Mediterr J Rheumatol 2022;33(1):7-13
The Immunomodulatory Properties of Vitamin D
Authors Information

Department of Physiology, Medical School, University of Athens, Athens, Greece


Since its discovery, vitamin D was shown to have both immunostimulatory and immunomodulatory effects on the immune system. A growing body of evidence so far linked vitamin D deficiency with the development and severity of several systemic and organ specific autoimmune/inflammatory diseases, such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. In the present report, the multiple and diverse effects of vitamin D on the immune system are reviewed.

Cite this article as: Athanassiou L, Mavragani CP, Koutsilieris M. The Immunomodulatory Properties of Vitamin D. Mediterr J Rheumatol 2022;33(1):7-13.

Article Submitted: 1 Sep 2021; Revised Form: 26 Jan 2022; Article Accepted: 15 Feb 2022; Available Online: 31 Mar 2022


This work is licensed under a Creative Commons Attribution 4.0 International License.

©Athanassiou L, Mavragani CP, Koutsilieris M.

Full Text


While vitamin D is well-known for its actions on bone and mineral metabolism,1,2 extraskeletal effects are increasingly recognized3,4; its influences on the immune system have been the focus of intense research.5-7 In earlier years, immunostimulatory effects were recognised,8 followed by subsequent observations revealing the relationship of vitamin D deficiency9,10 with the development of autoimmune diseases,5,10 given the ability of vitamin D to induce immune tolerance.11,12 In rheumatoid arthritis, vitamin D deficiency has been found to be prevalent in patients with rheumatoid arthritis13-16 and inflammatory bowel disease17 in association with increased disease activity.14,16 Similar observations were made in patients with systemic lupus erythematosus18-20 and systemic sclerosis,21 with the reported associations with disease activity being rather conflicting.18,22-24 Vitamin D deficiency has been also observed in patients with multiple sclerosis (MS),25-28 and vitamin D administration may be a complementary agent in MS treatment.26

Vitamin D deficiency has also been reported in patients with diabetes mellitus type 129-32 and has been implicated in the development of the disease,30,33 potentially through modulating inflammatory pathways.34 Vitamin D receptors have been found in many cells of the immune system,35-38 such as T lymphocytes36,39,40 and macrophages,41 among others. Moreover, 1a-hydroxylase, the enzyme responsible for the formation of the active compound of the vitamin D system, namely 1,25(OH)2D3, has been found to be expressed in cells of the immune system,42-44 thus enabling the formation and action of the active compound of the vitamin D system, namely 1,25(OH)2D3. Type I interferons (IFNs) (IFN α/β) are proteins that normally provide protection from viral infections, through induction of hundreds of genes implicated in antiviral response; the so-called “IFN signature”. A significant role of the type I interferon (IFN) system in the pathogenesis of systemic autoimmune diseases has been well documented.45,46 Vitamin D has been shown in an experimental lupus model to modulate interferon-1 responses.47In the current review, the immunomodulatory properties of vitamin D are reviewed.



While it is well established that vitamin D enhances intestinal calcium absorption, an effect mediated via regulation of calcium transport proteins in the small intestine,48 exhibiting a central role in the maintenance of bone health, extra skeletal actions are less explored. Amongst them extremely important are its effects on the immune system (Figure 1). Cells of the immune system harbour the vitamin D activating enzyme 1-α-hydroxylase and express the vitamin D receptor (VDR).43,44 The extra-renal 1-α-hydroxylase is not regulated by PTH and thus production of 1,25(OH)2D3 is dependent on concentrations of the substrate 25(OH)D3 and it may be regulated by inflammatory signals, such as lipopolysaccharide and cytokines.42,49 Cells of the immune system which express the VDR and harbour 1-α-hydroxylase are macrophages, T cells, dendritic cells, monocytes, and B cells36,50 (Figure 2).

Vitamin D is involved both in the regulation of the innate immunity as it enhances the body defence system against microbes and other pathogenic organisms, as well as in the modulation of the adaptive immune system through direct effects on T cell activation and on the phenotype and function of antigen-presenting cells; in particular, dendritic cells.

Figure 1. The effects of vitamin D on the immune system.5,11,25,35

Figure 2. Cells of the immune system which are targets of vitamin D, macrophages,41,59,61,79 neutrophils,38 T lymphocytes,39,40,87 dendritic cells,83 B lymphocytes.111



Vitamin D regulates the innate immune system.2,5,51 The innate immune system -an older evolutionary defence strategy- is a first line of defence against infection,52,53 and one of the two main immunity arms in vertebrates, including humans.53 Its major functions include recruitment of immune cells, activation of the complement cascade, identification and removal of foreign substances, activation of the adaptive immune response, and the utilization of physical and chemical barriers against infectious agents.53 The vitamin D receptor (VDR) is expressed both in the keratinocytes54,55 and cells of the innate immune system such as macrophages and monocytes,56-59 thus ensuring its action on two lines of body defence.

