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• W1967949987 abstract "In the 1960s, the prevalence of asthma and allergic diseases began to increase worldwide. Currently, the burden of the disease is more than 300 million people affected. We hypothesize that as populations grow more prosperous, more time is spent indoors, and there is less exposure to sunlight, leading to decreased cutaneous vitamin D production. Coupled with inadequate intake from foods and supplements, this then leads to vitamin D deficiency, particularly in pregnant women, resulting in more asthma and allergy in their offspring. Vitamin D has been linked to immune system and lung development in utero, and our epidemiologic studies show that higher vitamin D intake by pregnant mothers reduces asthma risk by as much as 40% in children 3 to 5 years old. Vitamin D deficiency has been associated with obesity, African American race (particularly in urban, inner-city settings), and recent immigrants to westernized countries, thus reflecting the epidemiologic patterns observed in the asthma epidemic. Providing adequate vitamin D supplementation in pregnancy may lead to significant decreases in asthma incidence in young children. In the 1960s, the prevalence of asthma and allergic diseases began to increase worldwide. Currently, the burden of the disease is more than 300 million people affected. We hypothesize that as populations grow more prosperous, more time is spent indoors, and there is less exposure to sunlight, leading to decreased cutaneous vitamin D production. Coupled with inadequate intake from foods and supplements, this then leads to vitamin D deficiency, particularly in pregnant women, resulting in more asthma and allergy in their offspring. Vitamin D has been linked to immune system and lung development in utero, and our epidemiologic studies show that higher vitamin D intake by pregnant mothers reduces asthma risk by as much as 40% in children 3 to 5 years old. Vitamin D deficiency has been associated with obesity, African American race (particularly in urban, inner-city settings), and recent immigrants to westernized countries, thus reflecting the epidemiologic patterns observed in the asthma epidemic. Providing adequate vitamin D supplementation in pregnancy may lead to significant decreases in asthma incidence in young children. Beginning in the 1960s, the prevalence of asthma and allergic diseases has increased worldwide.1Eder W. Ege M.J. von Mutius E. The asthma epidemic.N Engl J Med. 2006; 355: 2226-2235Crossref PubMed Scopus (1291) Google Scholar Currently, the burden of the disease in both the developed and the developing world is significant and increasing rapidly with more than 300 million people affected worldwide, with industrialized countries furthest away from the equator (eg, Australia, New Zealand, and the United Kingdom) having the highest prevalence.2Masoli 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: 469-478Crossref PubMed Scopus (2580) Google Scholar Asthma is one of the leading causes of morbidity in children, with 90% of all cases diagnosed by age 6 years. It remains the most common chronic disease of childhood in the world and incurs significant healthcare costs. The worldwide International Study of Asthma and Allergy in Children (ISAAC) studies have been helpful in showing that asthma and allergic diseases have the highest prevalence in developed countries. Much research effort has been expended in attempting to explain this pattern of the rise in asthma, and the most cited hypothesis to explain the epidemic is the hygiene hypothesis.3Strachan D.P. Family size, infection and atopy: the first decade of the “hygiene hypothesis.”.Thorax. 2000; 55: S2-S10Crossref PubMed Google Scholar This hypothesis arose from the original observations of the inverse association between family size and atopy risk, and posits that smaller families in developed westernized countries lead to decreased exposure to infections in early life. This decreased exposure to infections in early life is supposed to result in asthma and atopy because of improper development of the immune system caused by inadequate upregulation of TH1 immune responses and missing immune deviation from a predominantly TH2 to a balanced TH1/TH2 response.4Romagnani S. Immunologic influences on allergy and the TH1/TH2 balance.J Allergy Clin Immunol. 