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Potential mechanisms for the hypothesized link between sunshine, vitamin D, and food allergy in children

2010; Elsevier BV; Volume: 126; Issue: 2 Linguagem: Inglês

10.1016/j.jaci.2010.06.011

ISSN

1097-6825

Autores

Milo F. Vassallo, Carlos A. Camargo,

Tópico(s)

IL-33, ST2, and ILC Pathways

Resumo

Epidemiologic data suggest that the incidence of food allergy (FA) is increasing among children, yet a satisfactory model of its pathogenesis remains elusive. FA is the consequence of maladaptive immune responses to common and otherwise innocuous food antigens. Concurrent with the increase in FA is an epidemic of vitamin D deficiency (VDD) caused by several factors, especially decreased sunlight/UVB exposure. There is growing appreciation of the importance of the pleiotropic hormone vitamin D in the development of tolerance, immune system defenses, and epithelial barrier integrity. We propose a "multiple-hit" model in which VDD in a developmentally critical period increases susceptibility to colonization with abnormal intestinal microbial flora and gastrointestinal infections, contributing to abnormal intestinal barrier permeability and excess and inappropriate exposure of the immune system to dietary allergens. A compounding effect (and additional "hit") of VDD is the promotion of a pro-sensitization immune imbalance that might compromise immunologic tolerance and contribute to FA. We propose that early correction of VDD might promote mucosal immunity, healthy microbial ecology, and allergen tolerance and thereby blunt the FA epidemic in children. Epidemiologic data suggest that the incidence of food allergy (FA) is increasing among children, yet a satisfactory model of its pathogenesis remains elusive. FA is the consequence of maladaptive immune responses to common and otherwise innocuous food antigens. Concurrent with the increase in FA is an epidemic of vitamin D deficiency (VDD) caused by several factors, especially decreased sunlight/UVB exposure. There is growing appreciation of the importance of the pleiotropic hormone vitamin D in the development of tolerance, immune system defenses, and epithelial barrier integrity. We propose a "multiple-hit" model in which VDD in a developmentally critical period increases susceptibility to colonization with abnormal intestinal microbial flora and gastrointestinal infections, contributing to abnormal intestinal barrier permeability and excess and inappropriate exposure of the immune system to dietary allergens. A compounding effect (and additional "hit") of VDD is the promotion of a pro-sensitization immune imbalance that might compromise immunologic tolerance and contribute to FA. We propose that early correction of VDD might promote mucosal immunity, healthy microbial ecology, and allergen tolerance and thereby blunt the FA epidemic in children. Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com.The global burden of IgE-mediated food allergy (FA) is increasing.1Cochrane S. Beyer K. Clausen M. Wjst M. Hiller R. Nicoletti C. et al.Factors influencing the incidence and prevalence of food allergy.Allergy. 2009; 64: 1246-1255Crossref PubMed Scopus (63) Google Scholar, 2Branum A.M. Lukacs S.L. Food allergy among children in the United States.Pediatrics. 2009; 124: 1549-1555Crossref PubMed Scopus (564) Google Scholar The significant emotional, physical, and financial burdens of FA are felt in homes, schools, and health care systems. Despite recent advances in our understanding of FA, many basic questions remain unanswered: Why is the incidence of FA increasing? Who will have FA? Why are young children at particular risk? How and why do some children outgrow FA? Moreover, effective interventions for FA are lacking. Primary prevention of FA by modifying the maternal diet during pregnancy appears ineffective.3Lack G. Epidemiologic risks for food allergy.J Allergy Clin Immunol. 2008; 121: 1331-1336Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar At present, the only recommended preventive measure, with inconsistent support, is exclusive breast-feeding until 4 to 6 months of age.3Lack G. Epidemiologic risks for food allergy.J Allergy Clin Immunol. 