The beneficial effects of vitamin D on the innate immune system were appreciated early on, as it was implemented as a treatment of infections for a period longer than 150 years, including mycobacterial diseases, such as tuberculosis and leprosy.60-63 Thus, in 1849, Williams reported favourable results after the administration of cod liver oil, an excellent source of vitamin D, in the treatment of patients with tuberculosis.64 Half a century later, Niels Finsen successfully used UV light, an effective method to increase vitamin D levels, for the treatment of lupus vulgaris, a form of skin sarcoidosis- receiving the third Nobel prize in Medicine.6,65 Moreover, Alfred Windaus, contributed to the discovery of the chemical structure of vitamin D2 and vitamin D3 found in cod-liver-oil, also receiving the Nobel prize.7,8,66 Thereafter, several groups used vitamin D2 and D3 as a treatment for tuberculosis.7,67 Rook et al.68 demonstrated in the 1980s that 1,25(OH)2D3 inhibited the proliferation of M. tuberculosis in cell cultures. Vitamin D enhances the production of defensin β2 and cathelicidin in response to infection by macrophages, monocytes, and keratinocytes.49 Humans have only one cathelicidin,69 which is produced by cells of the immune system, including neutrophils, macrophages, and cells lining epithelial surfaces that are constantly exposed to potential pathogens such as the skin, the respiratory, and the gastrointestinal tract.70-72 Cathelicidin has broad antimicrobial activity against gram-positive and gram-negative bacteria, an effect mediated through cell lysis via cell membrane destabilization,73 as well as activity against certain viruses and fungi.74 Treatment with 1,25(OH)2D3 upregulates cathelicidin mRNA in several cell lines, ensuring antimicrobial peptide production on a variety of different cells.75 25(OH)D3 is the major circulating form of vitamin D used to determine vitamin D status and is important for local production of 1,25(OH)2D3, which upregulates cathelicidin production in both skin and macrophages. Exposing human monocytes to pathogens, increases the expression of both 1,25(OH)2D3 and VDR, thus increasing both the local production of 1,25(OH)2D3 and the ability of the cell to respond to it.49 As keratinocytes possess 25-α-hydroxylase, UV light may directly stimulate cathelicidin production by providing the substrate 25(OH)D3 directly from vitamin D3 produced within the skin.76,77 Macrophages are phagocytic antigen-presenting cells, which are involved in the first line of defence against pathogens. 1,25(OH)2D3 has various roles in macrophage differentiation and activation. Macrophage exposure to 1,25(OH)2D3 can enhance the differentiation of macrophages from monocytes and upon exposure to inflammatory immune signals the expression of 1a-hydroxylase is enhanced, thus allowing the macrophage to locally produce the bioactive metabolite of vitamin D, namely 1,25(OH)2D3,42,78 which is necessary for immune modulation. Macrophages respond to vitamin D increasing their antimicrobial activity in an heterogeneous manner; thus, those activated after an interleukin-15 stimulus respond adequately, in contrast, interleukin-10 stimulus leads to weak responses.79,80 Taken together, the ability of the immune cells to hydroxylate 25(OH)D3 locally, suggests that in patients with infections it may be better to administer 25(OH)D3 rather than hydroxylated metabolites to allow for local production and the feedback system to function.

Neutrophils are the most abundant white blood cell population in the human, and they contribute to a line of defence against microbial pathogens. Neutrophils can clear microbes through many mechanisms including phagocytosis and generation of reactive oxygen species and express a functional vitamin D receptor.38 In accordance, 1,25(OH)2D3 administration has been shown to reduce the production of inflammatory cytokines and reactive oxygen species81 and to downregulate neutrophil function and activity.

Monocytes and in particular dendritic cells represent antigen presenting cells, which are important in the initiation of the adaptive immune response. Both cell types can be either immunogenic or tolerogenic and thereby modulate T cell responses.82,83 Tolerogenic antigen presenting cells are characterised by a reduced expression of co-stimulatory molecules and a cytokine production favouring regulatory T cell (Treg) induction.84 Dendritic cells are antigen presenting cells, which survey the microenvironment and are specialised in antigen uptake and processing. Dendritic cells are crucial regulators of the delicate balance between immunogenicity and immune tolerance.85 In dendritic cells 1,25(OH)2D3 can interfere with the differentiation and maturation process, thus resulting in an altered morphology, phenotype and function leading to a semimature or tolerogenic phenotype.86,87 Vitamin D has been shown to manipulate monocytes and dendritic cells at different levels enabling them to exert tolerogenic activities, which could be exploited to better control autoimmune diseases.86