2004; 113: 395-400Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar, 5Romagnani S. The increased prevalence of allergy and the hygiene hypothesis: missing immune deviation, reduced immune suppression, or both?.Immunology. 2004; 112: 352-363Crossref PubMed Scopus (355) Google Scholar Although this hypothesis is attractive and has experimental evidence to back it, the studies on asthma have been inconsistent,6Ramsey C.D. Celedon J.C. The hygiene hypothesis and asthma.Curr Opin Pulm Med. 2005; 11: 14-20Crossref PubMed Scopus (74) Google Scholar and it alone cannot explain all the aspects of the patterns of the asthma epidemic, such as the link between obesity and asthma, the high prevalence in poor urban environments (where children who have asthma are also at risk for infections), and the concomitant rise in TH1-mediated autoimmune disorders. Thus, there is something else helping to drive the epidemic, and it is likely that there is another environmental exposure (or lack thereof) that can more completely explain the epidemiologic patterns of the asthma and allergy epidemic. We hypothesize that as populations grow more prosperous and more westernized, more time is spent indoors and there is less exposure to sunlight, leading to vitamin D deficiency, subsequently resulting in more asthma and allergy. Although sunlight has many beneficial effects through several biologic pathways, to date the weight of the evidence for the link with asthma appears to be with vitamin D. Thus, prenatal deficiency of vitamin D may affect fetal lung and immune system development, and this is likely to be exacerbated by postnatal vitamin D deficiency. Vitamin D is both a nutrient and a hormone. However, unlike usual nutrients, vitamin D does not naturally occur in foods that human beings eat, except oily fish and fish liver oil, egg yolk, and offal.7Lamberg-Allardt C. Vitamin D in foods and as supplements.Prog Biophys Mol Biol. 2006; 92: 33-38Crossref PubMed Scopus (167) Google Scholar In addition, there can be wide variation in the vitamin D content of these natural sources (eg, farmed versus wild salmon), and cooking methods (eg, frying versus baking) can deplete the amount of vitamin D in these foods.8Lu Z. Chen T.C. Zhang A. Persons K.S. 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: 642-644Crossref PubMed Scopus (171) Google Scholar Therefore, most of the vitamin D that we ingest comes from fortified foods (in the United States, milk, some milk products such as yogurt and margarine, and breakfast cereals are fortified with vitamin D9Food and Nutrition Board, Institute of Medicine Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. National Academy Press, Washington (DC)1997Google Scholar, 10Calvo M.S. Whiting S.J. Barton C.N. Vitamin D fortification in the United States and Canada: current status and data needs.Am J Clin Nutr. 2004; 80: 1710S-1716SPubMed Google Scholar) and from supplements. The Institute of Medicine9Food and Nutrition Board, Institute of Medicine Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. National Academy Press, Washington (DC)1997Google Scholar currently recommends intakes of 200 IU/d from birth through age 50 years, 400 IU/d for those age 51 to 70 years, and 600 IU/d for those older than 70 years. However, there is now widespread consensus that these recommendations are woefully inadequate for overall health.11Vieth 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: 649-650PubMed Scopus (548) Google Scholar Currently, most experts define vitamin D deficiency as a circulating 25-hydroxyvitamin D3 (25[OH]D) serum level of <50 nmol/L (20 ng/mL).12Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10830) Google Scholar Evaluations of most relations between vitamin D and health and various disorders lead to the conclusion that a desirable (or sufficient) circulating vitamin D level (measured as 25[OH]D) is 75 to 100 nmol/L (30-40 ng/mL)11Vieth 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: 649-650PubMed Scopus (548) Google Scholar, 13Bischoff-Ferrari H.A. Giovannucci E. Willett W.C. Dietrich T. Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes.Am J Clin Nutr. 2006; 84: 18-28PubMed Scopus (1950) Google Scholar and recommended intakes have only a modest effect on blood concentrations of 25(OH)D.13Bischoff-Ferrari H.A. Giovannucci E. Willett W.C. Dietrich T. Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes.Am J Clin Nutr. 2006; 84: 18-28PubMed Scopus (1950) Google Scholar 25(OH)D levels of between 50 and 75 nmol/L (20-30 ng/mL) are considered relative insufficiency. The level of 25(OH)D needed for optimal immune functioning is unknown, but levels even higher than 100 nmol/L may be necessary.14Taback S.P. Simons F.E. Anaphylaxis and vitamin D: a role for the sunshine hormone?.J Allergy Clin Immunol. 2007; 120: 128-130Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 15Hollis B.W. Wagner C.L. Drezner M.K. Binkley N.C. 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: 631-634Crossref PubMed Scopus (149) Google Scholar From an evolutionary standpoint, human beings do not require vitamin D in the food supply because we have a photosynthetic mechanism in the skin. 7-Dehydrocholesterol is distributed in the skin. After exposure to sunlight, specifically to the UVB range of the spectrum, 7-dehydrocholesterol is converted to previtamin D3, which is then transformed to vitamin D3 by a thermally induced isomerization process. Vitamin D3 then undergoes hydroxylation in the liver to 25(OH)D and then in the kidney to its biologically active form 1,25-dihydroxyvitamin D3. Many other tissues, specifically respiratory epithelial cells and cells involved in the immune response, harbor the hydroxylase and therefore are able to convert circulating 25(OH)D to 1,25-dihydroxyvitamin D3, and have particular relevance for local immune cell signaling. Serum 25(OH)D is the major circulating metabolite of vitamin D and reflects input from cutaneous synthesis and dietary intake. Because cutaneous synthesis of vitamin D is easily affected by behaviors such as time spent indoors, clothing,16Matsuoka 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: 1099-1103PubMed Google Scholar and sunscreen use,17Holick M. Matsuoka L. Wortsman J. Regular use of sunscreen on vitamin D levels.Arch Dermatol. 1995; 131: 1337-1339Crossref PubMed Google Scholar inadequate dietary intake of this vitamin significantly magnifies the problem of deficiency. Vitamin D deficiency has been documented in many populations worldwide,18Holick M.F. High prevalence of vitamin D inadequacy and implications for health.Mayo Clin Proc. 2006; 81: 353-373Abstract Full Text Full Text PDF PubMed Scopus (1527) Google Scholar, 19Nesby-O'Dell S. Scanlon K.S. Cogswell M.E. Gillespie C. Hollis B.W. Looker A.C. 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: 187-192PubMed Scopus (836) Google Scholar even in areas of the world with abundant sun exposure.20Binkley N. Novotny R. Krueger D. Kawahara T. Daida Y.G. Lensmeyer G. et al.Low vitamin D status despite abundant sun exposure.J Clin Endocrinol Metab. 2007; 92: 2130-2135Crossref PubMed Scopus (345) Google Scholar Because of its potential role in decreasing the risk for a multitude of chronic diseases associated with westernization,12Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10830) Google Scholar vitamin D deficiency is an important public health problem. Season, latitude, time of day, skin pigmentation, aging, clothing, and sunscreen use all influence the cutaneous production of vitamin D. Even in populations residing in equatorial areas, vitamin D deficiency exists and has been ascribed to behaviors such as clothing preferences (eg, women wearing veils and other concealing clothing21Meddeb N. Sahli H. Chahed M. Abdelmoula J. Feki M. Salah H. et al.Vitamin D deficiency in Tunisia.Osteoporos Int. 2005; 16: 180-183Crossref PubMed Scopus (119) Google Scholar, 22Guzel 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: 765-770Crossref PubMed Scopus (117) Google Scholar) and other lifestyle factors.18Holick M.F. High prevalence of vitamin D inadequacy and implications for health.Mayo Clin Proc. 2006; 81: 353-373Abstract Full Text Full Text PDF PubMed Scopus (1527) Google Scholar, 23Gannage-Yared M.H. Chemali R. Yaacoub N. Halaby G. Hypovitaminosis D in a sunny country: relation to lifestyle and bone markers.J Bone Miner Res. 2000; 15: 1856-1862Crossref PubMed Scopus (337) Google Scholar Vitamin D deficiency has been linked with obesity24Wortsman J. Matsuoka L. Chen T. Lu Z. Holick M.F. Decreased bioavailability of vitamin D in obesity.Am J Clin Nutr. 2000; 72: 690-693Crossref PubMed Scopus (2472) Google Scholar; African American race,19Nesby-O'Dell S. Scanlon K.S. Cogswell M.E. Gillespie C. Hollis B.W. Looker A.C. 