Vitamin D metabolizing enzymes and vitamin D receptors are present in many cell types including various immune cells such as antigen-presenting-cells, T cells, B cells and monocytes. In vitro data show that, in addition to modulating innate immune cells, vitamin D also promotes a more tolerogenic immunological status. In vivo data from animals and from human vitamin D supplementation studies have shown beneficial effects of vitamin D on immune function, in particular in the context of autoimmunity. In this review, currently available data are summarized to give an overview of the effects of vitamin D on the immune system in general and on the regulation of inflammatory responses, as well as regulatory mechanisms connected to autoimmune diseases particularly in type 1 diabetes mellitus.
References
[1]
Bouillon, R.; Carmeliet, G.; Verlinden, L.; van Etten, E.; Verstuyf, A.; Luderer, H.F.; Lieben, L.; Mathieu, C.; Demay, M. Vitamin D and human health: Lessons from vitamin D receptor null mice. Endocr. Rev. 2008, 29, 726–776, doi:10.1210/er.2008-0004.
[2]
Hewison, M. An update on vitamin D and human immunity. Clin. Endocrinol. 2012, 76, 315–325, doi:10.1111/j.1365-2265.2011.04261.x.
[3]
Weick, M.T. A history of rickets in the United States. Am. J. Clin. Nutr. 1967, 20, 1234–1241.
[4]
？zkan, B. Nutritional rickets. J. Clin. Res. Pediatr. Endocrinol. 2010, 2, 137–143, doi:10.4274/jcrpe.v2i4.137.
[5]
Walker, V.P.; Modlin, R.L. The vitamin D connection to pediatric infections and immune function. Pediatr. Res. 2009, 65, 106R–113R, doi:10.1203/PDR.0b013e31819dba91.
Holick, M.F. Vitamin D deficiency. N. Engl. J. Med. 2007, 357, 266–281, doi:10.1056/NEJMra070553.
[8]
Battault, S.; Whiting, S.J.; Peltier, S.L.; Sadrin, S.; Gerber, G.; Maixent, J.M. Vitamin D metabolism, functions and needs: From science to health claims. Eur. J. Nutr. 2013, 52, 429–441, doi:10.1007/s00394-012-0430-5.
[9]
Hewison, M.; Gacad, M.A.; Lemire, J.; Adams, J.S. Vitamin D as a cytokine and hematopoetic factor. Rev. Endocr. Metab. Disord. 2001, 2, 217–227, doi:10.1023/A:1010015013211.
[10]
Adams, J.S.; Hewison, M. Update in vitamin D. J. Clin. Endocrinol. Metab. 2010, 95, 471–478, doi:10.1210/jc.2009-1773.
[11]
Lamberg-Allardt, C. Vitamin D in foods and as supplements. Prog. Biophys. Mol. Biol. 2006, 92, 33–38, doi:10.1016/j.pbiomolbio.2006.02.017.
[12]
Wacker, M.; Holick, M.F. Vitamin D—Effects on skeletal and extraskeletal health and the need for supplementation. Nutrients. 2013, 5, 111–148, doi:10.3390/nu5010111.
[13]
Calvo, M.S.; Whiting, S.J. Overview of the proceedings from Experimental Biology 2004 symposium: Vitamin D insufficiency: A significant risk factor in chronic diseases and potential disease-specific biomarkers of vitamin D sufficiency. J. Nutr. 2005, 135, 301–303.
[14]
Tripkovic, L.; Lambert, H.; Hart, K.; Smith, C.P.; Bucca, G.; Penson, S.; Chope, G.; Hypp？nen, E.; Berry, J.; Vieth, R.; et al. Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: A systematic review and meta-analysis. Am. J. Clin. Nutr. 2012, 95, 1357–1364, doi:10.3945/ajcn.111.031070.
[15]
Wang, T.J.; Zhang, F.; Richards, J.B.; Kestenbaum, B.; van Meurs, J.B.; Berry, D.; Kiel, D.P.; Streeten, E.A.; Ohlsson, C.; Koller, D.L.; et al. Common genetic determinants of vitamin D insufficiency: A genome-wide association study. Lancet 2010, 376, 180–188, doi:10.1016/S0140-6736(10)60588-0.
[16]
Maxwell, J.D. Seasonal variation in vitamin D. Proc. Nutr. Soc. 1994, 53, 533–543, doi:10.1079/PNS19940063.