Although primarily an activator of the innate immune system to enhance immediate response to infection, vitamin D also acts to regulate the adaptive immune system. The adaptive immune system includes both humoral immunity components and cell mediated immunity components, both directed against invading pathogens. Adaptive immunity leads to immunological memory after an initial response to a specific pathogen, resulting in an enhanced response to future encounters with that pathogen88 through faster and enhanced production of neutralising antibodies.89

Treg cells (Tregs) are an immunosuppressive subpopulation of T cells, which modulate the immune system, maintaining self-tolerance, and preventing autoimmunity.90 Vitamin D can promote development and function of Tregs in vitro.91 Effector T cells are directly and indirectly affected leading to a shift in the Th1/Th2 balance toward Th2 and a reduction of the Th17 response.91 Once T cells are activated, 1,25(OH)2Dinhibits IL-2 production.92 T cells harbour the vitamin D receptor.36 The behaviour of T cells is modulated by vitamin D indirectly via its effects on dendritic cells. The vitamin D receptor is expressed at low levels in freshly isolated CD8+ and CD4+ T cells.36,40,93,94 Following activation and addition of 1,25(OH)2D3 the expression of the vitamin D receptor is induced. In addition, activated CD8+ cells can produce 1a-hydroxylase, which can convert 25(OH)D3 to the active 1,25(OH)2D3.95 Thus, the regulation of T cells responsiveness to vitamin D is a late event.96 Vitamin D and 1,25(OH)2D3 inhibit T cell proliferation and cytokine production, an event occurring after activation.36,93 It has been hypothesised that following an infection, T cells are induced which are important for clearing the pathogen. The effect of vitamin D does not occur until after the T cell response to the infectious organism has begun. In the infection models, T cells eliminate the pathogen, and the antigen is removed from the system, whereas in an immune mediated disease the antigen persists and T cells are chronically activated, producing inflammatory cytokines.97 It has been proposed that vitamin D deficiency results in a reduced capacity to turn off T cells following activation.96 In a previous study, peripheral blood mononuclear cells which were stimulated with T-cell specific mitogens in the presence of 1,25(OH)2D3 proliferated less and produced less inflammatory cytokines, including interferon-γ.98

B cells express immunoglobulin receptors in their plasma membrane, recognising antigenic epitopes. They produce autoantibodies and form B cell follicles with germinal centre activity. Once activated, B cells can upregulate the expression of vitamin D receptor and 1a-hydroxylase.99 1,25(OH)2D3 in B cells can induce apoptosis, inhibiting memory B cell formation and preventing differentiation of B cells to immunoglobulin-producing plasma cells.100



Vitamin D has immunomodulatory properties,50,101,102 and early on after its discovery, it was shown to have immunostimulatory effects as well.In the course of the years, and as the autoimmune diseases were found to increase in prevalence,103 a worldwide prevalence of vitamin D deficiency was observed,1,104 implying a significant role of vitamin D in inducing immune tolerance,11,12,86 (Figure 1) and a potential role of vitamin D deficiency in the development of autoimmune diseases.10,105,106 Extensive research provided evidence that vitamin D deficiency may induce the development of rheumatoid arthritis13-16,107-109 and that it is related to its activity and severity14,16 (Table 1). A cross-talk between oestrogen and vitamin D has been postulated, suggesting a sex-specific effect of vitamin D in autoimmunity.110 Research also provided evidence that vitamin D deficiency may be related to systemic lupus erythematosus18-20,22,23and multiple sclerosis.25,27,111-113Vitamin D deficiency appears to be also highly prevalent in patients with inflammatory bowel disease17(Crohn’s disease and ulcerative colitis) in relation to disease activity.114 Vitamin D supports the integrity of the intestinal barrier and is related to microbiota homeostasis in this cohort of patients115,116 and may contribute to the prevention of inflammatory bowel disease by supporting the integrity of the intestinal barrier, ensuring bacterial homeostasis and ameliorating disease progression via anti-inflammatory action.117 Vitamin D deficiency in inflammatory bowel disease is aggravated by decreased absorption of the vitamin via the gastrointestinal tract.116 Additionally, vitamin D seemed to induce remission in a cohort of patients with Crohn’s disease.118 It has been postulated that vitamin D resistance may be observed in some patients necessitating an individualised approach in the treatment of vitamin D deficiency.119


Table 1. Autoimmune diseases and relationship of disease activity or severity to vitamin D deficiency (RA,13-16, 21 SLE,17-21 multiple sclerosis,23-26,98,99 inflammatory bowel disease,27,98,99,103-15 systemic sclerosis28).


In conclusion, vitamin D is a likely immunomodulatory agent. It has immune stimulating properties, as it enhances the function of the innate immune system, and it may induce immune tolerance. Vitamin D deficiency may be related to the development of autoimmune diseases.



There is no conflict of interest.