2008; 121: 1331-1336Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar The mainstay of secondary prevention is allergen avoidance, which can be extremely challenging. Methods to desensitize patients to food allergens are being explored, but as critical as this will be to some patients, such approaches have yet to achieve consistently safe and broadly applicable results.4Burks A.W. Laubach S. Jones S.M. Oral tolerance, food allergy, and immunotherapy: implications for future treatment.J Allergy Clin Immunol. 2008; 121: 1344-1350Abstract Full Text Full Text PDF PubMed Scopus (191) Google ScholarWe propose that deficiency of the immunomodulatory hormone vitamin D might contribute to the recent increase in FA. In this article we synthesize disparate lines of epidemiologic, clinical, and basic science research in support of this hypothesis. Our objective is to stimulate discussion and additional research on this pressing problem.Vitamin D deficiencyConcurrent with the recent increase in FA is an epidemic of vitamin D deficiency (VDD).5Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10457) Google Scholar Vitamin D is a hormone with multiple physiologic actions,5Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10457) Google Scholar the metabolites of which are stored in tissues and circulate in plasma (Table I).6Heaney R.P. Horst R.L. Cullen D.M. Armas L.A. Vitamin D3 distribution and status in the body.J Am Coll Nutr. 2009; 28: 252-256Crossref PubMed Scopus (151) Google Scholar The most abundant metabolite is a prohormone, 25-hydroxyvitamin D (25[OH]D). Levels of serum 25(OH)D are influenced most by exposure to UVB radiation in sunlight, which is necessary for synthesis of vitamin D in the skin and accounts for most vitamin D in human subjects.7Holick M.F. Vitamin D: a millennium perspective.J Cell Biochem. 2003; 88: 296-307Crossref PubMed Scopus (1034) Google Scholar Because of differences in UVB exposure, levels of 25(OH)D fluctuate with season (lowest in winter and highest in summer) and latitude (inversely with distance from the equator).7Holick M.F. Vitamin D: a millennium perspective.J Cell Biochem. 2003; 88: 296-307Crossref PubMed Scopus (1034) Google Scholar, 8Mullins R.J. Clark S. Camargo Jr., C.A. Regional variation in epinephrine autoinjector prescriptions in Australia: more evidence for the vitamin D-anaphylaxis hypothesis.Ann Allergy Asthma Immunol. 2009; 103: 488-495Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar For example, due to absorption in the atmosphere, there is insufficient UVB intensity in most of the United States (and all of Canada and Europe) for cutaneous synthesis of 25(OH)D between the months of November and March, regardless of exposure to sunlight.7Holick M.F. Vitamin D: a millennium perspective.J Cell Biochem. 2003; 88: 296-307Crossref PubMed Scopus (1034) Google Scholar The precise thresholds of serum 25(OH)D that define insufficiency and deficiency are debated, but there is an emerging consensus that these thresholds should be increased,9Hollis B.W. Nutrition: US recommendations fail to correct vitamin D deficiency.Nat Rev Endocrinol. 2009; 5: 534-536Crossref PubMed Scopus (10) Google Scholar particularly with recognition of vitamin D's many immunologic and noncalcemic effects.5Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10457) Google Scholar, 10Dimeloe 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: 86-95Crossref PubMed Scopus (112) Google Scholar, 11Ginde A.A. Mansbach J.M. Camargo Jr., C.A. Vitamin D, respiratory infections, and asthma.Curr Allergy Asthma Rep. 2009; 9: 81-87Crossref PubMed Scopus (144) Google Scholar Prevalence estimates vary, but in many industrialized countries, up to 50% of the population has insufficient vitamin D, with perhaps 10% being deficient.5Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10457) Google Scholar, 12Ginde A.A. Liu M.C. Camargo Jr., C.A. Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004.Arch Intern Med. 2009; 169: 626-632Crossref PubMed Scopus (884) Google Scholar A recent study estimated that almost 50% of US children were vitamin D insufficient and 1 in 6 were deficient.13Mansbach J.M. Ginde A.A. Camargo Jr., C.A. Serum 25-hydroxyvitamin D levels among US children aged 1 to 11 years: do children need more vitamin D?.Pediatrics. 