Mounting Evidence for Vitamin D as an Environmental Factor Affecting Autoimmune Disease Prevalence

Low vitamin D status has been implicated in the etiology of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, insulin-dependent diabetes mellitus, and inflammatory bowel disease. The optimal level of vitamin D intake required to support optimal immune function is not known but is likely to be at least that required for healthy bones. Experimentally, vitamin D deficiency results in the increased incidence of autoimmune disease. Mechanistically, the data point to a role for vitamin D in the development of self-tolerance. The vitamin D hormone (1,25-dihydroxy vitamin D3) regulates T helper cell (Th1) and dendritic cell function while inducing regulatory T-cell function. The net result is a decrease in the Th1-driven autoimmune response and decreased severity of symptoms. This review discusses the accumulating evidence pointing to a link between vitamin D and autoimmunity. Increased vitamin D intakes might decrease the incidence and severity of autoimmune diseases and the rate of bone fracture.

[1]  H. DeLuca,et al.  1,25-dihydroxyvitamin D3 is a positive regulator for the two anti-encephalitogenic cytokines TGF-beta 1 and IL-4. , 1998, Journal of immunology.

[2]  T. Meehan,et al.  The vitamin D receptor is necessary for 1α,25-dihydroxyvitamin D3 to suppress experimental autoimmune encephalomyelitis in mice ☆ , 2002 .

[3]  S. Walsh,et al.  Autoimmune diseases: a leading cause of death among young and middle-aged women in the United States. , 2000, American journal of public health.

[4]  B. Györffy,et al.  Gender-specific association of vitamin D receptor polymorphism combinations with type 1 diabetes mellitus. , 2002, European journal of endocrinology.

[5]  M. Uskoković,et al.  A 1alpha,25-dihydroxyvitamin D(3) analog enhances regulatory T-cells and arrests autoimmune diabetes in NOD mice. , 2002, Diabetes.

[6]  C. Folwaczny,et al.  Candidate Genes Colocalized to Linkage Regions in Inflammatory Bowel Disease , 2002, Digestion.

[7]  P. Lips Which circulating level of 25-hydroxyvitamin D is appropriate? , 2004, The Journal of Steroid Biochemistry and Molecular Biology.

[8]  J. Welsh,et al.  A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases. , 2003, Molecular endocrinology.

[9]  T. Hünig,et al.  IL-2 and autoimmune disease. , 2002, Cytokine & growth factor reviews.

[10]  L. Freedman,et al.  1,25-dihydroxyvitamin D3 inhibits IFN-gamma and IL-4 levels during in vitro polarization of primary murine CD4+ T cells. , 2002, Journal of immunology.

[11]  K. Myhr,et al.  Effect of dietary advice and n‐3 supplementation in newly diagnosed MS patients , 2000, Acta neurologica Scandinavica.

[12]  P. Eskildsen,et al.  Regulators of calcium homeostasis and bone mineral density in patients with Crohn's disease. , 1998, Scandinavian journal of gastroenterology.

[13]  H. DeLuca,et al.  Vitamin D and autoimmune diabetes , 2003, Journal of cellular biochemistry.

[14]  M. Holick,et al.  Regulation of cutaneous previtamin D3 photosynthesis in man: skin pigment is not an essential regulator. , 1981, Science.

[15]  Elina Hyppönen,et al.  Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study , 2001, The Lancet.

[16]  P. Goldberg,et al.  Multiple sclerosis: decreased relapse rate through dietary supplementation with calcium, magnesium and vitamin D. , 1986, Medical hypotheses.

[17]  T. Zemunik,et al.  Vitamin D receptor polymorphism and susceptibility to type 1 diabetes in the Dalmatian population. , 2003, Diabetes research and clinical practice.

[18]  M. Cantorna,et al.  1,25-Dihydroxycholecalciferol prevents and ameliorates symptoms of experimental murine inflammatory bowel disease. , 2000, The Journal of nutrition.

[19]  C. Mathieu,et al.  In Vitro and In Vivo Analysis of the Immune System of Vitamin D Receptor Knockout Mice , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[20]  M. Holick,et al.  Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. , 2004, The American journal of clinical nutrition.

[21]  L. Adorini,et al.  1α,25-Dihydroxyvitamin D3 Inhibits Differentiation, Maturation, Activation, and Survival of Dendritic Cells Leading to Impaired Alloreactive T Cell Activation , 2000, The Journal of Immunology.

[22]  J. Franklyn,et al.  Effect of vitamin D receptor gene alleles on bone loss in early rheumatoid arthritis. , 1998, The Journal of rheumatology.

[23]  F. Cosman,et al.  Cytokine profile in patients with multiple sclerosis following vitamin D supplementation , 2003, Journal of Neuroimmunology.

[24]  N. Pejnović,et al.  Disease modifying and immunomodulatory effects of high dose 1 alpha (OH) D3 in rheumatoid arthritis patients. , 1999, Clinical and experimental rheumatology.

[25]  J. Todd,et al.  The study of CTLA‐4 and vitamin D receptor polymorphisms in the Romanian type 1 diabetes population , 2002, Journal of cellular and molecular medicine.

[26]  O. Majdic,et al.  1,25-Dihydroxyvitamin D(3) inhibits dendritic cell differentiation and maturation in vitro. , 2000, Experimental hematology.

[27]  W. Sibley,et al.  Seasonal variation of multiple sclerosis exacerbations in Arizona , 1983, Neurology.

[28]  Huub F. J. Savelkoul,et al.  1α,25-Dihydroxyvitamin D3 Has a Direct Effect on Naive CD4+ T Cells to Enhance the Development of Th2 Cells1 , 2001, The Journal of Immunology.

[29]  D. Goodkin,et al.  Seasonal variation of multiple sclerosis exacerbations in North Dakota. , 1989, Archives of neurology.