[17]
Van der Mei, I.A.; Ponsonby, A.L.; Engelsen, O.; Pasco, J.A.; McGrath, J.J.; Eyles, D.W.; Blizzard, L.; Dwyer, T.; Lucas, R.; Jones, G. The high prevalence of vitamin D insufficiency across Australian populations is only partly explained by season and latitude. Environ. Health Perspect. 2007, 115, 1132–1139, doi:10.1289/ehp.9937.
[18]
Andersen, R.; Brot, C.; Jakobsen, J.; Mejborn, H.; M？lgaard, C.; Skovgaard, L.T.; Trolle, E.; Tetens, I.; Ovesen, L. Seasonal changes in vitamin D status among Danish adolescent girls and elderly women: The influence of sun exposure and vitamin D intake. Eur. J. Clin. Nutr. 2013, 67, 270–274, doi:10.1038/ejcn.2013.3.
[19]
Pittaway, J.K.; Ahuja, K.D.K.; Beckett, J.M.; Bird, M.-L.; Robertson, I.K.; Ball, M.J. Make vitamin D while the sun shines, take supplements when it doesn’t: A longitudinal, observational study of older adults in Tasmania, Australia. PLoS One 2013, 8, e59063.
[20]
Danai, P.A.; Sinha, S.; Moss, M.; Haber, M.J.; Martin, G.S. Seasonal variation in the epidemiology of sepsis. Crit. Care Med. 2007, 35, 410–415, doi:10.1097/01.CCM.0000253405.17038.43.
[21]
White, A.N.J.; Ng, V.; Spain, C.V.; Johnson, C.C.; Kinlin, L.M.; Fisman, D.N. Let the sun shine in: Effects of ultraviolet radiation on invasive pneumococcal disease risk in Philadelphia, Pennsylvania. BMC Infect. Dis. 2009, 9, 196, doi:10.1186/1471-2334-9-196.
[22]
Heaney, R.P. Vitamin D-baseline status and effective dose. N. Engl. J. Med. 2012, 367, 77–78, doi:10.1056/NEJMe1206858.
[23]
Baeke, F.; Takiishi, T.; Korf, H.; Gysemans, C.; Mathieu, C. Vitamin D: Modulator of the immune system. Curr. Opin. Pharmacol. 2010, 10, 482–496, doi:10.1016/j.coph.2010.04.001.
[24]
Heaney, R.P. Assessing vitamin D status. Curr. Opin. Clin. Nutr. Metab. Care 2011, 14, 440–444, doi:10.1097/MCO.0b013e328348ed85.
[25]
Ross, A.C.; Manson, J.E.; Abrams, S.A.; Aloia, J.F.; Brannon, P.M.; Clinton, S.K.; Durazo-Arvizu, R.A.; Gallagher, J.C.; Gallo, R.L.; Jones, G.; et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know. JCEM 2011, 96, 53–58.
[26]
Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D; Institute of Medicine: Washington, DC, USA, 2010.
[27]
Holick, M.F.; Binkley, N.C.; Bischoff-Ferrari, H.A.; Gordon, C.M.; Hanley, D.A.; Heaney, R.P.; Murad, H.M.; Weaver, C.M. Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline. JCEM 2011, 96, 1911–1930.
[28]
EFSA Panel on Dietetic Products Nutrition and Allergies Scientific Opinion on the Tolerable Upper Intake Level of vitamin D1. EFSA J. 2012, 10, 1–45.
[29]
Vieth, R. Vitamin D toxicity, policy, and science. J. Bone Miner. Res. 2007, 22, 64–68, doi:10.1359/jbmr.07s221.
[30]
Zittermann, A.; Prokop, S.; Gummert, J.F.; Borgermann, J. Safety issues of vitamin D supplementation. Anticancer Agents Med. Chem. 2013, 13, 4–10, doi:10.2174/187152013804487290.
[31]
Vieth, R. The mechanisms of vitamin D toxicity. Bone Miner. 1990, 11, 267–272, doi:10.1016/0169-6009(90)90023-9.
[32]
Vieth, R. Critique of the considerations for establishing the tolerable upper intake level for vitamin D: Critical need for revision upwards. J. Nutr. 2006, 136, 1117–1122.
[33]
Jones, G. Pharmacokinetics of vitamin D toxicity. Am. J. Clin. Nutr. 2008, 88, 582–586.
[34]
Lowe, H.; Cusano, N.E.; Binkley, N.; Blaner, W.S.; Bilezikian, J.P. Vitamin D toxicity due to a commonly available “over the counter” remedy from the Dominican Republic. JCEM 2011, 96, 291–295.
