Control of autoimmune diseases by the vitamin D endocrine system


1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the biologically active form of vitamin D3, is a secosteroid hormone essential for bone and mineral homeostasis. It regulates the growth and differentiation of multiple cell types, and displays immunoregulatory and anti-inflammatory properties. Cells involved in innate and adaptive immune responses—including macrophages, dendritic cells, T cells and B cells—express the vitamin D receptor (VDR), and can both produce and respond to 1,25(OH)2D3. The net effect of the vitamin D system on the immune response is an enhancement of innate immunity coupled with multifaceted regulation of adaptive immunity. Epidemiological evidence indicates a significant association between vitamin D deficiency and an increased incidence of several autoimmune diseases, and clarification of the physiological role of endogenous VDR agonists in the regulation of autoimmune responses will guide the development of pharmacological VDR agonists for use in the clinic. The antiproliferative, prodifferentiative, antibacterial, immunomodulatory and anti-inflammatory properties of synthetic VDR agonists could be exploited to treat a variety of autoimmune diseases, from rheumatoid arthritis to systemic lupus erythematosus, and possibly also multiple sclerosis, type 1 diabetes, inflammatory bowel diseases, and autoimmune prostatitis.

Key Points

  • Key cell types in the immune system, including macrophages, dendritic cells, T cells and B cells, express the vitamin D receptor (VDR) and can produce bioactive 1,25(OH)2D3

  • VDR-mediated signaling promotes innate immunity and modulates adaptive immune responses

  • Vitamin D deficiency is associated with increased incidence of autoimmune diseases

  • The anti-inflammatory, protolerogenic, antiproliferative, prodifferentiative, antibacterial, and antiangiogenic properties of VDR agonists offer opportunities for the treatment of autoimmune diseases

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Production of 1,25(OH)2D3 by leukocytes.
Figure 2: Mechanisms involved in the regulation of autoimmune responses by vitamin D receptor agonists.


  1. 1

    Deluca HF and Cantorna MT (2001) Vitamin D: its role and uses in immunology. Faseb J 15: 2579–2585

  2. 2

    Griffin MD et al. (2003) Vitamin D and its analogs as regulators of immune activation and antigen presentation. Annu Rev Nutr 23: 117–145

  3. 3

    Adorini L (2005) Intervention in autoimmunity: the potential of vitamin D receptor agonists. Cell Immunol 233: 115–124

  4. 4

    van Etten E and Mathieu C (2005) Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts. J Steroid Biochem Mol Biol 97: 93–101

  5. 5

    Arnson Y et al. (2007) Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis 66: 1137–1142

  6. 6

    Cantorna MT (2006) Vitamin D and its role in immunology: multiple sclerosis, and inflammatory bowel disease. Prog Biophys Mol Biol 92: 60–64

  7. 7

    Adorini L et al. (2004) Pharmacological induction of tolerogenic dendritic cells and regulatory T cells. Semin Immunol 16: 127–134

  8. 8

    Overbergh L et al. (2000) Identification and immune regulation of 25-hydroxyvitamin D-1-α-hydroxylase in murine macrophages. Clin Exp Immunol 120: 139–146

  9. 9

    Liu PT et al. (2006) Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311: 1770–1773

  10. 10

    Hewison M et al. (2003) Differential regulation of vitamin D receptor and its ligand in human monocyte-derived dendritic cells. J Immunol 170: 5382–5390

  11. 11

    Sigmundsdottir H et al. (2007) DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27. Nat Immunol 8: 285–293

  12. 12

    Cadranel J et al. (1990) 1,25(OH)2D3 production by T lymphocytes and alveolar macrophages recovered by lavage from normocalcemic patients with tuberculosis. J Clin Invest 85: 1588–1593

  13. 13

    Chen S et al. (2007) Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol 179: 1634–1647

  14. 14

    Holick MF (2007) Vitamin D deficiency. N Engl J Med 357: 266–281

  15. 15

    Holick MF (2008) Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol [10.1016/j.annepidem.2007.12.001]

  16. 16

    Carlberg C (2003) Current understanding of the function of the nuclear vitamin D receptor in response to its natural and synthetic ligands. Recent Results Cancer Res 164: 29–42

  17. 17

    Schauber J et al. (2007) Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J Clin Invest 117: 803–811

  18. 18

    Wang TT et al. (2004) Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 173: 2909–2912

  19. 19

    Penna G and Adorini L (2000) 1α,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol 164: 2405–2411

  20. 20

    Penna G et al. (2005) Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4+Foxp3+ regulatory T cells by 1,25-dihydroxyvitamin D3 . Blood 106: 3490–3497

  21. 21

    Gregori S et al. (2001) Regulatory T cells induced by 1α,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J Immunol 167: 1945–1953

  22. 22

    Griffin MD et al. (2001) Dendritic cell modulation by 1α,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc Natl Acad Sci USA 98: 6800–6805