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: 187-192PubMed Scopus (836) Google Scholar particularly in inner-city settings25Lee J.M. Smith J.R. Philipp B.L. Chen T.C. Mathieu J. Holick M.F. Vitamin d deficiency in a healthy group of mothers and newborn infants.Clin Pediatr (Phila). 2007; 46: 42-44Crossref PubMed Scopus (236) Google Scholar; and recent immigrants to westernized countries.26Skull 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: 47-51Crossref PubMed Scopus (58) Google Scholar Therefore, the epidemiology of vitamin D deficiency appears to reflect many patterns that have been observed with the asthma epidemic. A specific segment of the population that is at risk for vitamin D deficiency is the group of pregnant women and lactating mothers, given the demands for vitamin D of the developing fetus and neonate.27Hollis B.W. Wagner C.L. Assessment of dietary vitamin D requirements during pregnancy and lactation.Am J Clin Nutr. 2004; 79: 717-726PubMed Google Scholar This has added significance because deficiency in the mother is affecting both her and her child, and maternal vitamin D status may underlie the conflicting results of studies investigating breast-feeding as a risk or protective factor for asthma and allergies.28Friedman N. Zeiger R. The role of breast-feeding in the development of allergies and asthma.J Allergy Clin Immunol. 2005; 115: 1238-1248Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar Although beyond the scope of this commentary, recent extensive reviews of the effects of vitamin D on the immune system have been published.29Cantorna 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: 1717S-1720SPubMed Google Scholar, 30van Etten E. Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts.J Steroid Biochem Mol Biol. 2005; 97: 93-101Crossref PubMed Scopus (711) Google Scholar, 31May E. Asadullah K. Zugel U. Immunoregulation through 1,25-dihydroxyvitamin D3 and its analogs.Curr Drug Targets Inflamm Allergy. 2004; 3: 377-393Crossref PubMed Scopus (77) Google Scholar, 32Cantorna M.T. Vitamin D and its role in immunology: multiple sclerosis, and inflammatory bowel disease.Prog Biophys Mol Biol. 2006; 92: 60-64Crossref PubMed Scopus (247) Google Scholar As stated in an editorial in this Journal,14Taback S.P. Simons F.E. Anaphylaxis and vitamin D: a role for the sunshine hormone?.J Allergy Clin Immunol. 2007; 120: 128-130Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar the role of vitamin D in inhibiting TH1 immune responses has been well studied, but its effects on TH2 responses are more complex and not fully elucidated. Vitamin D receptors (VDRs)33Dickson I. New approaches to vitamin D.Nature. 1987; 325: 18Crossref PubMed Scopus (30) Google Scholar, 34Minghetti P.P. Norman A.W. 1,25(OH)2-vitamin D3 receptors: gene regulation and genetic circuitry.FASEB J. 1988; 2: 3043-3053Crossref PubMed Scopus (446) Google Scholar and vitamin D metabolic enzymes18Holick M.F. High prevalence of vitamin D inadequacy and implications for health.Mayo Clin Proc. 2006; 81: 353-373Abstract Full Text Full Text PDF PubMed Scopus (1527) Google Scholar, 35Akeno 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: 2233-2240Crossref PubMed Scopus (86) Google Scholar have been identified in many other tissues aside from bone and the intestine, suggesting involvement in the metabolism and function of many cell types. Specifically, VDR is expressed in cells of the immune system, such as T cells,36Mahon 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: 922-932Crossref PubMed Scopus (375) Google Scholar activated B cells,37Heine G. Anton K. Henz B.M. Worm M. 1alpha,25-dihydroxyvitamin D3 inhibits anti-CD40 plus IL-4-mediated IgE production in vitro.Eur J Immunol. 2002; 32: 3395-3404PubMed Google Scholar and dendritic cells.38Adorini L. Penna G. Giarratana N. Roncari A. Amuchastegui S. Daniel K.C. et al.Dendritic cells as key targets for immunomodulation by Vitamin D receptor ligands.J Steroid Biochem Mol Biol. 2004; 89-90: 437-441Crossref PubMed Scopus (183) Google Scholar The 1-α-hydroxylase is also expressed in dendritic cells,39Hewison M. Burke F. Evans K.N. Lammas D.A. Sansom D.M. Liu P. et al.Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health and disease.J Steroid Biochem Mol Biol. 2007; 103: 316-321Crossref PubMed Scopus (336) Google Scholar suggesting that 25(OH)D can be converted to the metabolically active form locally and thus plays a role in immune signaling. Evidence exists that vitamin D induces a shift in the balance between TH1 and TH2-type cytokines toward TH2 dominance,29Cantorna 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: 1717S-1720SPubMed Google Scholar, 40Matheu 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: 585-592Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar resulting in reduced secretion of TH1 cytokines IL-2 and IFN-γ40Matheu 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: 585-592Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, 41Iho 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: 331-336Crossref PubMed Scopus (28) Google Scholar, 42Reichel H. Koeffler H.P. Tobler A. Norman A.W. 1 Alpha,25-Dihydroxyvitamin D3 inhibits gamma-interferon synthesis by normal human peripheral blood lymphocytes.Proc Natl Acad Sci U S A. 1987; 84: 3385-3389Crossref PubMed Scopus (298) Google Scholar and an increase in the TH2 cytokine IL-4.43Boonstra A. Barrat F.J. Crain C. Heath V.L. Savelkoul H.F. 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: 4974-4980PubMed Google Scholar, 44Cantorna M.T. Woodward W.D. Hayes C.E. DeLuca H.F. 1,25-Dihydroxyvitamin D3 is a positive regulator for the two anti-encephalitogenic cytokines TGF-beta 1 and IL-4.J Immunol. 1998; 160: 5314-5319PubMed Google Scholar In contrast, in CD4+ as well as CD8+ human cord blood cells, vitamin D not only inhibits IL-12–generated IFN-γ production but also suppresses IL-4 and IL-4–induced expression of IL-13.45Pichler 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: 12-18PubMed Google Scholar, 46Annesi-Maesano I. Perinatal events, vitamin D, and the development of allergy.Pediatr Res. 2002; 52: 3-5PubMed Google Scholar The seemingly contradictory effects of vitamin D on TH1-TH2 dominance may lie, in part, in the timing of vitamin D exposure of the cells to vitamin D (ie, prenatal versus postnatal), and also in the effects of vitamin D on T-regulatory (Treg) cells. Vitamin D has been shown to promote the induction of Treg cells.47Gregori S. Casorati M. Amuchastegui S. Smiroldo S. Davalli A.M. Adorini L. Regulatory T cells induced by 1 alpha,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance.J Immunol. 2001; 167: 1945-1953PubMed Google Scholar, 48Gregori 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: 1367-1374Crossref PubMed Scopus (429) Google Scholar, 49Meehan M.A. Kerman R.H. Lemire J.M. 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: 400-409Crossref PubMed Scopus (61) Google Scholar Even in a subgroup of patients who had established TH2 disorder (eg, steroid resistant asthma), administration of vitamin D was shown to reverse steroid resistance through induction of IL-10–secreting Treg cells.50Xystrakis E. Kusumakar S. Boswell S. Peek E. Urry Z. Richards D.F. et al.Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients.J Clin Invest. 2006; 116: 146-155Crossref PubMed Scopus (496) Google Scholar The effects of vitamin D on Treg cell development and function and subsequent effects on TH1 and TH2 balance and function need further study. In addition to effects on adaptive immunity, there is also a newly recognized role of vitamin D in innate immune responses to microbial agents. It is becoming apparent that vitamin D participates in Toll-like receptor signaling in response to infections by upregulating the production of cathelicidin and other antimicrobial peptides.51Wang T.T. Nestel F.P. 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: 2909-2912PubMed Google Scholar, 52Liu P.T. Stenger S. Li H. Wenzel L. Tan B.H. Krutzik S.R. et al.Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response.Science. 2006; 311: 1770-1773Crossref PubMed Scopus (3053) Google Scholar, 53Liu P.T. Krutzik S.R. Modlin R.L. Therapeutic implications of the TLR and VDR partnership.Trends Mol Med. 2007; 13: 117-124Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 54Schauber J. Dorschner R.A. Coda A.B. Buchau A.S. Liu P.T. Kiken D. et al.Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism.J Clin Invest. 