[35]
KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int. 2009, S1–S130, doi:10.1038/ki.2009.188.
[36]
Shoback, D. Clinical practice. Hypoparathyroidism. N. Engl. J. Med. 2008, 359, 391–403, doi:10.1056/NEJMcp0803050.
[37]
Bilezikian, J.P.; Khan, A.; Potts, J.T.; Brandi, M.L.; Clarke, B.L.; Shoback, D.; Jüppner, H.; D’Amour, P.; Fox, J.; Rejnmark, L.; et al. Hypoparathyroidism in the adult: Epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for future reseach. J. Bone Miner. Res. 2011, 26, 2317–2337, doi:10.1002/jbmr.483.
[38]
Mantovani, G. Clinical review: Pseudohypoparathyroidism: Diagnosis and treatment. JCEM 2011, 96, 3020–3030.
[39]
Grad, R. Cod and the consumptive: A brief history of cod-liver oil in the treatment of pulmonary tuberculosis. Pharm. Hist. 2004, 46, 106–120.
[40]
Wang, T.; Nestel, F.P.; Bourdeau, V.; Nagai, Y.; Wang, Q.; Liao, J.; Lin, R.; Hanrahan, J.H.; White, J.H. Cutting edge: 1,25-Dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J. Immunol. 2004, 173, 2909–2912.
[41]
Gombart, A.F.; Borregaard, N.; Koeffler, H.P. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J. 2005, 19, 1067–1077, doi:10.1096/fj.04-3284com.
[42]
White, J.H. Vitamin D metabolism and signaling in the immune system. Rev. Endocr. Metab. Disord. 2012, 13, 21–29, doi:10.1007/s11154-011-9195-z.
[43]
Liu, P.T.; Stenger, S.; Li, H.; Wenzel, L.; Tan, B.H.; Krutzik, S.R.; Ochoa, M.T.; Schauber, J.; Wu, K.; Meinken, C.; et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006, 311, 1770–1773, doi:10.1126/science.1123933.
[44]
Edfeldt, K.; Liu, P.T.; Chun, R.; Fabri, M.; Schenk, M.; Wheelwright, M.; Keegan, C.; Krutzik, S.R.; Adams, J.S.; Hewison, M.; et al. T-cell cytokines differentially control human monocyte antimicrobial responses by regulating vitamin D metabolism. Proc. Natl. Acad. Sci. USA 2010, 107, 22593–22598, doi:10.1073/pnas.1011624108.
[45]
Ramanathan, B.; Davis, E.G.; Ross, C.R.; Blecha, F. Cathelicidins: Microbicidal activity, mechanisms of action, and roles in innate immunity. Microbes Infect. 2002, 4, 361–372, doi:10.1016/S1286-4579(02)01549-6.
[46]
S？rensen, O.; Cowland, J.B.; Askaa, J.; Borregaard, N. An ELISA for hCAP-18, the cathelicidin present in human neutrophils and plasma. J. Immunol. Methods 1997, 206, 53–59, doi:10.1016/S0022-1759(97)00084-7.
[47]
Jeng, L.; Yamshchikov, A.V; Judd, S.E.; Blumberg, H.M.; Martin, G.S.; Ziegler, T.R.; Tangpricha, V. Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis. J. Transl. Med. 2009, 7, 28, doi:10.1186/1479-5876-7-28.
Laaksi, I.; Ruohola, J.-P.; Tuohimaa, P.; Auvinen, A.; Haataja, R.; Pihlajam？ki, H.; Ylikomi, T. An association of serum vitamin D concentrations <40 nmol/L with acute respiratory tract infection in young Finnish men. Am. J. Clin. Nutr. 2007, 86, 714–717.
[50]
Ginde, A.A.; Mansbach, J.M.; Camargo, C.A. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch. Intern. Med. 2009, 169, 384–390, doi:10.1001/archinternmed.2008.560.
[51]
Cannell, J.J.; Vieth, R.; Willett, W.; Zasloff, M.; Hathcock, J.N.; White, J.H.; Tanumihardjo, S.A.; Larson-Meyer, D.E.; Bischoff-Ferrari, H.A.; Lamberg-Allardt, C.J.; et al. Cod liver oil, vitamin A toxicity, frequent respiratory infections, and the vitamin D deficiency epidemic. Ann. Otol. Rhinol. Laryngol. 2008, 117, 864–870.
