The best characterized effect of vitamin D is on the small intestine and the bone. In the small intestine, vitamin D increases the absorption of calcium by increasing the expression of a specific calcium channel. In bone, vitamin D induces the differentiation of pre-osteoclasts into mature osteoclasts, ultimately promoting removal of calcium and phosphorus from the bone (1-3).
Vitamin D enters the human body via two sources: exposure of the skin to sunlight and diet (1). Solar radiation in the UVB waveband (wavelength, 290 to 315 nm) converts 7-dehydrocholesterol to previtamin D3 which is converted to vitamin D3 (1-5).
Natural dietary sources of vitamin D are wild fresh salmon (800 IU of D3 per 3.5 oz), cod liver oil (700 IU of D3 per 1 tps), sun-dried Shiitake mushrooms (1600 IU of D2 per 3.5 oz), fortified foods such as milk (100 IU of D3 per 8 ox), and other supplements. Vitamin D2 is produced through the ultraviolet irradiation of ergosterol, and vitamin D3 is produced through the ultraviolet irradiation of 7-dehydrocholesterol. Both of those vitamin D forms are used as vitamin D supplements (5).
Vitamin D made in the skin (D3) or ingested (either D2 or D3) travels in the bloodstream bounds to vitamin D-binding protein, and reaches the liver where it is converted to 25-hydroxyvitamin D3 [25(OH)D3]. This is the major circulating form of vitamin D, the one measured by clinical laboratories to determine the vitamin D status. A normal level of circulating 25(OH)D3 is between 20 and 80 ng/mL. Levels below 20 ng/mL are considered indicative of vitamin D deficiency. Vitamin 25(OH)D3 is biologically inactive and must be converted in the kidneys to the biologically active form, 1,25 dihydroxy vitamin D (1,25(OH)2D3) (5).
Until 1980, vitamin D has not been imagined to have a role in the functioning of the immune system (6).
The discovery of vitamin D receptor (VDR) in lymphocytes, promyelocytes, macrophages, dendritic cells (DC) and islet cells of pancreas resulted in the idea that vitamin D had functions beyond calcium and phosphorus metabolism and that idea prompted investigations into noncalcemic actions of the vitamin D hormone (6,7).
It has been shown that vitamin D has an important role in the regulation of the immune system. 1,25dihydroxyvitamin D3 (1,25 (OH)2D3) has been determined to suppress the development of autoimmune diseases. However, it does not have any effect on immunity to infectious organisms and other immune system mediated-diseases such as experimental asthma (7). Dendritic cells, T helper 1 (Th1) and Th2 cells are direct targets of 1,25 (OH)2D3 (8).
VDR is not found in appreciable amounts in the B lymphocyte, but in significant concentrations in the T lymphocytes and macrophages (6,9). However, its highest concentration is in the immature immune cells of the thymus and the mature CD8 T lymphocytes. Immune cells are able to synthesize and secrete 1,25(OH)2D3 as they contain 1?-hydroxylase enzyme, which is necessary for the final activation step in the conversion of vitamin D3 to the biological active form (10). The 1?-hydroxylase enzyme in immune cells is identical to the renal enzyme, but regulation of its expression and activity is different. Whereas the renal enzyme is principally under the control of calcaemic and bone signals (such as parathyroid hormone and 1,25(OH)2D3, itself), the 1?-hydroxylase enzyme in the macrophage is primarily regulated by immune signals, interferon ? (IFN-?) and toll-like receptor agonist which is the powerful stimulator of that enzyme (10).
Many studies have shown that some autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, experimental autoimmune encephalomyelitis, type 1 diabetes, and inflammatory bowel disease (IBD) can be not only prevented but also suppressed by 1.25(OH)2D3 (6). Recent studies have shown significant association of vitamin D deficiency with obesity, type 2 diabetes mellitus and and Hashimoto’s thyroiditis (11-25).
Th1 cells secrete IFN-γ, interleukin-2 (IL-2), and tumor necrosis factor-alpha (TNF-α) and Th2 cells secrete IL-4 and IL-5. All of those cytokines are important for strong antibody-mediated immunity. Activation of Th1 cells is needed for cell-mediated immunity such as host responses to intracellular pathogens and tumors. Th1 cells are misdirected against self proteins in autoimmune diseases such as type 1 diabetes mellitus. Th2 cells are essential in immune responses to extracellular pathogens such as bacteria and parasites. Dendritic cells, Th1 and Th2 cells are direct targets of 1,25(OH)2D3. Normally, expression of VDRs on quiescent CD4+ T cells is very low, but increases 5-fold after the activations of T cells (7,26). 1,25(OH)2D3 reduces the proliferation of purified Th1 cells and the productions of IFN-γ, IL-2, IL-5 and TNF-α, but, induces IL-4, and transforming growth factor (TGFB) synthesis, which is able to suppress inflammatory T cell activity in Th2 cells (7,26). One of the evidences of that, a murine model of the human disease multiple sclerosis cannot be suppressed by 1,25(OH)2D3 in IL-4-deficient mice (11). The effects of 1,25(OH)2D3 on inhibition of the autoimmune diseases invivo has been shown to depend on IL-2 (27) and IL-4 secretions (28). 1,25(OH)2D3 decreases Th1 cell cytokines, but increases secretion of IL-4 which is one of the Th2 cell cytokines. When vitamin D signaling is absent, Th1 phenotype is the strongest phenotype in T cell compartment (7). Furthermore, Abe et al. and Tanaka et al. determined that vitamin D can not only inhibit promyelocytes proliferation, but induces their differentiation into monocytes as well (6,29,30).