  1. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357(3):266-81.
  2. Christakos S, Li S, De La Cruz J, Bikle DD. New developments in our understanding of vitamin metabolism, action and treatment. Metabolism 2019;98:112-20.
  3. Christakos S, Seth T, Wei R, Veldurthy V, Sun C, Kim KI, et al. Vitamin D and health: beyond bone. MD Advis 2014;7(3):28-32.
  4. Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G. Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects. Physiol Rev 2016;96(1):365-408.
  5. Wei R, Christakos S. Mechanisms Underlying the Regulation of Innate and Adaptive Immunity by Vitamin D. Nutrients 2015;7(10):8251-60.
  6. Moller KI, Kongshoj B, Philipsen PA, Thomsen VO, Wulf HC. How Finsen's light cured lupus vulgaris. Photodermatol Photoimmunol Photomed 2005;21(3):118-124.
  7. Haas J. [Vigantol--Adolf Windaus and the history of vitamin D]. Wurzbg Medizinhist Mitt 2007;26:144-81.
  8. Shampo MA, Kyle RA. Adolf Windaus--Nobel Prize for research on sterols. Mayo Clin Proc 2001;76(2):119.
  9. Czaja AJ, Montano-Loza AJ. Evolving Role of Vitamin D in Immune-Mediated Disease and Its Implications in Autoimmune Hepatitis. Dig Dis Sci 2019;64(2):324-44.
  10. Illescas-Montes R, Melguizo-Rodríguez L, Ruiz C, Costela-Ruiz VJ. Vitamin D and autoimmune diseases. Life Sci 2019;233:116744.
  11. Badenhoop K, Kahles H, Penna-Martinez M. Vitamin D, immune tolerance, and prevention of type 1 diabetes. Curr Diab Rep 2012;12(6):635-42.
  12. Cyprian F, Lefkou E, Varoudi K, Girardi G. Immunomodulatory Effects of Vitamin D in Pregnancy and Beyond. Front Immunol 2019;10:2739.
  13. Buondonno I, Rovera G, Sassi F, Rigoni MM, Lomater C, Parisi S, et al. Vitamin D and immunomodulation in early rheumatoid arthritis: A randomized double-blind placebo-controlled study. PLoS One 2017;12(6):e0178463.
  14. Kostoglou-Athanassiou I, Athanassiou P, Lyraki A, Raftakis I, Antoniadis C. Vitamin D and rheumatoid arthritis. Ther Adv Endocrinol Metab 2012;3(6):181-187.
  15. Ishikawa LLW, Colavite PM, Fraga-Silva TFC, Mimura LAN, França TGD, Zorzella-Pezavento SFG, et al. Vitamin D Deficiency and Rheumatoid Arthritis. Clin Rev Allergy Immunol 2017;52(3):373-88.
  16. Lee YH, Bae SC. Vitamin D level in rheumatoid arthritis and its correlation with the disease activity: a meta-analysis. Clin Exp Rheumatol 2016;34(5):827-33.
  17. Hausmann J, Kubesch A, Amiri M, Filmann N, Blumenstein I. Vitamin D Deficiency is Associated with Increased Disease Activity in Patients with Inflammatory Bowel Disease. J Clin Med 2019;8(9).
  18. Amital H, Szekanecz Z, Szucs G, Dankó K, Nagy E, Csépány T, et al. Serum concentrations of 25-OH vitamin D in patients with systemic lupus erythematosus (SLE) are inversely related to disease activity: is it time to routinely supplement patients with SLE with vitamin D? Ann Rheum Dis 2010;69(6):1155-7.
  19. Guan SY, Cai HY, Wang P, Lv TT, Liu LN, et al. Association between circulating 25-hydroxyvitamin D and systemic lupus erythematosus: A systematic review and meta-analysis. Int J Rheum Dis. 2019;22:1803-13.
  20. Mok CC, Birmingham DJ, Leung HW, Hebert LA, Song H, Rovin BH. Vitamin D levels in Chinese patients with systemic lupus erythematosus: relationship with disease activity, vascular risk factors and atherosclerosis. Rheumatology (Oxford) 2012;51(4):644-52.
  21. An L, Sun MH, Chen F, Li JR. Vitamin D levels in systemic sclerosis patients: a meta-analysis. Drug Des Devel Ther 2017;11:3119-25.
  22. Watad A, Neumann SG, Soriano A, Amital H, Shoenfeld Y. Vitamin D and Systemic Lupus Erythematosus: Myth or Reality? Isr Med Assoc J 2016;18(3-4):177-82.
  23. Bae SC, Lee YH. Vitamin D level and risk of systemic lupus erythematosus and rheumatoid arthritis: a Mendelian randomization. Clin Rheumatol 2018;37(9):2415-21.
  24. Winters SJ. Systemic Lupus Erythematosus and Vitamin D: Should We Recommend That Our Patients Take Supplements? Am J Med Sci 2019;358(2):93-4.