  23. 23

    Dong X et al. (2005) Regulation of RelB in dendritic cells by means of modulated association of vitamin D receptor and histone deacetylase 3 with the promoter. Proc Natl Acad Sci USA 102: 16007–16012

  24. 24

    Penna G et al. (2007) 1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells. J Immunol 178: 145–153

  25. 25

    Liu YJ (2005) IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol 23: 275–306

  26. 26

    Lemire JM et al. (1995) Immunosuppressive actions of 1,25-dihydroxyvitamin D3: preferential inhibition of TH1 functions. J Nutr 125 (6 Suppl): 1704S–1708S

  27. 27

    Mattner F et al. (2000) Inhibition of TH1 development and treatment of chronic-relapsing experimental allergic encephalomyelitis by a non-hypercalcemic analogue of 1,25-dihydroxyvitamin D(3). Eur J Immunol 30: 498–508

  28. 28

    Alroy I et al. (1995) Transcriptional repression of the interleukin-2 gene by vitamin D3: direct inhibition NFATp/AP-1 complex formation by a nuclear hormone receptor. Mol Cell Biol 15: 5789–5799

  29. 29

    Cippitelli M and Santoni A (1998) Vitamin D3: a transcriptional modulator of the IFN-γ gene. Eur J Immunol 28: 3017–3030

  30. 30

    Boonstra A et al. (2001) 1α,25-Dihydroxyvitamin D3 has a direct effect on naive CD4+ T cells to enhance the development of TH2 cells. J Immunol 167: 4974–4980

  31. 31

    Mahon BD et al. (2003) The targets of vitamin D depend on the differentiation and activation status of CD4 positive T cells. J Cell Biochem 89: 922–932

  32. 32

    Penna G et al. (2006) Treatment of experimental autoimmune prostatitis in nonobese diabetic mice by the vitamin D receptor agonist elocalcitol. J Immunol 177: 8504–8511

  33. 33

    Steinman L (2007) A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell-mediated tissue damage. Nat Med 13: 139–145

  34. 34

    Gregori G et al. (2002) A 1α,25-dihydroxyvitamin D3 analog enhances regulatory T cells and arrests autoimmune diabetes in NOD mice. Diabetes 51: 1367–1374

  35. 35

    Barrat FJ et al. (2002) 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. J Exp Med 195: 603–616

  36. 36

    Gorman S et al. (2007) Topically applied 1,25-dihydroxyvitamin D3 enhances the suppressive activity of CD4+CD25+ cells in the draining lymph nodes. J Immunol 179: 6273–6283

  37. 37

    Curiel TJ et al. (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10: 942–949

  38. 38

    Bischoff-Ferrari HA et al. (2006) Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 84: 18–28

  39. 39

    Cantorna MT and Mahon BD (2004) Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence. Exp Biol Med (Maywood) 229: 1136–1142

  40. 40

    Grant WB (2006) Epidemiology of disease risks in relation to vitamin D insufficiency. Prog Biophys Mol Biol 92: 65–79

  41. 41

    Munger KL et al. (2006) Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 296: 2832–2838

  42. 42

    Brown SJ (2006) The role of vitamin D in multiple sclerosis. Ann Pharmacother 40: 1158–1161

  43. 43

    Hypponen E et al. (2001) Intake of vitamin D and risk of type 1 diabetes: a birth–cohort study. Lancet 358: 1500–1503

  44. 44

    Zipitis CS and Akobeng AK (2008) Vitamin D supplementation in early childhood and risk of type 1 diabetes: a systematic review and meta-analysis. Arch Dis Child [10.1136/adc.2007.128579]

  45. 45

    Merlino LA et al. (2004) Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study. Arthritis Rheum 50: 72–77

  46. 46

    Kamen DL et al. (2006) Vitamin D deficiency in systemic lupus erythematosus. Autoimmun Rev 5: 114–117

  47. 47

    Costenbader KH et al. (2008) Vitamin D intake and risks of systemic lupus erythematosus and rheumatoid arthritis in women. Ann Rheum Dis 67: 530–535

  48. 48

    Pappa HM et al. (2006) Report on the vitamin D status of adult and pediatric patients with inflammatory bowel disease and its significance for bone health and disease. Inflamm Bowel Dis 12: 1162–1174

  49. 49

    Uitterlinden AG et al. (2004) Genetics and biology of vitamin D receptor polymorphisms. Gene 338: 143–156

  50. 50

    Valdivielso JM and Fernandez E (2006) Vitamin D receptor polymorphisms and diseases. Clin Chim Acta 371: 1–12

  51. 51

    Nagpal S et al. (2005) Noncalcemic actions of vitamin D receptor ligands. Endocr Rev 26: 662–687

  52. 52

    Menter A and Griffiths CE (2007) Current and future management of psoriasis. Lancet 370: 272–284

