, removing the driving force for continued inflammation.

In this way, the sunlight-derived hormone could reduce the risk of chronic CNS inflammation and Autoimmune-mediated NeuroDegenerative Disease.

Copyright 2007 Wiley-Liss, Inc.


Vitamin D Levels In People With Multiple Sclerosis And Community Controls In Tasmania, Australia

van der Mei IA, Ponsonby AL, Dwyer T, Blizzard L, Taylor BV, Kilpatrick T, Butzkueven H, McMichael AJ
J Neurol 2007 May;254(5):581-90
Menzies Research Institute, Private Bag 23, Hobart, Tasmania, 7001, Australia. Ingrid
PMID# 17426912

Adequate 25(OH)D levels are required to prevent adverse effects on bone health. Population-based data on factors associated with 25(OH)D levels of people with MS have been lacking.

To examine the prevalence and determinants of Vitamin D insufficiency in a population-based sample of MS cases and controls, and to compare 25(OH)D status between MS cases and controls, taking into account case disability.

We conducted a population based case-control study in Tasmania, Australia (latitude 41-43 degrees S):

On 136 prevalent cases with MS confirmed by Magnetic Resonance Imaging and 272 community controls, matched on sex and year of birth.

Measurements included Serum 25(OH)D, sun exposure, skin type, dietary Vitamin D intake and disability including EDSS.

A high prevalence of Vitamin D insufficiency was found in MS cases and controls.

Among MS cases, increasing disability was strongly associated with lower levels of 25(OH)D and with reduced sun exposure.

Cases with higher disability (EDSS > 3) were more likely to have Vitamin D insufficiency than controls (OR = 3.07 (1.37, 6.90) for 25(OH)D < /= 40 nmol/l), but cases with low disability were not (OR = 0.87 (0.41, 1.86)).

The strong associations between disability, sun exposure and Vitamin D status indicate that reduced exposure to the sun, related to higher disability:

May contribute to the high prevalence of Vitamin D insufficiency found in this population-based MS case sample.

Active detection of Vitamin D insufficiency among people with MS and intervention to restore Vitamin D status to adequate levels should be considered as part of the clinical management of MS.


Assessment Of 25-HydroxyVitamin-D And 1,25-DihydroxyVitamin-D3 Concentrations In Male And Female Multiple Sclerosis Patients And Control Volunteers

Barnes MS, Bonham MP, Robson PJ, Strain JJ, Lowe-Strong AS, Eaton-Evans J, Ginty F, Wallace JM
Mult Scler 2007 Jun;13(5):670-2
Northern Ireland Centre for Food and Health (NICHE), University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK
PMID# 17548449

Populations with insufficient ultraviolet exposure and who consume diets low in Vitamin-D have low Vitamin-D status (plasma 25-HydroxyVitamin-D (25(OH)D) concentrations) and a reported higher incidence of Multiple Sclerosis (MS).

The active form of Vitamin-D, 1,25-DihydroxyVitamin-D3 (1,25(OH)2D3), is an effective AntiInflammatory molecule. No research to date has assessed 1,25(OH)2D3 concentrations in individuals with MS.

In this study, Plasma concentrations of 25(OH)D, 1,25(OH)2D3 and ParaThyroid Hormone (PTH) were measured in 29 individuals with MS and 22 age- and sex-matched control volunteers.

There were no significant differences in Plasma PTH, 25(OH)D and 1,25(OH)2D3 concentrations between individuals with MS and control volunteers.

Women with MS had significantly higher 25(OH)D and 1,25(OH)2D3 concentrations than men with MS (79.1+/-45.4 versus 50.2+/-15.3 nmol/L, P=0.019 and 103.8+/-36.8 versus 70.4+/-28.7 pmol/L, P=0.019, respectively).

There was a significant positive correlation between 25(OH)D and 1,25(OH)2D3 concentrations in all subjects (r = 0.564, P = 0.000), but secondary analysis revealed that the correlation was driven by women with MS (r = 0.677, P = 0.001).