[52]
Cannell, J.J.; Vieth, R.; Umhau, J.C.; Holick, M.F.; Grant, W.B.; Madronich, S.; Garland, C.F.; Giovannucci, E. Epidemic influenza and vitamin D. Epidemiol. Infect. 2006, 134, 1129–1140, doi:10.1017/S0950268806007175.
[53]
Black, P.N.; Scragg, R. Relationship between serum 25-hydroxyvitamin d and pulmonary function in the third national health and nutrition examination survey. Chest 2005, 128, 3792–3798.
[54]
Janssens, W.; Bouillon, R.; Claes, B.; Carremans, C.; Lehouck, A.; Buysschaert, I.; Coolen, J.; Mathieu, C.; Decramer, M.; Lambrechts, D. Vitamin D deficiency is highly prevalent in COPD and correlates with variants in the vitamin D-binding gene. Thorax 2010, 65, 215–220, doi:10.1136/thx.2009.120659.
[55]
Litonjua, A.A.; Weiss, S.T. Is vitamin D deficiency to blame for the asthma epidemic? J. Allergy Clin. Immunol. 2007, 120, 1031–1035, doi:10.1016/j.jaci.2007.08.028.
[56]
Dimeloe, S.; Nanzer, A.; Ryanna, K.; Hawrylowicz, C. Regulatory T cells, inflammation and the allergic response: The role of glucocorticoids and vitamin D. J. Steroid Biochem. Mol. Biol. 2010, 120, 86–95, doi:10.1016/j.jsbmb.2010.02.029.
[57]
Murdoch, D.R.; Slow, S.; Chambers, S.T.; Jennings, L.C.; Stewart, A.W.; Priest, P.C.; Florkowski, C.M.; Livesey, J.H.; Camargo, C.A.; Scragg, R. Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: The VIDARIS randomized controlled trial. JAMA 2012, 308, 1333–1339, doi:10.1001/jama.2012.12505.
[58]
Camargo, C.A.; Ganmaa, D.; Frazier, A.L.; Kirchberg, F.F.; Stuart, J.J.; Kleinman, K.; Sumberzul, N.; Rich-Edwards, J.W. Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia. Pediatrics 2012, 130, e561–e567, doi:10.1542/peds.2011-3029.
[59]
Bergman, P.; Norlin, A.-C.; Hansen, S.; Rekha, R.S.; Agerberth, B.; Bj？rkhem-Bergman, L.; Ekstr？m, L.; Lindh, J.D.; Andersson, J. Vitamin D3 supplementation in patients with frequent respiratory tract infections: A randomised and double-blind intervention study. BMJ Open 2012, 2, doi:10.1136/bmjopen-2012-001663.
[60]
Rigby, W.F.; Waugh, M.G. Decreased accessory cell function and costimulatory activity by 1,25-dihydroxyvitamin D3-treated monocytes. Arthritis Rheum. 1992, 35, 110–119, doi:10.1002/art.1780350117.
[61]
Steinman, R.M.; Banchereau, J. Taking dendritic cells into medicine. Nature 2007, 449, 419–426, doi:10.1038/nature06175.
[62]
Banchereau, J.; Steinman, R.M. Dendritic cells and the control of immunity. Nature 1998, 392, 245–252, doi:10.1038/32588.
[63]
Mora, J.R.; Iwata, M.; von Andrian, U.H. Vitamin effects on the immune system: Vitamins A and D take centre stage. Nat. Rev. Immunol. 2008, 8, 685–698, doi:10.1038/nri2378.
[64]
Penna, G.; Amuchastegui, S.; Giarratana, N.; Daniel, K.C.; Vulcano, M.; Sozzani, S.; Adorini, L. 1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells. J. Immunol. 2007, 178, 145–153.
[65]
Veldman, C.M.; Cantorna, M.T.; DeLuca, H.F. Expression of 1,25-dihydroxyvitamin D3 receptor in the immune system. Arch. Biochem. Biophys. 2000, 374, 334–338.
[66]
Ferreira, G.B.; van Etten, E.; Verstuyf, A.; Waer, M.; Overbergh, L.; Gysemans, C.; Mathieu, C. 1,25-Dihydroxyvitamin D3 alters murine dendritic cell behaviour in vitro and in vivo. Diabetes Metab. Res. Rev. 2011, 27, 933–941, doi:10.1002/dmrr.1275.
[67]
Müller, K.; Diamant, M.; Bendtzen, K. Inhibition of production and function of interleukin-6 by 1,25-dihydroxyvitamin D3. Immunol. Lett. 1991, 28, 115–120, doi:10.1016/0165-2478(91)90108-M.