  53. 53

    Ma Y et al. (2006) Identification and characterization of noncalcemic, tissue-selective, nonsecosteroidal vitamin D receptor modulators. J Clin Invest 116: 892–904

  54. 54

    Cantorna MT et al. (1998) 1,25-Dihydroxycholecalciferol inhibits the progression of arthritis in murine models of human arthritis. J Nutr 128: 68–72

  55. 55

    Larsson P et al. (1998) A vitamin D analogue (MC 1288) has immunomodulatory properties and suppresses collagen-induced arthritis (CIA) without causing hypercalcaemia. Clin Exp Immunol 114: 277–283

  56. 56

    Tetlow LC and Woolley DE (1999) The effects of 1 alpha,25-dihydroxyvitamin D3 on matrix metalloproteinase and prostaglandin E2 production by cells of the rheumatoid lesion. Arthritis Res 1: 63–70

  57. 57

    Cutolo M et al. (2007) Vitamin D in rheumatoid arthritis. Autoimmun Rev 7: 59–64

  58. 58

    Andjelkovic Z et al. (1999) Disease modifying and immunomodulatory effects of high dose 1 alpha (OH) D3 in rheumatoid arthritis patients. Clin Exp Rheumatol 17: 453–456

  59. 59

    Santiago-Raber ML et al. (2004) Genetic basis of murine lupus. Autoimmun Rev 3: 33–39

  60. 60

    Abe J et al. (1990) Prevention of immunological disorders in MRL/l mice by a new synthetic analogue of vitamin D3: 22-oxa-1 α,25-dihydroxyvitamin D3 . J Nutr Sci Vitaminol (Tokyo) 36: 21–31

  61. 61

    Lemire JM et al. (1992) 1,25-Dihydroxyvitamin D3 attenuates the expression of experimental murine lupus of MRL/l mice. Autoimmunity 12: 143–148

  62. 62

    Linker-Israeli M et al. (2001) Vitamin D3 and its synthetic analogs inhibit the spontaneous in vitro immunoglobulin production by SLE-derived PBMC. Clin Immunol 99: 82–93

  63. 63

    Giarratana N et al. (2004) A vitamin D analog down-regulates proinflammatory chemokine production by pancreatic islets inhibiting T cell recruitment and type 1 diabetes development. J Immunol 173: 2280–2287

  64. 64

    Gysemans C et al. (2008) Unaltered diabetes presentation in NOD mice lacking the vitamin D receptor. Diabetes 57: 269–275

  65. 65

    Muthian G et al. (2006) 1,25 Dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFNgamma axis leading to TH1 response in experimental allergic encephalomyelitis. J Neurosci Res 83: 1299–1309

  66. 66

    Spach KM et al. (2006) IL-10 signaling is essential for 1,25-dihydroxyvitamin D3-mediated inhibition of experimental autoimmune encephalomyelitis. J Immunol 177: 6030–6037

  67. 67

    Froicu M and Cantorna MT (2007) Vitamin D and the vitamin D receptor are critical for control of the innate immune response to colonic injury. BMC Immunol 8: 5

  68. 68

    Zhu Y et al. (2005) Calcium and 1 alpha,25-dihydroxyvitamin D3 target the TNF-alpha pathway to suppress experimental inflammatory bowel disease. Eur J Immunol 35: 217–224

  69. 69

    Pontari MA and Ruggieri MR (2004) Mechanisms in prostatitis/chronic pelvic pain syndrome. J Urol 172: 839–845

  70. 70

    Crescioli C et al. (2004) Inhibition of prostate cell growth by BXL-628, a calcitriol analogue selected for a phase II clinical trial in patients with benign prostate hyperplasia. Eur J Endocrinol 150: 591–603

  71. 71

    Campbell MJ and Adorini L (2006) The vitamin D receptor as a therapeutic target. Expert Opin Ther Targets 10: 735–748

  72. 72

    Levin A and Li YC (2005) Vitamin D and its analogues: do they protect against cardiovascular disease in patients with kidney disease. Kidney Int 68: 1973–1981

  73. 73

    Michos ED and Melamed ML (2008) Vitamin D and cardiovascular disease risk. Curr Opin Clin Nutr Metab Care 11: 7–12

  74. 74

    Kalueff AV et al. (2006) The vitamin D neuroendocrine system as a target for novel neurotropic drugs. CNS Neurol Disord Drug Targets 5: 363–371

Download references

Author information

Correspondence to Luciano Adorini.

Ethics declarations

Competing interests

L Adorini is the cofounder and former Chief Scientific Officer of BioXell and G Penna is an employee of BioXell. L Adorini holds BioXell stock, and L Adorini and G Penna are named as co-inventors on patents held by BioXell.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Adorini, L., Penna, G. Control of autoimmune diseases by the vitamin D endocrine system. Nat Rev Rheumatol 4, 404–412 (2008).

Download citation

Further reading