Significant sex differences in Vitamin-D metabolism were observed and were most marked in individuals with MS, suggesting that Vitamin-D requirements may differ between the sexes, as well as by underlying disease state.


Expanding Role For Vitamin-D In Chronic Kidney Disease: Importance Of Blood 25-OH-D Levels And Extra-Renal 1alpha-Hydroxylase In The Classical And Nonclassical Actions Of 1alpha,25-DihydroxyVitamin-D(3)

Jones G
Semin Dial 2007 Jul-Aug;20(4):316-24
Queen's University, Departments of BioChemistry and Medicine, Kingston, Ontario, Canada
PMID# 17635821

Recent advances in the understanding of Vitamin-D have revolutionized our view of this old nutritional factor and suggested that it has much wider effects on the body than ever believed before.

In addition to its well-known effects on Calcium/Phosphate homeostasis, Vitamin-D, through its hormonal form, 1alpha,25-DihydroxyVitamin-D(3) or Calcitriol, is a cell differentiating factor.

And AntiProliferative agent with actions on a variety of tissues around the body (e.g., skin, muscle, Immune System).

By influencing gene expression in multiple tissues, Calcitriol influences many physiological processes besides Calcium/Phosphate homeostasis including muscle and Keratinocyte differentiation, Insulin secretion, blood pressure regulation, and the Immune Response.

The incidence of various diseases including Epithelial Cancers, Multiple Sclerosis, muscle weakness as well as bone-related disorders has been correlated with Vitamin-D deficiency/insufficiency and has led to a re-evaluation of recommended daily intakes both in the normal subject and CKD patient.

Critical developments have been the emergence of the value of blood 25-OH-D measurement as a tool in predicting Vitamin-D-related problems.

And this has in turn emphasized the importance of the extra re-responsible for the final step in Vitamin-D activation.

The widespread expression of this extra-Renal Enzyme supports the view that it exists to boost IntraCellular concentrations of Calcitriol within some target tissues.

In order to modulate a unique set of genes specifically in those tissues, a process which is therefore dependent upon circulating 25-OH-D.

For CKD patients with their tendency to Vitamin-D substrate insufficiency coupled with their documented loss of the Renal 1alpha-hydroxylase in late stages, this new information has profound implications.

Physicians must start to manage the Vitamin-D insufficiency by Vitamin-D supplements throughout stages 1-5 whilst continuing to provide Calcitriol replacement therapy, in the form of Calcitriol or its analogs, in stages 3-5.


IL-10 Signaling Is Essential For 1,25-DihydroxyVitamin-D3-Mediated Inhibition of Experimental Autoimmune Encephalomyelitis

Spach KM, Nashold FE, Dittel BN, Hayes CE
J Immunol 2006 Nov 1;177(9):6030-7
University of Wisconsin, College of Agricultural and Life Sciences, Department of Nutritional Sciences, 433 Babcock Drive, Madison, WI 53706, USA
PMID# 17056528

Multiple Sclerosis (MS) results from an aberrant, NeuroAntigen-specific, T-Cell-mediated Autoimmune Response.

Because MS prevalence and severity decrease sharply with increasing sunlight exposure, and sunlight supports Vitamin-D(3) synthesis, we proposed that Vitamin-D(3) and 1,25-DihydroxyVitamin-D(3) (1,25-(OH)(2)D(3)) may protect against MS.

In support of this hypothesis, 1,25-(OH)(2)D(3) strongly inhibited Experimental Autoimmune Encephalomyelitis (EAE). This inhibition required Lymphocytes other than the Encephalitogenic T-Cells.

In this study, we tested the hypothesis that 1,25-(OH)(2)D(3) might inhibit EAE through the action of IL-10-producing Regulatory Lymphocytes.

We report that Vitamin-D(3) and 1,25-(OH)(2)D(3) strongly inhibited Myelin Oligodendrocyte Peptide (MOG(35-55))-induced EAE in C57BL/6 mice, but completely failed to inhibit EAE in mice with a disrupted IL-10 or IL-10R gene.