  25. Correale J, Ysrraelit MC, Gaitan MI. Immunomodulatory effects of Vitamin D in multiple sclerosis. Brain 2009;132(Pt 5):1146-60.
  26. Jagannath VA, Filippini G, Di Pietrantonj C, Asokan GV, Robak EW, Whamond L, et al. Vitamin D for the management of multiple sclerosis. Cochrane Database Syst Rev 2018;9:Cd008422.
  27. Kragt J, van Amerongen B, Killestein J, Dijkstra C, Uitdehaag B, Polman Ch, et al. Higher levels of 25-hydroxyvitamin D are associated with a lower incidence of multiple sclerosis only in women. Mult Scler 2009;15(1):9-15.
  28. Mark BL, Carson JA. Vitamin D and autoimmune disease--implications for practice from the multiple sclerosis literature. J Am Diet Assoc 2006;106(3):418-24.
  29. Daga RA, Laway BA, Shah ZA, Mir SA, Kotwal SK, Zargar AH. High prevalence of vitamin D deficiency among newly diagnosed youth-onset diabetes mellitus in north India. Arq Bras Endocrinol Metabol 2012;56(7):423-8.
  30. Dong JY, Zhang WG, Chen JJ, Zhang ZL, Han SF, Qin LQ. Vitamin D intake and risk of type 1 diabetes: a meta-analysis of observational studies. Nutrients 2013;5(9):3551-62.
  31. Greer RM, Rogers MA, Bowling FG, Buntain HM, Harris M, Leong GM, et al. Australian children and adolescents with type 1 diabetes have low vitamin D levels. Med J Aust Med J Aust. 2007 Jul 2;187(1):59-60.
  32. Greer RM, Portelli SL, Hung BS, et al. Serum vitamin D levels are lower in Australian children and adolescents with type 1 diabetes than in children without diabetes. Pediatr Diabetes. 2013;14(1):31-41.
  33. Giulietti A, Gysemans C, Stoffels K, Cleghorn GJ, McMahon SK, Batch JA, et al. Vitamin D deficiency in early life accelerates Type 1 diabetes in non-obese diabetic mice. Diabetologia 2004;47(3):451-62.
  34. Mangin M, Sinha R, Fincher K. Inflammation and vitamin D: the infection connection. Inflamm Res 2014;63(10):803-19.
  35. Dankers W, Colin EM, van Hamburg JP, Lubberts E. Vitamin D in Autoimmunity: Molecular Mechanisms and Therapeutic Potential. Front Immunol 2016;7:697.
  36. Veldman CM, Cantorna MT, DeLuca HF. Expression of 1,25-dihydroxyvitamin D(3) receptor in the immune system. Arch Biochem Biophys 2000;374(2):334-338.
  37. Froicu M, Cantorna MT. Vitamin D and the vitamin D receptor are critical for control of the innate immune response to colonic injury. BMC Immunol 2007;8:5.
  38. Takahashi K, Nakayama Y, Horiuchi H, Ohta T, Komoriya K, Ohmori H, et al. Human neutrophils express messenger RNA of vitamin D receptor and respond to 1alpha,25-dihydroxyvitamin D3. Immunopharmacol Immunotoxicol 2002;24(3):335-47.
  39. Baeke F, Korf H, Overbergh L, van Etten E, Verstuyf A, Gysemans C, et al. Human T lymphocytes are direct targets of 1,25-dihydroxyvitamin D3 in the immune system. J Steroid Biochem Mol Biol 2010;121(1-2):221-7.
  40. 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(5):922-32.
  41. Heulens N, Korf H, Mathyssen C, Everaerts S, De Smidt E, Dooms C, et al. 1,25-Dihydroxyvitamin D Modulates Antibacterial and Inflammatory Response in Human Cigarette Smoke-Exposed Macrophages. PLoS One 2016;11(8):e0160482.
  42. Stoffels K, Overbergh L, Giulietti A, Verlinden L, Bouillon R, Mathieu C. Immune regulation of 25-hydroxyvitamin-D3-1alpha-hydroxylase in human monocytes. J Bone Miner Res. 2006;21(1):37-47.
  43. Morán-Auth Y, Penna-Martinez M, Shoghi F, Ramos-Lopez E, Badenhoop K. Vitamin D status and gene transcription in immune cells. J Steroid Biochem Mol Biol 2013;136:83-5.
  44. Szymczak I, Pawliczak R. The Active Metabolite of Vitamin D3 as a Potential Immunomodulator. Scand J Immunol 2016;83(2):83-91.
  45. Mavragani CP, Crow MK. Activation of the type I interferon pathway in primary Sjogren's syndrome. J Autoimmun 2010;35(3):225-31.
  46. Crow MK, Olferiev M, Kirou KA. Type I Interferons in Autoimmune Disease. Annu Rev Pathol 2019;14:369-93.