[68]
Adorini, L.; Penna, G.; Giarratana, N.; Uskokovic, M. Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting allograft rejection and autoimmune diseases. J. Cell. Biochem. 2003, 88, 227–233, doi:10.1002/jcb.10340.
[69]
Griffin, M.D.; Lutz, W.; Phan, V.A.; Bachman, L.A.; McKean, D.J.; Kumar, R. 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 2001, 98, 6800–6805.
[70]
Panda, D.K.; Miao, D.; Tremblay, M.L.; Sirois, J.; Farookhi, R.; Hendy, G.N.; Goltzman, D. Targeted ablation of the 25-hydroxyvitamin D 1a-hydroxylase enzyme: Evidence for skeletal, reproductive , and immune dysfunction. Proc. Natl. Acad. Sci. USA 2001, 98, 7498–7503.
[71]
Enioutina, E.Y.; Bareyan, D.; Raymond, A. TLR-induced local metabolism of vitamin D3 plays an important role in the diversification of adaptive immune responses. J. Immunol. 2009, 182, 4296–4305, doi:10.4049/jimmunol.0804344.
[72]
Coussens, A.K.; Wilkinson, R.J.; Hanifa, Y.; Nikolayevskyy, V.; Elkington, P.T.; Islam, K.; Timms, P.M.; Venton, T.R.; Bothamley, G.H.; Packe, G.E.; et al. Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment. Proc. Natl. Acad. Sci. USA 2012, 109, 15449–15454, doi:10.1073/pnas.1200072109.
[73]
Provvedini, D.M.; Tsoukas, C.D.; Deftos, L.J.; Manolagas, S.C. 1,25-Dihydroxyvitamin D3 receptors in human leukocytes. Science 1983, 221, 1181–1183.
[74]
Lemire, J.M.; Adams, J.S.; Sakai, R.; Jordan, S.C. 1a,25-dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J. Clin. Investig. 1984, 74, 657–661, doi:10.1172/JCI111465.
[75]
Chen, S.; Sims, G.P.; Chen, X.X.; Gu, Y.Y.; Chen, S.; Lipsky, P.E. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J. Immunol. 2007, 179, 1634–1647.
[76]
Mahon, B.D.; Wittke, A.; Weaver, V.; Cantorna, M.T. The targets of vitamin D depend on the differentiation and activation status of CD4 positive T cells. J. Cell. Biochem. 2003, 89, 922–932, doi:10.1002/jcb.10580.
[77]
Lemire, J.M.; Adams, J.S.; Kermani-Arab, V.; Bakke, A.C.; Sakai, R.; Jordan, S.C. 1,25-Dihydroxyvitamin D3 suppresses human T helper/inducer lymphocyte activity in vitro. J. Immunol. 1985, 134, 3032–3035.
[78]
Cantorna, M.T. Mechanisms underlying the effect of vitamin D on the immune system. Proc. Nutr. Soc. 2011, 69, 286–289, doi:10.1017/S0029665110001722.
[79]
Baeke, F.; Korf, H.; Overbergh, L.; Verstuyf, A.; Thorrez, L.; van Lommel, L.; Waer, M.; Schuit, F.; Gysemans, C.; Mathieu, C. The vitamin D analog, TX527, promotes a human CD4+CD25highCD127low regulatory T cell profile and induces a migratory signature specific for homing to sites of inflammation. J. Immunol. 2011, 186, 132–142, doi:10.4049/jimmunol.1000695.
[80]
Lemire, J.M.; Archer, D.C.; Beck, L.; Spiegelberg, H.L. Immunosuppressive actions of 1,25-dihydroxyvitamin D3: Preferential inhibition of Th1 functions. J. Nutr. 1995, 125, 1704S–1708S.
[81]
Van Belle, T.L.; Gysemans, C.; Mathieu, C. Vitamin D in autoimmune, infectious and allergic diseases: A vital player? Best Pract. Res. Clin. Endocrinol. Metab. 2011, 25, 617–632, doi:10.1016/j.beem.2011.04.009.
[82]
Palmer, M.T.; Lee, Y.K.; Maynard, C.L.; Oliver, J.R.; Bikle, D.D.; Jetten, A.M.; Weaver, C.T. Lineage-specific effects of 1,25-dihydroxyvitamin D3 on the development of effector CD4 T cells. J. Biol. Chem. 2011, 286, 997–1004.