Thus, a functional IL-10-IL-10R pathway was essential for 1,25-(OH)(2)D(3) to inhibit EAE.

The 1,25-(OH)(2)D(3) also failed to inhibit EAE in reciprocal, mixed bone marrow chimeras constructed by transferring IL-10-deficient bone marrow into irradiated wild-type mice and vice versa.

Thus, 1,25-(OH)(2)D(3) may be enhancing an anti-inflammatory loop involving Hemopoietic Cell-produced IL-10 acting on Brain Parenchymal Cells and vice versa.

If this interpretation is correct, and humans have a similar bidirectional IL-10-dependent loop, then an IL-10-IL-10R pathway defect could abrogate the anti-inflammatory and NeuroProtective functions of sunlight and Vitamin-D(3).

In this way, a genetic IL-10-IL-10R pathway defect could interact with an environmental risk factor, Vitamin-D(3) insufficiency, to increase MS risk and severity.


Vitamin-D Physiology

Lips P
Prog Biophys Mol Biol 2006 Sep;92(1):4-8
VU University Medical Center, Department of Endocrinology, P.O. Box 7057, 1007 MB Amsterdam, Netherlands
PMID# 16563471

Vitamin-D3 is synthesized in the skin during summer under the influence of ultraviolet light of the sun, or it is obtained from food, especially fatty fish.

After hydroxylation in the Liver into 25-HydroxyVitamin-D (25(OH)D) and Kidney into 1,25-DihydroxyVitamin-D (1,25(OH)2D), the active metabolite can enter the cell, bind to the Vitamin-D-Receptor and subsequently to a responsive gene such as that of Calcium binding protein.

After transcription and translation the protein is formed, e.g. Osteocalcin or Calcium binding protein. The Calcium binding protein mediates Calcium absorption from the gut.

The production of 1,25(OH)2D is stimulated by ParaThyroid Hormone (PTH) and decreased by Calcium.

Risk factors for Vitamin-D deficiency are premature birth, skin pigmentation, low sunshine exposure, obesity, malabsorption and advanced age.

Risk groups are immigrants and the elderly. Vitamin-D status is dependent upon sunshine exposure but within Europe, Serum 25(OH)D levels are higher in Northern than in Southern European countries.

Severe Vitamin-D deficiency causes rickets or osteomalacia, where the new bone, the Osteoid, is not mineralized. Less severe Vitamin-D deficiency causes an increase of Serum PTH leading to bone resorption, Osteoporosis and fractures.

A negative relationship exists between Serum 25(OH)D and Serum PTH. The threshold of Serum 25(OH)D, where Serum PTH starts to rise is about 75nmol/l according to most surveys.

Vitamin-D supplementation to Vitamin-D-deficient elderly suppresses Serum PTH, increases bone mineral density and may decrease fracture incidence especially in nursing home residents.

The effects of 1,25(OH)2D and the Vitamin-D receptor have been investigated in patients with genetic defects of Vitamin-D metabolism and in knock-out mouse models.

These experiments have demonstrated that for active Calcium absorption, longitudinal bone growth and the activity of Osteoblasts and Osteoclasts both 1,25(OH)2D and the Vitamin-D receptor are essential.

On the other side, bone mineralization can occur by high ambient Calcium concentration, so by high doses of oral calcium or Calcium infusion.

The active metabolite 1,25(OH)2D has its effects through the Vitamin-D Receptor leading to gene expression, e.g. the Calcium binding protein or Osteocalcin or through a Plasma membrane receptor and second messengers such as cyclic AMP.

The latter responses are very rapid and include the effects on the Pancreas, Vascular smooth muscle and Monocytes. Muscle cells contain Vitamin-D Receptor and several studies have demonstrated that Serum 25(OH)D is related to physical performance.

The active metabolite 1,25(OH)2D has an AntiProliferative effect and downregulates inflammatory markers.