  47. Reynolds JA, Rosenberg AZ, Smith CK, Sergeant JC, Rice GI, Briggs TA, et al. Brief Report: Vitamin D Deficiency Is Associated With Endothelial Dysfunction and Increases Type I Interferon Gene Expression in a Murine Model of Systemic Lupus Erythematosus. Arthritis Rheumatol 2016;68(12):2929-35.
  48. Wacker M, Holick MF. Vitamin D - effects on skeletal and extraskeletal health and the need for supplementation. Nutrients 2013;5(1):111-48.
  49. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006;311(5768):1770-3.
  50. Sassi F, Tamone C, D'Amelio P. Vitamin D: Nutrient, Hormone, and Immunomodulator. Nutrients 2018;10(11).
  51. Jaime J, Vargas-Bermúdez DS, Yitbarek A, Reyes J, Rodríguez-Lecompte JC. Differential immunomodulatory effect of vitamin D (1,25 (OH)(2) D(3)) on the innate immune response in different types of cells infected in vitro with infectious bursal disease virus. Poult Sci 2020;99(9):4265-77.
  52. Hato T, Dagher PC. How the Innate Immune System Senses Trouble and Causes Trouble. Clin J Am Soc Nephrol 2015;10(8):1459-69.
  53. McComb S, Thiriot A, Akache B, Krishnan L, Stark F. Introduction to the Immune System. Methods Mol Biol 2019;2024:1-24.
  54. Ge X, Wang L, Li M, Xu N, Yu F, Yang F, et al. Vitamin D/VDR signaling inhibits LPS-induced IFNγ and IL-1β in Oral epithelia by regulating hypoxia-inducible factor-1α signaling pathway. Cell Commun Signal 2019;17(1):18.
  55. Bikle DD. The Vitamin D Receptor as Tumor Suppressor in Skin. Adv Exp Med Biol 2020;1268:285-306.
  56. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006;311(5768):1770-3.
  57. Martens PJ, Gysemans C, Verstuyf A, Mathieu AC. Vitamin D's Effect on Immune Function. Nutrients 2020;12(5).
  58. Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C. Vitamin D: modulator of the immune system. Curr Opin Pharmacol 2010;10(4):482-96.
  59. Kloc M, Ghobrial RM, Lipińska-Opałka A, Wawrzyniak A, Zdanowski R, Kalicki B, et al. Effects of vitamin D on macrophages and myeloid-derived suppressor cells (MDSCs) hyperinflammatory response in the lungs of COVID-19 patients. Cell Immunol 2021;360:104259.
  60. Oliveira ALG, Chaves AT, Menezes CAS, Guimarães NS, Bueno LL, Fujiwara RT, et al. Vitamin D receptor expression and hepcidin levels in the protection or severity of leprosy: a systematic review. Microbes Infect 2017;19(6):311-22.
  61. Cervantes JL, Oak E, Garcia J, Liu H, Lorenzini PA, Batra D, et al. Vitamin D modulates human macrophage response to Mycobacterium tuberculosis DNA. Tuberculosis (Edinb) 2019;116s:S131-s137.
  62. Singh I, Lavania M, Pathak VK, Ahuja M, Turankar RP, Singh V, et al. VDR polymorphism, gene expression and vitamin D levels in leprosy patients from North Indian population. PLoS Negl Trop Dis 2018;12(11):e0006823.
  63. Soeharto DA, Rifai DA, Marsudidjadja S, Roekman AE, Assegaf CK, Louisa M. Vitamin D as an Adjunctive Treatment to Standard Drugs in Pulmonary Tuberculosis Patients: An Evidence-Based Case Report. Adv Prev Med 2019;2019:5181847.
  64. Williams C. On the use and administration of cod-liver oil in pulmonary consumption. London J Med 1849;1:1-18.
  65. Finsen N. Nobel prize presentation speech by professor the count K.A.H. Morner, Rector of the Royal Caroline Institute on December 10, 1903. 1903.
  66. Wolf G. The discovery of vitamin D: the contribution of Adolf Windaus. J Nutr 2004;134(6):1299-302.
  67. Brighenti S, Bergman P, Martineau AR. Vitamin D and tuberculosis: where next? J Intern Med 2018 May 27.
  68. Rook GA, Steele J, Fraher L, Barker S, Karmali R, O'Riordan J, et al. Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 1986;57(1):159-63.
  69. Xhindoli D, Pacor S, Benincasa M, Scocchi M, Gennaro R, Tossi A. The human cathelicidin LL-37--A pore-forming antibacterial peptide and host-cell modulator. Biochim Biophys Acta 2016;1858(3):546-66.
  70. Weber G, Heilborn JD, Chamorro Jimenez CI, Hammarsjo A, Torma H, Stahle M. Vitamin D induces the antimicrobial protein hCAP18 in human skin. J Invest Dermatol 2005 May;124(5):1080-2.