[30]  L. Mosekilde,et al.  Inflammatory bowel disease and osteoporosis. , 1997, Scandinavian journal of gastroenterology.

[31]  Association of vitamin D receptor genotypes with early onset rheumatoid arthritis. , 2008, European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics.

[32]  C. Wagner,et al.  Assessment of dietary vitamin D requirements during pregnancy and lactation. , 2004, The American journal of clinical nutrition.

[33]  M. Holick,et al.  Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. , 2003, The American journal of clinical nutrition.

[34]  M. Cantorna,et al.  Vitamin D and autoimmunity: is vitamin D status an environmental factor affecting autoimmune disease prevalence? , 2000, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[35]  T. Gramlich,et al.  Dietary Supplementation with Fish Oil in Ulcerative Colitis , 1992, Annals of Internal Medicine.

[36]  M. Rocchi,et al.  Linkage analysis conditional on HLA status in a large North American pedigree supports the presence of a multiple sclerosis susceptibility locus on chromosome 12p12. , 2002, Human molecular genetics.

[37]  R. Vieth Why the optimal requirement for Vitamin D3 is probably much higher than what is officially recommended for adults , 2004, The Journal of Steroid Biochemistry and Molecular Biology.

[38]  T. Meehan,et al.  The vitamin D receptor is necessary for 1alpha,25-dihydroxyvitamin D(3) to suppress experimental autoimmune encephalomyelitis in mice. , 2002, Archives of biochemistry and biophysics.

[39]  H. DeLuca,et al.  1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[40]  H. Rieder,et al.  The seasonal incidence of multiple sclerosis in Switzerland. , 1970, European neurology.

[41]  R. Kumar,et al.  Potent inhibition of dendritic cell differentiation and maturation by vitamin D analogs. , 2000, Biochemical and biophysical research communications.

[42]  L. Freedman,et al.  1,25-Dihydroxyvitamin D3 Inhibits IFN-γ and IL-4 Levels During In Vitro Polarization of Primary Murine CD4+ T Cells1 , 2002, The Journal of Immunology.

[43]  R. Mutani,et al.  Transforming growth factor β1 (TGFβ1) mRNA level correlates with magnetic resonance imaging disease activity in Multiple Sclerosis patients , 1999, Neuroscience Letters.

[44]  R. Bretzel,et al.  VDR gene polymorphisms are overrepresented in german patients with type 1 diabetes compared to healthy controls without effect on biochemical parameters of bone metabolism. , 2002, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[45]  M. Cantorna,et al.  The targets of vitamin D depend on the differentiation and activation status of CD4 positive T cells , 2003, Journal of cellular biochemistry.

[46]  C. Gössl,et al.  Seasonal fluctuations of gadolinium‐enhancing magnetic resonance imaging lesions in multiple sclerosis , 2000, Annals of neurology.

[47]  P. Allavena,et al.  Vitamin D3 Affects Differentiation, Maturation, and Function of Human Monocyte-Derived Dendritic Cells1 , 2000, The Journal of Immunology.

[48]  R. Mutani,et al.  Transforming growth factor beta1 (TGFbeta1) mRNA level correlates with magnetic resonance imaging disease activity in multiple sclerosis patients. , 1999, Neuroscience letters.

[49]  T. Saruta,et al.  Vitamin D receptor gene polymorphism affects onset pattern of type 1 diabetes. , 2003, The Journal of clinical endocrinology and metabolism.

[50]  A. Sadovnick,et al.  Vitamin D intake and incidence of multiple sclerosis , 2004, Neurology.

[51]  M. Uskoković,et al.  A 1α,25-Dihydroxyvitamin D3 Analog Enhances Regulatory T-Cells and Arrests Autoimmune Diabetes in NOD Mice , 2002 .

[52]  R. Vieth,et al.  Vitamin D and seasonal fluctuations of gadolinium‐enhancing magnetic resonance imaging lesions in multiple sclerosis , 2000, Annals of neurology.

[53]  D. Jewell,et al.  Vitamin D receptor gene polymorphism: association with Crohn's disease susceptibility , 2000, Gut.

[54]  R. Vieth,et al.  Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level. , 2001, The American journal of clinical nutrition.

[55]  S. Kikuchi,et al.  No association of vitamin D-binding protein gene polymorphisms in Japanese patients with MS , 2002, Journal of Neuroimmunology.

[56]  H. Drexhage,et al.  1-alpha,25-Dihydroxyvitamin D3 (1,25(OH)(2)D(3)) hampers the maturation of fully active immature dendritic cells from monocytes. , 2001, European journal of endocrinology.

[57]  Joanne I. Yeh,et al.  Vitamin D receptor gene polymorphisms influence susceptibility to type 1 diabetes mellitus in the Taiwanese population , 2000, Clinical endocrinology.

[58]  K. Miyasaka,et al.  Association of vitamin D receptor gene polymorphism with multiple sclerosis in Japanese , 1999, Journal of the Neurological Sciences.

[59]  David F. Richards,et al.  In Vitro Generation of Interleukin 10–producing Regulatory CD4+ T Cells Is Induced by Immunosuppressive Drugs and Inhibited by T Helper Type 1 (Th1)– and Th2-inducing Cytokines , 2002, The Journal of experimental medicine.

[60]  G. Triadafilopoulos,et al.  Fish oil fatty acid supplementation in active ulcerative colitis: a double-blind, placebo-controlled, crossover study. , 1992, The American journal of gastroenterology.

[61]  J. Cerhan,et al.  Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study. , 2004, Arthritis and rheumatism.

[62]  N. Risch,et al.  Genetic analysis of vitamin D related genes in Canadian multiple sclerosis patients , 2000, Neurology.