The Journal of Allergy and Clinical Immunology
Volume 120, Issue 5 , Pages 1031-1035 , November 2007

Is vitamin D deficiency to blame for the asthma epidemic?

  • Augusto A. Litonjua, MD, MPH

      Affiliations

    • Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Mass
    • Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Mass
    • Center for Genomic Medicine, Brigham and Women's Hospital, Boston, Mass
    • Harvard Medical School, Boston, Mass
    • Corresponding Author InformationReprint requests: Augusto A. Litonjua, MD, MPH, 181 Longwood Avenue, Boston, MA 02115.
  • ,
  • Scott T. Weiss, MD, MS

      Affiliations

    • Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Mass
    • Center for Genomic Medicine, Brigham and Women's Hospital, Boston, Mass
    • Harvard Medical School, Boston, Mass

Received 23 May 2007 ,Revised 12 August 2007 ,Accepted 15 August 2007.

References 

  1. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med. 2006;355:2226–2235
  2. Masoli M, Fabian D, Holt S, Beasley R. Global Initiative for Asthma (GINA) Program. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy. 2004;59:469–478
  3. Strachan DP. Family size, infection and atopy: the first decade of the “hygiene hypothesis.”. Thorax. 2000;55:S2–S10
  4. Romagnani S. Immunologic influences on allergy and the TH1/TH2 balance. J Allergy Clin Immunol. 2004;113:395–400
  5. Romagnani S. The increased prevalence of allergy and the hygiene hypothesis: missing immune deviation, reduced immune suppression, or both?. Immunology. 2004;112:352–363
  6. Ramsey CD, Celedon JC. The hygiene hypothesis and asthma. Curr Opin Pulm Med. 2005;11:14–20
  7. Lamberg-Allardt C. Vitamin D in foods and as supplements. Prog Biophys Mol Biol. 2006;92:33–38
  8. Lu Z, Chen TC, Zhang A, Persons KS, Kohn N, Berkowitz R, et al. An evaluation of the vitamin D3 content in fish: Is the vitamin D content adequate to satisfy the dietary requirement for vitamin D?. J Steroid Biochem Mol Biol. 2007;103:642–644
  9. Food and Nutrition Board, Institute of Medicine . Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington (DC): National Academy Press; 1997;
  10. Calvo MS, Whiting SJ, Barton CN. Vitamin D fortification in the United States and Canada: current status and data needs. Am J Clin Nutr. 2004;80:1710S–1716S
  11. Vieth R, Bischoff-Ferrari H, Boucher B, Dawson-Hughes B, Garland C, Heaney R, et al. The urgent need to recommend an intake of vitamin D that is effective. Am J Clin Nutr. 2007;85:649–650
  12. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–281
  13. Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006;84:18–28
  14. Taback SP, Simons FE. Anaphylaxis and vitamin D: a role for the sunshine hormone?. J Allergy Clin Immunol. 2007;120:128–130
  15. Hollis BW, Wagner CL, Drezner MK, Binkley NC. Circulating vitamin D(3) and 25-hydroxyvitamin D in humans: an important tool to define adequate nutritional vitamin D status. J Steroid Biochem Mol Biol. 2007;103:631–634
  16. Matsuoka L, Wortsman J, Dannenberg M, Hollis B, Lu Z, Holick M. Clothing prevents ultraviolet-B radiation-dependent photosynthesis of vitamin D3. J Clin Endrocrinol Metab. 1992;75:1099–1103
  17. Holick M, Matsuoka L, Wortsman J. Regular use of sunscreen on vitamin D levels. Arch Dermatol. 1995;131:1337–1339
  18. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006;81:353–373
  19. Nesby-O'Dell S, Scanlon KS, Cogswell ME, Gillespie C, Hollis BW, Looker AC, et al. Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr. 2002;76:187–192
  20. Binkley N, Novotny R, Krueger D, Kawahara T, Daida YG, Lensmeyer G, et al. Low vitamin D status despite abundant sun exposure. J Clin Endocrinol Metab. 2007;92:2130–2135
  21. Meddeb N, Sahli H, Chahed M, Abdelmoula J, Feki M, Salah H, et al. Vitamin D deficiency in Tunisia. Osteoporos Int. 2005;16:180–183
  22. Guzel R, Kozanoglu E, Guler-Uysal F, Soyupak S, Sarpel T. Vitamin D status and bone mineral density of veiled and unveiled Turkish women. J Womens Health Gend Based Med. 2001;10:765–770
  23. Gannage-Yared MH, Chemali R, Yaacoub N, Halaby G. Hypovitaminosis D in a sunny country: relation to lifestyle and bone markers. J Bone Miner Res. 2000;15:1856–1862
  24. Wortsman J, Matsuoka L, Chen T, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr. 2000;72:690–693