[83]
Giulietti, A.; Gysemans, C.; Stoffels, K.; van Etten, E.; Decallonne, B.; Overbergh, L.; Bouillon, R.; Mathieu, C. Vitamin D deficiency in early life accelerates Type 1 diabetes in non-obese diabetic mice. Diabetologia 2004, 47, 451–462, doi:10.1007/s00125-004-1329-3.
[84]
Boonstra, A.; Barrat, F.J.; Crain, C.; Heath, V.L.; Savelkoul, H.F.J.; Garra, A.O. 1α,25-dihydroxyvitamin D3 has a direct effect on naive CD4+T cells to enhance the development of Th2 cells. J. Immunol. 2001, 167, 4974–4980.
[85]
Penna, G.; Amuchastegui, S.; Cossetti, C.; Aquilano, F.; Mariani, R.; Sanvito, F.; Doglioni, C.; Adorini, L. Diabetic mice by the vitamin D receptor agonist elocalcitol 1. J. Immunol. 2006, 177, 8504–8511.
Jeffery, L.E.; Burke, F.; Mura, M.; Zheng, Y.; Qureshi, O.S.; Hewison, M.; Walker, L.S.K.; Lammas, D.A.; Raza, K.; Sansom, D.M. 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J. Immunol. 2009, 183, 5458–5467, doi:10.4049/jimmunol.0803217.
[88]
Rudensky, A.Y. Regulatory T cells and foxP3. Immunol. Rev. 2011, 241, 260–268, doi:10.1111/j.1600-065X.2011.01018.x.
[89]
Barrat, F.J.; Cua, D.J.; Boonstra, A.; Richards, D.F.; Crain, C.; Savelkoul, H.F.; de Waal-malefyt, R.; Coffman, R.L.; Hawrylowicz, C.M.; Garra, A.O. 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. 2002, 195, 603–616, doi:10.1084/jem.20011629.
[90]
Ardalan, M.R.; Maljaei, H.; Shoja, M.M.; Piri, A.R.; Khosroshahi, H.T.; Noshad, H.; Argani, H. Calcitriol started in the donor, expands the population of CD4+ CD25+ T cells in renal transplant recipients. Transplant. Proc. 2007, 39, 951–953, doi:10.1016/j.transproceed.2007.04.012.
[91]
Prietl, B.; Pilz, S.; Wolf, M.; Tomaschitz, A.; Obermayer-Pietsch, B.; Graninger, W.; Pieber, T.R. Vitamin D supplementation and regulatory T cells in apparently healthy subjects: Vitamin D treatment for autoimmune diseases? Isr. Med. Assoc. J. 2010, 12, 136–139.
[92]
Bock, G.; Prietl, B.; Mader, J.K.; H？ller, E.; Wolf, M.; Pilz, S.; Graninger, W.B.; Obermayer-Pietsch, B.M. The effect of vitamin D supplementation on peripheral regulatory T cells and β cell function in healthy humans: A randomized controlled trial. Diabetes Metab. Res. Rev. 2011, 25, 942–945.
[93]
Gabbay, M.A.L.; Sato, M.N.; Finazzo, C.; Duarte, A.J.S.; Dib, S.A. Effect of cholecalciferol as adjunctive therapy with insulin on protective immunologic profile and decline of residual β-cell function in new-onset type 1 diabetes mellitus. Arch. Pediatr. Adolesc. Med. 2012, 166, 601–607, doi:10.1001/archpediatrics.2012.164.
[94]
Zittermann, A.; Tenderich, G.; Koerfer, R. Vitamin D and the adaptive immune system with special emphasis to allergic reactions and allograft rejection. Inflamm. Allergy Drug Targets 2009, 8, 161–168, doi:10.2174/187152809788462644.
[95]
Becker, K.G. The common genetic hypothesis of autoimmune/inflammatory disease. Curr. Opin. Allergy. Clin. Immunol. 2001, 1, 399–405.
[96]
Moroni, L.; Bianchi, I.; Lleo, A. Geoepidemiology, gender and autoimmune disease. Autoimmun. Rev. 2012, 11, A386–A392, doi:10.1016/j.autrev.2011.11.012.
[97]
Zittermann, A. Vitamin D in preventive medicine: Are we ignoring the evidence? Br. J. Nutr. 2003, 89, 552–572, doi:10.1079/BJN2003837.
[98]
Cantorna, M.T.; Zhu, Y.; Froicu, M.; Wittke, A. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am. J. Clin. Nutr. 2004, 80, 1717–1720.