  71. Bals R, Wang X, Zasloff M, Wilson JM. The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface. Proc Natl Acad Sci U S A 1998;95(16):9541-6.
  72. Gallo RL, Kim KJ, Bernfield M, Kozak CA, Zanetti M, Merluzzi L, et al. Identification of CRAMP, a cathelin-related antimicrobial peptide expressed in the embryonic and adult mouse. J Biol Chem 1997;272(20):13088-93.
  73. Agerberth B, Charo J, Werr J, Olsson B, Idali F, Lindbom L, et al. The human antimicrobial and chemotactic peptides LL-37 and alpha-defensins are expressed by specific lymphocyte and monocyte populations. Blood 2000;96(9):3086-93.
  74. Ramanathan B, Davis EG, Ross CR, Blecha F. Cathelicidins: microbicidal activity, mechanisms of action, and roles in innate immunity. Microbes Infect 2002;4(3):361-72.
  75. Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 2004;173(5):2909-12.
  76. Lehmann B, Rudolph T, Pietzsch J, Meurer M. Conversion of vitamin D3 to 1alpha,25-dihydroxyvitamin D3 in human skin equivalents. Exp Dermatol 2000;9(2):97-103.
  77. Lehmann B, Tiebel O, Meurer M. Expression of vitamin D3 25-hydroxylase (CYP27) mRNA after induction by vitamin D3 or UVB radiation in keratinocytes of human skin equivalents--a preliminary study. Arch Dermatol Res 1999;291(9):507-10.
  78. Korf H, Wenes M, Stijlemans B, Takiishi T, Robert S, Miani M, et al. 1,25-Dihydroxyvitamin D3 curtails the inflammatory and T cell stimulatory capacity of macrophages through an IL-10-dependent mechanism. Immunobiology 2012;217(12):1292-300.
  79. Krutzik SR, Hewison M, Liu PT, Robles JA, Stenger S, Adams JS, et al. IL-15 links TLR2/1-induced macrophage differentiation to the vitamin D-dependent antimicrobial pathway. J Immunol 2008;181(10):7115-20.
  80. Kim EW, Teles RMB, Haile S, Liu PT, Modlin RL. Vitamin D status contributes to the antimicrobial activity of macrophages against Mycobacterium leprae. PLoS Negl Trop Dis 2018;12(7):e0006608.
  81. Hirsch D, Archer FE, Joshi-Kale M, Vetrano AM, Weinberger B. Decreased anti-inflammatory responses to vitamin D in neonatal neutrophils. Mediators Inflamm 2011;2011:598345.
  82. Rigby WF, Waugh MG. Decreased accessory cell function and costimulatory activity by 1,25-dihydroxyvitamin D3-treated monocytes. Arthritis Rheum 1992;35(1):110-19.
  83. Steinman RM, Banchereau J. Taking dendritic cells into medicine. Nature 2007;449(7161):419-26.
  84. Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol 2003;21:685-711.
  85. Steinman RM. Some interfaces of dendritic cell biology. Apmis 2003;111(7-8):675-97.
  86. Adorini L, Penna G. Induction of tolerogenic dendritic cells by vitamin D receptor agonists. Handb Exp Pharmacol 2009(188):251-73.
  87. Adorini L, Penna G, Giarratana N, Roncari A, Amuchastegui S, Daniel KC, et al. Dendritic cells as key targets for immunomodulation by Vitamin D receptor ligands. J Steroid Biochem Mol Biol 2004;89-90(1-5):437-41.
  88. Bonilla FA, Oettgen HC. Adaptive immunity. J Allergy Clin Immunol 2010;125(2 Suppl 2):S33-40.
  89. Lovely GA, Sen R. Evolving adaptive immunity. Genes Dev 2016;30(8):873-5.
  90. Sakaguchi S. Taking regulatory T cells into medicine. J Exp Med 2021;218(6).
  91. Peelen E, Knippenberg S, Muris AH, Thewissen M, Smolders J, Tervaert JW, et al. Effects of vitamin D on the peripheral adaptive immune system: a review. Autoimmun Rev 2011;10(12):733-43.
  92. Chen J, Bruce D, Cantorna MT. Vitamin D receptor expression controls proliferation of naïve CD8+ T cells and development of CD8 mediated gastrointestinal inflammation. BMC Immunol 2014;15:6.
  93. Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC. 1,25-dihydroxyvitamin D3 receptors in human leukocytes. Science 1983;221(4616):1181-3.
  94. Manolagas SC, Provvedini DM, Tsoukas CD. Interactions of 1,25-dihydroxyvitamin D3 and the immune system. Mol Cell Endocrinol 1985;43(2-3):113-22.
  95. Ooi JH, McDaniel KL, Weaver V, Cantorna MT. Murine CD8+ T cells but not macrophages express the vitamin D 1α-hydroxylase. J Nutr Biochem 2014;25(1):58-65.