2007; 117: 803-811Crossref PubMed Scopus (575) Google Scholar, 55Mallbris L. Edstrom D.W. Sundblad L. Granath F. Stahle M. UVB upregulates the antimicrobial protein hCAP18 mRNA in human skin.J Invest Dermatol. 2005; 125: 1072-1074Crossref PubMed Scopus (54) Google Scholar This effect of vitamin D is the likely explanation for the observations that sunlight can treat tuberculosis and other infections.55Mallbris L. Edstrom D.W. Sundblad L. Granath F. Stahle M. UVB upregulates the antimicrobial protein hCAP18 mRNA in human skin.J Invest Dermatol. 2005; 125: 1072-1074Crossref PubMed Scopus (54) Google Scholar, 56Zasloff M. Fighting infections with vitamin D.Nat Med. 2006; 12: 388-390Crossref PubMed Scopus (155) Google Scholar These effects of vitamin D on the immune system make it a plausible critical regulator of immune system function, whose deficiency can predispose to asthma and allergies in the presence of other environmental stimuli. Because vitamin D deficiency also increases the risk for TH1 disorders (eg, multiple sclerosis, type 1 diabetes, inflammatory bowel disease), it serves as a unifying hypothesis to explain why the incidence of both TH1 and TH2-related disorders has risen over the same time span. We hypothesize that in the presence of vitamin D, Treg cells develop and function normally in suppressing inappropriate TH1 and TH2 responses to environmental exposure (ie, allergens, lack of infections, and so forth), leading to a more balanced immune response. On the other hand, if vitamin D is lacking, Treg cells do not develop and function normally, and in the presence of the appropriate environmental influence, TH1 or TH2 responses are allowed to proceed unabated, leading to disease. Ecologically, many of the patterns of vitamin D deficiency appear to parallel the patterns of the asthma epidemic. Countries furthest from the equator, including Australia and New Zealand, have some of the highest rates of asthma.2Masoli 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: 469-478Crossref PubMed Scopus (2580) Google Scholar Although Australia and New Zealand have high levels of sun exposure, vitamin D deficiency is a significant public health issue in those countries as well,57Munns C. Zacharin M.R. Rodda C.P. Batch J.A. Morley R. Cranswick N.E. 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: 268-272PubMed Google Scholar signifying that human behavioral patterns (ie, sunscreen use and sun avoidance behaviors) are significant determinants of vitamin D status. Genetic studies have provided early evidence of a potential role of vitamin D in asthma. Two North American family-based studies showed associations between VDR polymorphisms and asthma,58Raby B.A. Lazarus R. Silverman E.K. 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: 1057-1065Crossref PubMed Scopus (233) Google Scholar, 59Poon A.H. 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: 967-973Crossref PubMed Scopus (214) Google Scholar but other studies have not found these associations.60Vollmert 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: 1841-1850Crossref PubMed Scopus (53) Google Scholar, 61Wjst M. Variants in the vitamin D receptor gene and asthma.BMC Genet. 2005; 6: 2Crossref PubMed Scopus (66) Google Scholar Other genes in the vitamin D signaling pathway may also be important.62Wjst 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: 60Crossref PubMed Scopus (109) Google Scholar Vitamin D modulates many genes related to asthma and allergy.63Wjst M. The vitamin D slant on allergy.Pediatr Allergy Immunol. 2006; 17: 477-483Crossref PubMed Scopus (76) Google Scholar On the contrary, VDR knockout mice do not develop experimental allergic asthma,64Wittke A. Weaver V. Mahon B.D. August A. Cantorna M.T. Vitamin D receptor-deficient mice fail to develop experimental allergic asthma.J Immunol. 2004; 173: 3432-3436PubMed Google Scholar and the VDR appears to be necessary for induction of some forms of lung inflammation65Wittke A. Chang A. Froicu M. Harandi O.F. Weaver V. August A. et al.Vitamin D receptor expression by the lung micro-environment is required for maximal in" @default.
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• W1967949987 title "Is vitamin D deficiency to blame for the asthma epidemic?" @default.
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