2009; 124: 1404-1410Crossref PubMed Scopus (245) Google ScholarTable ICharacteristics of selected vitamin D metabolitesNameCharacteristicsVitamin D3 = cholecalciferolPrecursor of 25(OH)D; accounts for >90% of 25(OH)D in most human subjectsSources: synthesized by cutaneous epithelial cells on exposure to UVB; nutritional supplements; present in small amounts in some foods (eg, fish)Vitamin D2 = ergocalciferolPrecursor of 25(OH)DSources: nutritional supplements; present in small amounts in some foods (eg, mushrooms).25(OH)D = calcidiolProhormonePlasma levels exceed 1,25(OH)2D by >1,000-foldOptimally calculated as the sum of 25(OH)D3 + 25(OH)D2Useful clinically to determine sufficiency status1,25(OH)2D = calcitriolBiologically activeSynthesized from 25(OH)D prohormoneProduction tightly controlled by regulation of metabolic enzymesNot useful clinically to determine sufficiency status Open table in a new tab Lifestyle changes in the latter half of the 20th century (eg, increased time indoors) have led to decreases in exposure to sunlight, which (particularly at latitudes far from the equator) have contributed to the current VDD epidemic5Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10457) Google Scholar and the need for vitamin D supplementation. The re-emergence of VDD-related rickets in the 1990s led the American Academy of Pediatrics to recommend supplementation of infants with 200 IU/d in 2003, which they subsequently increased to 400 IU/d and extended to children and adolescents in 2008.14Weisberg P. Scanlon K.S. Li R. Cogswell M.E. Nutritional rickets among children in the United States: review of cases reported between 1986 and 2003.Am J Clin Nutr. 2004; 80: 1697S-1705SPubMed Google Scholar, 15Gartner L.M. Greer F.R. Prevention of rickets and vitamin D deficiency: new guidelines for vitamin D intake.Pediatrics. 2003; 111: 908-910Crossref PubMed Scopus (420) Google Scholar, 16Wagner C.L. Greer F.R. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents.Pediatrics. 2008; 122: 1142-1152Crossref PubMed Scopus (1177) Google Scholar Although quantitative trend data of vitamin D status are scant, in children with chronic kidney disease (a population in which 25[OH]D levels have been routinely measured), a trend of increasing VDD has been observed.17Ali F.N. Arguelles L.M. Langman C.B. Price H.E. Vitamin D deficiency in children with chronic kidney disease: uncovering an epidemic.Pediatrics. 2009; 123: 791-796Crossref PubMed Scopus (51) Google Scholar Lack of widespread recognition of the diverse functions of vitamin D until recently and the challenges of vitamin D metabolite measurement18Holick M.F. Vitamin D status: measurement, interpretation, and clinical application.Ann Epidemiol. 2009; 19: 73-78Abstract Full Text Full Text PDF PubMed Scopus (1050) Google Scholar, 19Hollis B.W. Measuring 25-hydroxyvitamin D in a clinical environment: challenges and needs.Am J Clin Nutr. 2008; 88: 507S-510SPubMed Google Scholar have contributed to the paucity of serum 25(OH)D trend data.The vitamin D–FA hypothesisIn the current article we propose a model that brings together seemingly disparate research to explain how VDD might contribute to FA (Fig 1). In brief, we hypothesize that VDD, in addition to compromising immune tolerance, increases susceptibility to infections and alters microbial ecology at the mucosal site of richest antigenic exposure, the gastrointestinal tract. Gastrointestinal infections permit excessive breach of barrier and other defenses against dietary and microbial antigens in the intestinal lumen. Once in violation of defenses, these factors might synergistically promote maladaptive allergic responses to food antigens, which manifest as FA in genetically susceptible subjects.Clinically, VDD has been linked to atopic dermatitis20Sidbury R. Sullivan A.F. Thadhani R.I. Camargo Jr., C.A. Randomized controlled trial of vitamin D supplementation for winter-related atopic dermatitis in Boston: a pilot study.Br J Dermatol. 2008; 159: 245-247Crossref PubMed Scopus (180) Google Scholar and recurrent wheeze,11Ginde A.A. Mansbach J.M. Camargo Jr., C.A. Vitamin D, respiratory infections, and asthma.Curr Allergy Asthma Rep. 2009; 9: 81-87Crossref PubMed Scopus (144) Google Scholar, 21Camargo Jr., C.A. Rifas-Shiman S.L. Litonjua A.A. Rich-Edwards J.W. Weiss S.T. Gold D.R. et al.Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age.Am J Clin Nutr. 2007; 85: 788-795PubMed Google Scholar, 22Devereux G. Litonjua A.A. Turner S.W. Craig L.C. McNeill G. Martindale S. et al.Maternal vitamin D intake during pregnancy and early childhood wheezing.Am J Clin Nutr. 2007; 85: 853-859PubMed Google Scholar which are 2 components of the "atopic march" of early childhood. Another component of this pediatric disease progression is FA, which might suggest a potential role for VDD in the pathogenesis of FA as well. In 2007, Camargo et al23Camargo Jr., C.A. Clark S. Kaplan M.S. Lieberman P. Wood R.A. Regional differences in EpiPen prescriptions in the United States: the potential role of vitamin D.J Allergy Clin Immunol. 2007; 120: 131-136Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar first implicated VDD as a potential risk factor for FA on the basis of (1) similar epidemiologic trends for UVB exposure and VDD (2) evidence of a striking north-south gradient in the prescription of epinephrine autoinjectors (a proxy for FA/anaphylaxis) in the United States. The epinephrine autoinjector finding was recently replicated and extended to hospitalizations for anaphylaxis in Australia.8Mullins R.J. Clark S. Camargo Jr., C.A. Regional variation in epinephrine autoinjector prescriptions in Australia: more evidence for the vitamin D-anaphylaxis hypothesis.Ann Allergy Asthma Immunol. 2009; 103: 488-495Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar Moreover, north-south gradients have been reported for both emergency department visits24Rudders S. Espinola J. Camargo Jr., C.A. North-south differences in US emergency department visits for acute allergic reactions.Ann Allergy Asthma Immunol. 2010; 104: 413-416Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar and hospitalizations25Sheehan W.J. Graham D. Ma L. Baxi S. Phipatanakul W. Higher incidence of pediatric anaphylaxis in northern areas of the United States.J Allergy Clin Immunol. 2009; 124: 850-852Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar for FA. Several studies have described that birth in seasons of low UVB intensity (associated with lower vitamin D levels) is more common among children reporting or given a diagnosis of FA.26Green T.D. LaBelle V.S. Steele P.H. Kim E.H. Lee L.A. Mankad V.S. et al.Clinical characteristics of peanut-allergic children: recent changes.Pediatrics. 2007; 120: 1304-1310Crossref PubMed Scopus (61) Google Scholar, 27Sicherer S.H. Furlong T.J. Munoz-Furlong A. Burks A.W. Sampson H.A. A voluntary registry for peanut and tree nut allergy: characteristics of the first 5149 registrants.J Allergy Clin Immunol. 2001; 108: 128-132Abstract Full Text PDF PubMed Scopus (317) Google Scholar, 28Vassallo M.F. Banerji A. Rudders S.A. Clark S. Mullins R.J. Camargo Jr., C.A. Season of birth is associated with food allergy in children.Ann Allergy Asthma Immunol. 2010; 104: 307-313Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar Although the precise biological mechanism for these epidemiologic associations is not yet known, we hypothesize that VDD is the common biologically plausible thread and that this hormonal deficiency contributes to FA risk.Risk factors for VDD, such as obesity and race, have been associated with food allergen sensitization. For example, the prevalence of obesity (a risk factor for VDD29Lagunova Z. Porojnicu A.C. Lindberg F. Hexeberg S. Moan J. The dependency of vitamin D status on body mass index, gender, age and season.Anticancer Res. 2009; 29: 3713-3720PubMed Google Scholar and associated with decreased bioavailability of vitamin D metabolites30Wortsman J. Matsuoka L.Y. Chen T.C. Lu Z. Holick M.F. Decreased bioavailability of vitamin D in obesity.Am J Clin Nutr. 2000; 72: 690-693Crossref PubMed Scopus (2368) Google Scholar) has increased in children and adults over the past 20 years.31Flegal K.M. Carroll M.D. Ogden C.L. Curtin L.R. Prevalence and trends in obesity among US adults, 1999-2008.JAMA. 2010; 303: 235-241Crossref PubMed Scopus (5269) Google Scholar, 32Ogden C.L. Carroll M.D. Curtin