  96. Ooi JH, Chen J, Cantorna MT. Vitamin D regulation of immune function in the gut: why do T cells have vitamin D receptors? Mol Aspects Med 2012;33(1):77-82.
  97. Cantorna MT, Waddell A. The vitamin D receptor turns off chronically activated T cells. Ann N Y Acad Sci 2014;1317:70-5.
  98. Rigby WF, Denome S, Fanger MW. Regulation of lymphokine production and human T lymphocyte activation by 1,25-dihydroxyvitamin D3. Specific inhibition at the level of messenger RNA. J Clin Invest 1987;79(6):1659-64.
  99. Chen S, Sims GP, Chen XX, Gu YY, Lipsky PE. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol 2007;179(3):1634-47.
  100. Lemire JM, Adams JS, Sakai R, Jordan SC. 1 alpha,25-dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J Clin Invest 1984;74(2):657-61.
  101. Bouillon R, Marcocci C, Carmeliet G, et al. Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions. Endocr Rev 2019;40(4):1109-51.
  102. Bikle DD. Extraskeletal actions of vitamin D. Ann N Y Acad Sci 2016;1376(1):29-52.
  103. Lerner A, Patricia J, Torsten M. The world incidence and prevalence of autoimmune diseases is increasing. Int J Celiac Dis 2015;3(4):151-5.
  104. Holick MF. The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention. Rev Endocr Metab Disord 2017;18(2):153-65.
  105. Booth DR, Ding N, Parnell GP, Shahijanian F, Coulter S, Schibeci SD, et al. Cistromic and genetic evidence that the vitamin D receptor mediates susceptibility to latitude-dependent autoimmune diseases. Genes Immun 2016;17(4):213-9.
  106. Murdaca G, Tonacci A, Negrini S, Greco M, Borro M, Puppo F, et al. Emerging role of vitamin D in autoimmune diseases: An update on evidence and therapeutic implications. Autoimmun Rev 2019;18(9):102350.
  107. Bellan M, Sainaghi PP, Pirisi M. Role of Vitamin D in Rheumatoid Arthritis. Adv Exp Med Biol 2017;996:155-68.
  108. Bragazzi NL, Watad A, Neumann SG, Simon M, Brown SB, Abu Much A, et al. Vitamin D and rheumatoid arthritis: an ongoing mystery. Curr Opin Rheumatol 2017;29(4):378-88.
  109. Song GG, Bae SC, Lee YH. Association between vitamin D intake and the risk of rheumatoid arthritis: a meta-analysis. Clin Rheumatol 2012;31(12):1733-9.
  110. Dupuis ML, Pagano MT, Pierdominici M, Ortona E. The role of vitamin D in autoimmune diseases: could sex make the difference? Biol Sex Differ 2021;12(1):12.
  111. Cantorna MT. Vitamin D and its role in immunology: multiple sclerosis, and inflammatory bowel disease. Prog Biophys Mol Biol 2006;92(1):60-4.
  112. Cantorna MT. Vitamin D, multiple sclerosis and inflammatory bowel disease. Arch Biochem Biophys 2012;523(1):103-6.
  113. Gianfrancesco MA, Stridh P, Rhead B, Shao X, Xu E, Graves JS, et al. Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS. Neurology 2017;88(17):1623-9.
  114. Sairenji T, Collins KL, Evans DV. An Update on Inflammatory Bowel Disease. Prim Care. 2017;44(4):673-692.
  115. de Souza HS, Fiocchi C. Immunopathogenesis of IBD: current state of the art. Nat Rev Gastroenterol Hepatol 2016;13(1):13-27.
  116. Fletcher J, Cooper SC, Ghosh S, Hewison M. The Role of Vitamin D in Inflammatory Bowel Disease: Mechanism to Management. Nutrients 2019;11(5).
  117. Yang Y, Cui X, Li J, Wang H, Li Y, Chen Y, et al. Clinical evaluation of vitamin D status and its relationship with disease activity and changes of intestinal immune function in patients with Crohn's disease in the Chinese population. Scand J Gastroenterol 2021;56(1):20-9.
  118. Yang L, Weaver V, Smith JP, Bingaman S, Hartman TJ, Cantorna MT. Therapeutic effect of vitamin d supplementation in a pilot study of Crohn's patients. Clin Transl Gastroenterol 2013;4(4):e33.
  119. Lemke D, Klement RJ, Schweiger F, Schweiger B, Spitz J. Vitamin D Resistance as a Possible Cause of Autoimmune Diseases: A Hypothesis Confirmed by a Therapeutic High-Dose Vitamin D Protocol. Front Immunol 2021;12:655739.