  25. Lee JM, Smith JR, Philipp BL, Chen TC, Mathieu J, Holick MF. Vitamin d deficiency in a healthy group of mothers and newborn infants. Clin Pediatr (Phila). 2007;46:42–44
  26. Skull S, Ngeow J, Biggs B, Street A, Ebeling P. Vitamin D deficiency is common and unrecognized among recently arrived adult immigrants from the Horn of Africa. Intern Med J. 2003;33:47–51
  27. Hollis BW, Wagner CL. Assessment of dietary vitamin D requirements during pregnancy and lactation. Am J Clin Nutr. 2004;79:717–726
  28. Friedman N, Zeiger R. The role of breast-feeding in the development of allergies and asthma. J Allergy Clin Immunol. 2005;115:1238–1248
  29. Cantorna MT, Zhu Y, Froicu M, Wittke A. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am J Clin Nutr. 2004;80:1717S–1720S
  30. van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts. J Steroid Biochem Mol Biol. 2005;97:93–101
  31. May E, Asadullah K, Zugel U. Immunoregulation through 1,25-dihydroxyvitamin D3 and its analogs. Curr Drug Targets Inflamm Allergy. 2004;3:377–393
  32. Cantorna MT. Vitamin D and its role in immunology: multiple sclerosis, and inflammatory bowel disease. Prog Biophys Mol Biol. 2006;92:60–64
  33. Dickson I. New approaches to vitamin D. Nature. 1987;325:18
  34. Minghetti PP, Norman AW. 1,25(OH)2-vitamin D3 receptors: gene regulation and genetic circuitry. FASEB J. 1988;2:3043–3053
  35. Akeno N, Saikatsu S, Kawane T, Horiuchi N. Mouse vitamin D-24-hydroxylase: molecular cloning, tissue distribution, and transcriptional regulation by 1alpha,25-dihydroxyvitamin D3. Endocrinology. 1997;138:2233–2240
  36. 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;89:922–932
  37. Heine G, Anton K, Henz BM, Worm M. 1alpha,25-dihydroxyvitamin D3 inhibits anti-CD40 plus IL-4-mediated IgE production in vitro. Eur J Immunol. 2002;32:3395–3404
  38. 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;89-90:437–441
  39. Hewison M, Burke F, Evans KN, Lammas DA, Sansom DM, Liu P, et al. Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health and disease. J Steroid Biochem Mol Biol. 2007;103:316–321
  40. Matheu V, Back O, Mondoc E, Issazadeh-Navikas S. Dual effects of vitamin D-induced alteration of TH1/TH2 cytokine expression: enhancing IgE production and decreasing airway eosinophilia in murine allergic airway disease. J Allergy Clin Immunol. 2003;112:585–592
  41. Iho S, Kura F, Sugiyama H, Takahashi T, Hoshino T. The role of monocytes in the suppression of PHA-induced proliferation and IL 2 production of human mononuclear cells by 1,25-dihydroxyvitamin D3. Immunol Lett. 1985;11:331–336
  42. Reichel H, Koeffler HP, Tobler A, Norman AW. 1 Alpha,25-Dihydroxyvitamin D3 inhibits gamma-interferon synthesis by normal human peripheral blood lymphocytes. Proc Natl Acad Sci U S A. 1987;84:3385–3389
  43. Boonstra A, Barrat FJ, Crain C, Heath VL, Savelkoul HF, O'Garra A. 1Alpha,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
  44. Cantorna MT, Woodward WD, Hayes CE, DeLuca HF. 1,25-Dihydroxyvitamin D3 is a positive regulator for the two anti-encephalitogenic cytokines TGF-beta 1 and IL-4. J Immunol. 1998;160:5314–5319
  45. Pichler J, Gerstmayr M, Szepfalusi Z, Urbanek R, Peterlik M, Willheim M. 1 alpha,25(OH)2D3 inhibits not only Th1 but also Th2 differentiation in human cord blood T cells. Pediatr Res. 2002;52:12–18
  46. Annesi-Maesano I. Perinatal events, vitamin D, and the development of allergy. Pediatr Res. 2002;52:3–5
  47. Gregori S, Casorati M, Amuchastegui S, Smiroldo S, Davalli AM, Adorini L. Regulatory T cells induced by 1 alpha,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J Immunol. 2001;167:1945–1953
  48. 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;51:1367–1374
  49. Meehan MA, Kerman RH, Lemire JM. 1,25-Dihydroxyvitamin D3 enhances the generation of nonspecific suppressor cells while inhibiting the induction of cytotoxic cells in a human MLR. Cell Immunol. 1992;140:400–409
  50. Xystrakis E, Kusumakar S, Boswell S, Peek E, Urry Z, Richards DF, et al. Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest. 2006;116:146–155
  51. 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;173:2909–2912
  52. 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;311:1770–1773
  53. Liu PT, Krutzik SR, Modlin RL. Therapeutic implications of the TLR and VDR partnership. Trends Mol Med. 2007;13:117–124
  54. Schauber J, Dorschner RA, Coda AB, Buchau AS, Liu PT, Kiken D, et al. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J Clin Invest. 2007;117:803–811