Vitamin D or VDR deficient hosts have high Th1 cell cytokine levels, although they have low levels of Th2 cell cytokines. When vitamin D signaling is absent, IBDs are more serious and asthma which is driven by Th2 cells does not develop. Results of recent studies suggest a model in which 1.25(OH)2D3 treatment for autoimmune diseases results in inhibition of Th1 cells proliferations and cytokine productions but induction of Th2 cells and Th2 cells cytokine synthesis (7,31). Moreover, 1.25(OH)2D3 inhibits DC differentiation and maturation, leading to down-regulated expression of MHC-II, co-stimulatory molecules and IL-12 and, enhances IL-10 production and promotes DC apoptosis. Because of those effects, 1,25(OH)2D3 inhibits DC-dependent T cell activation (32). In vitro, it has been determined that 1.25 (OH)2D3 stimulates the phagocytosis and killing of bacteria by macrophages but suppresses the antigen presenting ability of those cells and DCs (33,34). IL-12 is produced by macrophages and DCs and is the major determinant of the direction in which the immune system will be activated, since it stimulates the development of CD4 Th1 cells and inhibits the development of Th2 cells. Inhibition of production of IL-12 by vitamin D invitro and a shift from Th1 to Th2 predominance can also be observed after in vivo administration of 1.25 (OH)2D3 (35,36).
VDR is not found in appreciable amounts in the B lymphocyte. However, Chen et al. (37) have suggested that vitamin D might play a role in regulating antibody production. They have found that 1.25(OH)2D3 not only inhibits activated B cells proliferations but induces their apoptosis as well.
In conclusion, vitamin D stimulates the phagocytosis and killing of bacteria by macrophages, but suppresses Th1 cell activation by inhibiting the antigen presenting capacity of macrophages and DCs. At the second stage, vitamin D inhibits the secretion of Th1 cytokines and increases IL-4 secretion of Th2 cell. Moreover, vitamin D is suggested to have effects on B lymphocytes proliferation, apoptosis and antibody production.
1. Holick MF. Resurrection of vitamin D deficiency and rickets. J Clin Invest 2006;116:2062-72.
2. Holick MF, Garabedian M. Vitamin D: photobiology, metabolism, mechanism of action, and clinical applications. In: Favus MJ, ed. Primer on the metabolic bone diseases and disorders of mineral metabolism (6 th ed). Washington; American Society for Bone and Mineral Research;2006;129-37.
3. Bouillon R. Vitamin D: from photosynthesis, metabolism, and action to clinical applications Endocrinology. In: DeGroot LJ, Jameson JL eds. Philadelphia; WB Saunders,2001;1009-28.
4. DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin 2004;80(Suppl):1689-96.
5. Michael F, Holick MF. Vitamin D deficiency. N Engl j Med 2007;357:266-81.
6. Deluca HF, Cantorna MT. Vitamin D: its role and uses in immunology. FASEB J 2001;15:2579-85.
7. Cantorna MT, Zhu Y, Froicu M, Wittke A. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am J Clin Nutr 2004;80:1717-20.
8. Van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts. J Steroid Biochem Mol Biol 2005;97:93-101.
9. Veldman, CM, Cantorna MT, DeLuca HF. Expression of 1,25 dihydroxyvitamin D(3) receptor in the immune system. Arch. Biochem Biophys 2000;374:334-8.
10. Overbergh L, Decallonne B, Valckx D, et al. Identification and immune regulation of 25-hydroxyvitamin D-1-alpha-hydroxylase in murine macrophages. Clin Exp Immunol 2000;120:139-46.
11. Alemzadeh R, Kichler J, Babar G, Calhoun M. Hypovitaminosis D in obese children and adolescents: relationship with adiposity, insulin sensitivity, ethnicity, and season. Metabolism 2008;57:183-91.
12. Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 2004;80(Suppl 6):1678-88.
13. Reis AF, Hauache OM, Velho G. Vitamin D endocrine system and the genetic susceptibility to diabetes, obesity and vascular disease. A review of evidence. Diabetes Metab 2005;31:318-25.