[99]
Bock, G.; Pieber, T.R.; Prietl, B. Vitamin D: Role in autoimmunity. CAB Rev. 2012, 7, 1–7.
[100]
Antico, A.; Tampoia, M.; Tozzoli, R.; Bizzaro, N. Can supplementation with vitamin D reduce the risk or modify the course of autoimmune diseases? A systematic review of the literature. Autoimmun. Rev. 2012, 12, 127–136, doi:10.1016/j.autrev.2012.07.007.
[101]
Hypp？nen, E.; L？？r？, E.; Reunanen, A.; J？rvelin, M.R.; Virtanen, S.M. Intake of vitamin D and risk of type 1 diabetes: A birth-cohort study. Lancet 2001, 358, 1500–1503, doi:10.1016/S0140-6736(01)06580-1.
[102]
Hypp？nen, E. Vitamin D and increasing incidence of type 1 diabetes-evidence for an association? Diabetes Obes. Metab. 2010, 12, 737–743, doi:10.1111/j.1463-1326.2010.01211.x.
[103]
Littorin, B.; Blom, P.; Sch？lin, A.; Arnqvist, H.J. Lower levels of plasma 25-hydroxyvitamin D among young adults at diagnosis of autoimmune type 1 diabetes compared with control subjects: Results from the nationwide Diabetes Incidence Study in Sweden (DISS). Diabetologia 2006, 49, 2847–2852, doi:10.1007/s00125-006-0426-x.
[104]
Takiishi, T.; Gysemans, C.; Bouillon, R.; Mathieu, C. Vitamin D and diabetes. Endocrinol. Metab. Clin. North. Am. 2010, 39, 419–446, doi:10.1016/j.ecl.2010.02.013.
[105]
Zipitis, C.S.; Akobeng, A.K. Vitamin D supplementation in early childhood and risk of type 1 diabetes: A systematic review and meta-analysis. Arch. Dis. Child. 2008, 93, 512–517, doi:10.1136/adc.2007.128579.
[106]
Vitamin D supplement in early childhood and risk for Type I (insulin-dependent) diabetes mellitus. The EURODIAB Substudy 2 Study Group. Diabetologia 1999, 42, 51–54, doi:10.1007/s001250051112.
[107]
Gregori, S.; Giarratana, N.; Smiroldo, S.; Uskokovic, M.; Adorini, L. A 1α,25-dihydroxyvitamin D3 analog enhances regulatory T-cells and arrests autoimmune diabetes in NOD mice. Diabetes 2002, 51, 1367–1374, doi:10.2337/diabetes.51.5.1367.
[108]
Mathieu, C.; Waer, M.; Laureys, J.; Rutgeerts, O.; Bouillon, R. Prevention of autoimmune diabetes in NOD mice by 1,25 dihydroxyvitamin D3. Diabetologia 1994, 37, 552–558, doi:10.1007/BF00403372.
[109]
Driver, J.P.; Foreman, O.; Mathieu, C.; van Etten, E.; Serreze, D.V. Comparative therapeutic effects of orally administered 1,25-dihydroxyvitamin D3 and 1α-hydroxyvitamin D3 on type-1 diabetes in non-obese diabetic mice fed a normal-calcaemic diet. Clin. Exp. Immunol. 2008, 151, 76–85.
[110]
Walter, M.; Kaupper, T.; Adler, K.; Foersch, J.; Bonifacio, E.; Ziegler, A.G. No effect of the 1α,25-dihydroxyvitamin D3 on beta-cell residual function and insulin requirement in adults with new-onset type 1 diabetes. Diabetes Care 2010, 33, 1443–1448, doi:10.2337/dc09-2297.
[111]
Bizzarri, C.; Pitocco, D.; Napoli, N.; di Stasio, E.; Maggi, D.; Manfrini, S.; Suraci, C.; Cavallo, M.G.; Cappa, M.; Ghirlanda, G.; et al. No protective effect of calcitriol on beta-cell function in recent-onset type 1 diabetes: The IMDIAB XIII trial. Diabetes Care 2010, 33, 1962–1963, doi:10.2337/dc10-0814.
[112]
Bailey, R.; Cooper, J.D.; Zeitels, L.; Smyth, D.J.; Yang, J.H.M.; Walker, N.M.; Hypp？nen, E.; Dunger, D.B.; Ramos-Lopez, E.; Badenhoop, K.; et al. Association of the vitamin D metabolism gene CYP27B1 with type 1 diabetes. Diabetes 2007, 56, 2616–2621, doi:10.2337/db07-0652.