Extrarenal synthesis of 1,25(OH)2D occurs under the influence of Cytokines and is important for the Paracrine regulation of cell differentiation and function.

This may explain that Vitamin-D deficiency can play a role in the pathogenesis of AutoImmune Diseases such as Multiple Sclerosis and Diabetes type 1, and Cancer.

In conclusion, the active metabolite 1,25(OH)2D has pleiotropic effects through the Vitamin-D receptor and Vitamin-D responsive elements of many genes and on the other side rapid non-genomic effects through a membrane receptor and second messengers.

Active Calcium absorption from the gut depends on adequate formation of 1,25(OH)2D and an intact Vitamin-D receptor.

Bone mineralization mainly depends on ambient Calcium concentration. Vitamin-D metabolites may play a role in the prevention of AutoImmune Disease and Cancer.


1,25 DihydroxyVitamin-D3 Modulates JAK-STAT Pathway In IL-12/IFN-gamma Axis Leading To Th1 Response In Experimental Allergic Encephalomyelitis

Muthian G, Raikwar HP, Rajasingh J, Bright JJ
J NeuroSci Res 2006 May 15;83(7):1299-309
Vanderbilt University Medical Center, Department of Neurology, Nashville, Tennessee, USA
PMID# 16547967

Experimental Allergic Encephalomyelitis (EAE) is a Th1 Cell-mediated Autoimmune Disease model of Multiple Sclerosis (MS).

Vitamin-D deficiency is commonly observed in MS patients and Vitamin-D supplements reduce the clinical symptoms of EAE and MS.

Earlier studies have shown that in vivo treatment with Vitamin-D analogs ameliorates EAE in association with the inhibition of IL-12 production and Th1 differentiation.

The mechanisms in the regulation of Th1 response by Vitamin-D in EAE/MS are, however, not known.

We show that in vivo treatment of C57BL/6 and SJL/J mice (i.p.) with 100 ng of 1,25 DihydroxyVitamin-D3, on every other day from Day 0-30, ameliorates EAE in association with the inhibition of IL-12 production and Neural Antigen-specific Th1 response.

In vitro treatment with 1,25(OH)2D3 inhibited IFN-γ-induced Tyrosine phosphorylation of STAT1, without affecting JAK2, in EOC-20 Microglial Cells.

Treatment of activated T-Cells with 1,25(OH)2D3 also inhibited the IL-12-induced Tyrosine phosphorylation of JAK2, TYK2, STAT3, and STAT4 in association with a decrease in T-Cell proliferation in vitro.

These findings highlight the fact that Vitamin-D modulates JAK-STAT signaling pathway in IL-12/IFN-γ axis leading to Th1 differentiation and further suggest its use in the treatment of MS and other Th1 Cell-mediated Autoimmune Diseases.

Copyright 2006 Wiley-Liss, Inc.


Vitamin-D And Autoimmune Disease--Implications For Practice From The Multiple Sclerosis Literature

Mark BL, Carson JA
J Am Diet Assoc 2006 Mar;106(3):418-24
University of Texas Southwestern Medical Center at Dallas, Department of Clinical Nutrition, 75390-8877, USA
PMID# 16503232

Recent studies and commentaries link Vitamin-D with several Autoimmune Diseases, including Multiple Sclerosis (MS).

Adequate Vitamin-D intake reduces inflammatory Cytokines through control of gene expression, thus inadequate Vitamin-D intake is suggested as a mechanism that could contribute to inflammation and, consequently, development of MS.

Poor Vitamin-D status has been associated with increased risk for development of MS, and patients with MS may suffer consequences of Vitamin-D deficiency, such as bone loss.

Animal studies and very limited human data suggest possible benefit from Vitamin-D supplementation in patients with MS.

Based on the current state of research, a key principle for practicing dietetics professionals is to include Vitamin-D status in nutritional assessment.

For those at risk for poor Vitamin-D status, intake can be enhanced by food-based advice and, when indicated, Vitamin-D supplementation.

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