14. Kadowaki S, Norman AW. Time course study of insulin secretion after 1,25-dihydroxyvitamin D3 administration. Endocrinology 1985;117:1765-71.
15. Lee S, Clark SA, Gill RK, Christakos S. ,25-Dihydroxyvitamin D3 and pancreatic beta-cell function: vitamin D receptors, gene expression, and insulin secretion. Endocrinology 1994; 134:1602-10.
16. Scragg R, Holdaway I, Singh V, et al. Serum 25-hydroxyvitamin D3 levels decreased in impaired glucose tolerance and diabetes mellitus. Diabetes Res Clin Pract 1995;27:181-8.
17. Hyppönen E, Power C. Vitamin D status and glucose homeostasis in the 1958 British birth cohort: the role of obesity. Diabetes Care 2006;29:2244-6.
18. Maggio CA, Pi-Sunyer FX. The prevention and treatment of obesity. Application to type 2 diabetes. Diabetes Care 1997;20:1744-66.
19. Rodríguez-Rodríguez E, Navia B, López-Sobaler AM, Ortega RM. Vitamin D in overweight/obese women and its relationship with dietetic and anthropometric variables. Obesity (Silver Spring) 2009;17:778-82.
20. McGill AT, Stewart JM, Lithander FE, Strik CM, Poppitt SD. Relationships of low serum vitamin D3 with anthropometry and markers of the metabolic syndrome and diabetes in overweight and obesity. Nutr J 2008;7:4.
21 . Ford ES, Ajani UA, McGuire LC, Liu S. Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults. Diabetes Care 2005;28:1228-30.
22. Vilarrasa N, Maravall J, Estepa A, et al. Low 25-hydroxyvitamin D concentrations in obese women: their clinical significance and relationship with anthropometric and body composition variables. J Endocrinol Invest 2007;30:653-8.
23. Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr 2004;79:820-5.
24. Tamer G, Arik S, Tamer I, Coksert D. Relative vitamin D insufficiency in Hashimoto’s thyroiditis. Thyroid 2011;21:891-6.
25. Tamer G, Mesci B, Tamer I, Kilic D, Arik S. Is vitamin D deficiency an independent risk factor for obesity and abdominal obesity in women? Endokrynol Pol 2012;63:196-201.
26. Mahon BD, Wittke A, Weaver V, Cantorna MT. The targets of vitamin D depend on the differentiation and activation status of CD4 positive T cells. J Cell Biochem 2003;89:922-32.
27. Bemiss CJ, Mahon BD, Henry A, Weaver V, Cantorna MT. Interleukin-2 is one of the targets of 1,25-dihydroxyvitamin D3 in the immune system. Arch Biochem Biophys 2002;402:249–54.
28. Cantorna MT, Humpal-Winter J, DeLuca HF. In vivo upregulation of interleukin-4 is one mechanism underlying the immunoregulatory effects of 1,25-dihydroxyvitamin D(3). Arch Biochem Biophys 2000;377:135–8.
29. Abe E, Miyaura C, Sakagami H, et al. Differentiation of mouse myeloid leukemia cells induced by 1 alpha,25-dihydroxyvitamin D3. Proc Natl Acad Sci USA 1981;78:4990-94.
30. Tanaka H, Abe E, Miyaura C, et al. 1 alpha,25-Dihydroxycholecalciferol and a human myeloid leukaemia cell line (HL-60). Biochem J 1982;204:713-9.
31. Cantorna MT. Vitamin D and autoimmunity: is vitamin D status an environmental factor affecting autoimmune disease prevalence? Proc Soc Exp Biol Med 2000;223:230-3.
32. Bischoff-Ferrari HA. Optimal serum 25-hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med Biol 2008;624:55-71.
33. van Etten E, Decallonne B, Bouillon R, Mathieu C. NOD bone marrow-derived dendritic cells are modulated by analogs of 1,25-dihydroxyvitamin D3 . J Steroid Biochem Mol Biol 2004;89-90:457-9.
34. Bischoff-Ferrari HA. Optimal serum 25-hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med Biol 2008;624:55-71.
35. Overbergh L, Decallonne B, Waer M, et al. 1alpha,25-dihydroxyvitamin D3 induces an autoantigen-specific T-helper 1/T-helper 2 immune shift in NOD mice immunized with GAD65 (p524-543). Diabetes 2000;49:1301-7.
36. Gregori S, Giarratana N, Smiroldo S, Uskokovic M, Adorini L. A 1alpha,25-dihydroxyvitamin D(3) analog enhances regulatory T-cells and arrests autoimmune diabetes in NOD mice. Diabetes 2002;51:1367-74.
37. Chen S, Sims GP, Chen XX, et al. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol 2007;179:1634-47.