[113]
Li, X.; Liao, L.; Yan, X.; Huang, G.; Lin, J.; Lei, M.; Wang, X.; Zhou, Z. Protective effects of 1-alpha-hydroxyvitamin D3 on residual beta-cell function in patients with adult-onset latent autoimmune diabetes (LADA). Diabetes Metab. Res. Rev. 2009, 25, 411–416, doi:10.1002/dmrr.977.
[114]
Pitocco, D.; Crinò, A.; di Stasio, E.; Manfrini, S.; Guglielmi, C.; Spera, S.; Anguissola, G.B.; Visalli, N.; Suraci, C.; Matteoli, M.C.; et al. The effects of calcitriol and nicotinamide on residual pancreatic beta-cell function in patients with recent-onset Type 1 diabetes (IMDIAB XI). Diabet. Med. 2006, 23, 920–923, doi:10.1111/j.1464-5491.2006.01921.x.
[115]
Munger, K.L.; Levin, L.I.; Hollis, B.W.; Howard, N.S.; Ascherio, A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006, 296, 2832–2838, doi:10.1001/jama.296.23.2832.
[116]
Kragt, J.; van Amerongen, B.; Killestein, J.; Dijkstra, C.; Uitdehaag, B.; Polman, C.; Lips, P. Higher levels of 25-hydroxyvitamin D are associated with a lower incidence of multiple sclerosis only in women. Mult. Scler. 2009, 15, 9–15, doi:10.1177/1352458508095920.
[117]
Munger, K.L.; Zhang, S.M.; O’Reilly, E.; Hernán, M.A.; Olek, M.J.; Willett, W.C.; Ascherio, A. Vitamin D intake and incidence of multiple sclerosis. Neurology 2004, 62, 60–65, doi:10.1212/01.WNL.0000101723.79681.38.
[118]
Soilu-H？nninen, M.; Aivo, J.; Lindstr？m, B.-M.; Elovaara, I.; Sumelahti, M.-L.; F？rkkil？, M.; Tienari, P.; Atula, S.; Sarasoja, T.; Herrala, L.; et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon β-1b in patients with multiple sclerosis. J. Neurol. Neurosurg. Psychiatr. 2012, 83, 565–571, doi:10.1136/jnnp-2011-301876.
[119]
Stein, M.S.; Liu, Y.; Gray, O.M.; Baker, J.E.; Kolbe, S.C.; Ditchfield, M.R.; Egan, G.F.; Mitchell, P.J.; Harrison, L.C.; Butzkueven, H.; et al. A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis. Neurology 2011, 77, 1611–1618, doi:10.1212/WNL.0b013e3182343274.
[120]
Kampman, M.T.; Steffensen, L.H.; Mellgren, S.I.; J？rgensen, L. Effect of vitamin D3 supplementation on relapses, disease progression, and measures of function in persons with multiple sclerosis: Exploratory outcomes from a double-blind randomised controlled trial. Mult. Scler. 2012, 18, 1144–1151, doi:10.1177/1352458511434607.
[121]
Chang, J.-H.; Cha, H.-R.; Lee, D.-S.; Seo, K.Y.; Kweon, M.-N. 1,25-Dihydroxyvitamin D3 inhibits the differentiation and migration of T(H)17 cells to protect against experimental autoimmune encephalomyelitis. PLoS One 2010, 5, e12925.
[122]
Smolders, J.; Thewissen, M.; Peelen, E.; Menheere, P.; Cohen, J.W.; Tervaert, J.W.C.; Damoiseaux, J.; Hupperts, R. Vitamin D status is positively correlated with regulatory T cell function in patients with multiple sclerosis. PLoS One 2009, 4, e6635, doi:10.1371/journal.pone.0006635.
[123]
Royal, W.; Mia, Y.; Li, H.; Naunton, K. Peripheral blood regulatory T cell measurements correlate with serum vitamin D levels in patients with multiple sclerosis. J. Neuroimmunol. 2009, 213, 135–141, doi:10.1016/j.jneuroim.2009.05.012.
[124]
Smolders, J.; Schuurman, K.G.; van Strien, M.E.; Melief, J.; Hendrickx, D.; Hol, E.M.; van Eden, C.; Luchetti, S.; Huitinga, I. Expression of vitamin D receptor and metabolizing enzymes in multiple sclerosis-affected brain tissue. J. Neuropathol. Exp. Neurol. 2013, 72, 91–105, doi:10.1097/NEN.0b013e31827f4fcc.