  55. Mallbris L, Edstrom DW, Sundblad L, Granath F, Stahle M. UVB upregulates the antimicrobial protein hCAP18 mRNA in human skin. J Invest Dermatol. 2005;125:1072–1074
  56. Zasloff M. Fighting infections with vitamin D. Nat Med. 2006;12:388–390
  57. Munns C, Zacharin MR, Rodda CP, Batch JA, Morley R, Cranswick NE, et al. Prevention and treatment of infant and childhood vitamin D deficiency in Australia and New Zealand: a consensus statement. Med J Aust. 2006;185:268–272
  58. Raby BA, Lazarus R, Silverman EK, Lake S, Lange C, Wjst M, et al. Association of vitamin D receptor gene polymorphisms with childhood and adult asthma. Am J Respir Crit Care Med. 2004;170:1057–1065
  59. Poon AH, Laprise C, Lemire M, Montpetit A, Sinnett D, Schurr E, et al. Association of vitamin D receptor genetic variants with susceptibility to asthma and atopy. Am J Respir Crit Care Med. 2004;170:967–973
  60. Vollmert C, Illig T, Altmuller J, Klugbauer S, Loesgen S, Dumitrescu L, et al. Single nucleotide polymorphism screening and association analysis: exclusion of integrin beta 7 and vitamin D receptor (chromosome 12q) as candidate genes for asthma. Clin Exp Allergy. 2004;34:1841–1850
  61. Wjst M. Variants in the vitamin D receptor gene and asthma. BMC Genet. 2005;6:2
  62. Wjst M, Altmuller J, Faus-Kessler T, Braig C, Bahnweg M, Andre E. Asthma families show transmission disequilibrium of gene variants in the vitamin D metabolism and signalling pathway. Respir Res. 2006;7:60
  63. Wjst M. The vitamin D slant on allergy. Pediatr Allergy Immunol. 2006;17:477–483
  64. Wittke A, Weaver V, Mahon BD, August A, Cantorna MT. Vitamin D receptor-deficient mice fail to develop experimental allergic asthma. J Immunol. 2004;173:3432–3436
  65. Wittke A, Chang A, Froicu M, Harandi OF, Weaver V, August A, et al. Vitamin D receptor expression by the lung micro-environment is required for maximal induction of lung inflammation. Arch Biochem Biophys. 2007;460:306–313
  66. Nguyen M, Trubert CL, Rizk-Rabin M, Rehan VK, Besancon F, Cayre YE, et al. 1,25-Dihydroxyvitamin D3 and fetal lung maturation: immunogold detection of VDR expression in pneumocytes type II cells and effect on fructose 1,6 bisphosphatase. J Steroid Biochem Mol Biol. 2004;89-90:93–97
  67. Nguyen TM, Guillozo H, Marin L, Tordet C, Koite S, Garabedian M. Evidence for a vitamin D paracrine system regulating maturation of developing rat lung epithelium. Am J Physiol. 1996;271:L392–L399
  68. Edelson J, Chan S, Jassal D, Post M, Tanswell A. Vitamin D stimulates DNA synthesis in alveolar type-II cells. Biochem Biophys Acta. 1994;1221:159–166
  69. Burns JS, Dockery DW, Speizer FE. Low levels of dietary vitamin D intake and pulmonary function in adolescents. Proc Am Thoracic Soc. 2006;3:A526
  70. Black PN, 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
  71. Bosse Y, Maghni K, Hudson TJ. 1{alpha},25-Dihydroxy-vitamin D3 stimulation of bronchial smooth muscle cells induces autocrine, contractility and remodelling processes. Physiol Genomics. 2007;29:161–168
  72. Devereux G, Litonjua AA, Turner S, Craig L, McNeill G, Martindale S, et al. Maternal vitamin D intake during pregnancy and early childhood wheezing. Am J Clin Nutr. 2007;85:853–859
  73. Camargo CA, Rifas-Shiman SL, Litonjua AA, Rich-Edwards JW, Weiss ST, Gold DR, et al. Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at age 3 years. Am J Clin Nutr. 2007;85:788–795
  74. Gale C, Robinson S, Harvey N, Javaid M, Jiang B, Martyn C, et al. Maternal vitamin D status during pregnancy and child outcomes. Eur J Clin Nutr. 2007;Feb 21 [epub ahead of print]
  75. Hypponen E, Sovio U, Wjst M, Patel S, Pekkanen J, Hartikainen AL, et al. Infant vitamin D supplementation and allergic conditions in adulthood: northern Finland birth cohort 1966. Ann N Y Acad Sci. 2004;1037:84–95

 Disclosure of potential conflict of interest: S. T. Weiss has consulting arrangements with Roche Pharmaceuticals, Glaxo Wellcome, Millennium Pharmaceuticals, Genentech, Schering-Plough, Variagenics, Genome Therapeutics, and Merck Frost and has received grant support from Glaxo Wellcome, AstraZeneca, and Pfizer. A. A. Litonjua has declared that he has no conflict of interest.

PII: S0091-6749(07)01600-4

doi: 10.1016/j.jaci.2007.08.028

The Journal of Allergy and Clinical Immunology
Volume 120, Issue 5 , Pages 1031-1035 , November 2007