L.R. Lamb M.M. Flegal K.M. Prevalence of high body mass index in US children and adolescents, 2007-2008.JAMA. 2010; 303: 242-249Crossref PubMed Scopus (2401) Google Scholar Potentially further implicating VDD in the development of FA is the observation that obesity/overweight status in children between 2 and 5 years of age is a risk factor for food allergen sensitization relative to normal-weight peers.33Visness C.M. London S.J. Daniels J.L. Kaufman J.S. Yeatts K.B. Siega-Riz A.M. et al.Association of obesity with IgE levels and allergy symptoms in children and adolescents: results from the National Health and Nutrition Examination Survey 2005-2006.J Allergy Clin Immunol. 2009; 123: 1163-1169Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar Additionally, characteristic racial variations in VDD (attributed to the effect of skin pigment on UVB penetration essential for 25[OH]D synthesis)12Ginde A.A. Liu M.C. Camargo Jr., C.A. Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004.Arch Intern Med. 2009; 169: 626-632Crossref PubMed Scopus (884) Google Scholar, 13Mansbach J.M. Ginde A.A. Camargo Jr., C.A. Serum 25-hydroxyvitamin D levels among US children aged 1 to 11 years: do children need more vitamin D?.Pediatrics. 2009; 124: 1404-1410Crossref PubMed Scopus (245) Google Scholar, 34Ginde A.A. Sullivan A.F. Mansbach J.M. Camargo Jr., C.A. Vitamin D insufficiency in pregnant and nonpregnant women of childbearing age in the United States.Am J Obstet Gynecol. 2010; 202: e1-e8PubMed Google Scholar parallel FA and sensitization2Branum A.M. Lukacs S.L. Food allergy among children in the United States.Pediatrics. 2009; 124: 1549-1555Crossref PubMed Scopus (564) Google Scholar because the prevalences of both conditions are highest among African Americans, followed by Hispanics and then non-Hispanic whites.Vitamin D, the immune system, and toleranceBeyond a central role in calcium and bone physiology, vitamin D metabolism, specifically conversion of 25(OH)D to the active form of vitamin D (1,25[OH]2D), has effects on epithelial cell, T-cell, B-cell, and dendritic cell functions that are important to innate and adaptive immunity.5Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10457) Google Scholar, 7Holick M.F. Vitamin D: a millennium perspective.J Cell Biochem. 2003; 88: 296-307Crossref PubMed Scopus (1034) Google Scholar, 10Dimeloe 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: 86-95Crossref PubMed Scopus (112) Google Scholar, 35Hewison M. Vitamin D and the intracrinology of innate immunity.Mol Cell Endocrinol. 2010; 321: 103-111Crossref PubMed Scopus (176) Google Scholar, 36Mora 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: 685-698Crossref PubMed Scopus (1070) Google Scholar, 37Szeles L. Keresztes G. Torocsik D. Balajthy Z. Krenacs L. Poliska S. et al.1,25-dihydroxyvitamin D3 is an autonomous regulator of the transcriptional changes leading to a tolerogenic dendritic cell phenotype.J Immunol. 2009; 182: 2074-2083Crossref PubMed Scopus (175) Google Scholar VDD is characterized by inadequate precursor 25(OH)D available for conversion to 1,25[OH]2D, which contributes to multiple pathologies (eg, osteopenia and susceptibility to infections).5Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10457) Google Scholar, 11Ginde A.A. Mansbach J.M. Camargo Jr., C.A. Vitamin D, respiratory infections, and asthma.Curr Allergy Asthma Rep. 2009; 9: 81-87Crossref PubMed Scopus (144) Google Scholar The proposed contribution of VDD to the development of FA is supported by emerging data that 1,25(OH)2D (1) promotes mechanisms essential for immunologic tolerance,10Dimeloe 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: 86-95Crossref PubMed Scopus (112) Google Scholar, 35Hewison M. Vitamin D and the intracrinology of innate immunity.Mol Cell Endocrinol. 2010; 321: 103-111Crossref PubMed Scopus (176) Google Scholar (2) characteristically suppresses pro-allergic immune responses,10Dimeloe 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: 86-95Crossref PubMed Scopus (112) Google Scholar, 36Mora 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: 685-698Crossref PubMed Scopus (1070) Google Scholar, 38Adorini 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: 227-233Crossref PubMed Scopus (206) Google Scholar and (3) maintains epithelial barrier integrity.39Kong J. Zhang Z. Musch M.W. Ning G. Sun J. Hart J. et al.Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier.Am J Physiol Gastrointest Liver Physiol. 2008; 294: G208-G216Crossref PubMed Scopus (487) Google Scholar Among the vitamin D–stimulated processes that contribute to tolerance are induction of tolerogenic dendritic cells,37Szeles L. Keresztes G. Torocsik D. Balajthy Z. Krenacs L. Poliska S. et al.1,25-dihydroxyvitamin D3 is an autonomous regulator of the transcriptional changes leading to a tolerogenic dendritic cell phenotype.J Immunol. 2009; 182: 2074-2083Crossref PubMed Scopus (175) Google Scholar development of CD4+CD25+Foxp3+ regulatory T (Treg) cells,10Dimeloe 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: 86-95Crossref PubMed Scopus (112) Google Scholar activation of T-cell and antigen receptor signaling,40von Essen M.R. Kongsbak M. Schjerling P. Olgaard K. Odum N. Geisler C. Vitamin D controls T cell antigen receptor signaling and activation of human T cells.Nat Immunol. 2010; 11: 344-349Crossref PubMed Scopus (406) Google Scholar and elaboration of tolerizing and anti-inflammatory cytokines, including IL-10.10Dimeloe 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: 86-95Crossref PubMed Scopus (112) Google Scholar, 36Mora 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: 685-698Crossref PubMed Scopus (1070) Google Scholar, 38Adorini 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: 227-233Crossref PubMed Scopus (206) Google Scholar Gene expression profiles of dendritic cells have identified many 1,25(OH)2D-regulated transcripts central to dendritic cell function.37Szeles L. Keresztes G. Torocsik D. Balajthy Z. Krenacs L. Poliska S. et al.1,25-dihydroxyvitamin D3 is an autonomous regulator of the transcriptional changes leading to a tolerogenic dendritic cell phenotype.J Immunol. 2009; 182: 2074-2083Crossref PubMed Scopus (175) Google Scholar The observation that 1,25(OH)2D-treated human dendritic cells have the capacity to convert CD4 T cells into IL-10–secreting Treg cells and suppress the proliferation of T cells41Unger W.W. Laban S. Kleijwegt F.S. van der Slik A.R. Roep B.O. Induction of Treg by monocyte-derived DC modulated by vitamin D3 or dexamethasone: differential role for PD-L1.Eur J Immunol. 2009; 39: 3147-3159Crossref PubMed Scopus (322) Google Scholar is particularly provocative in light of the clinical importance of CD4+CD25+Foxp3+ Treg cells in the development of tolerance to food allergens.42Shreffler W.G. Wanich N. Moloney M. Nowak-Wegrzyn A. Sampson H.A. Association of allergen-specific regulatory T cells with the onset of clinical tolerance to milk protein.J Allergy Clin Immunol. 2009; 123 (e7): 43-52Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar Moreover, experiments with human B cells have demonstrated that 1,25(OH)2D can directly suppress IgE production and stimulate IL-10 production.43Heine G. Niesner U. Chang H.D. Steinmeyer A. Zugel U. Zuberbier T. et al.1,25-dihydroxyvitamin D(3) promotes IL-10 production in human B cells.Eur J Immunol. 2008; 38: 2210-2218Crossref PubMed Scopus (246) Google Scholar Rochat et al44Rochat M.K. Ege M.J. Plabst D. Steinle J. Bitter S. Braun-Fahrlander C. et al.Maternal vitamin D intake during pregnancy increases gene expression of ILT3 and ILT4 in cord blood.Clin Exp Allergy. 2009; 40: 786-794Crossref PubMed Scopus (44) Google Scholar have recently linked vitamin D status during pregnancy with mechanisms of tolerance by observing that maternal intake of vitamin D was associated with expression of tolerogenic genes in cord blood.Vitamin D, microbes, and barrier functionVitamin D metabolites contribute to defenses at epithelial surfaces by stimulating production of antimicrobial peptides, such as defensins45Wang T.T. Dabbas B. Laperriere D. Bitton A.J. Soualhine H. Tavera-Mendoza L.E. et al.Direct and indirect induction by 1,25-dihydroxyvitamin D3 of the NOD2/CARD15-defensin beta2 innate immune pathway defective in Crohn disease.J Biol Chem. 2010; 285: 2227-2231Crossref PubMed Scopus (301) Google Scholar and cathelicidin.5Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10457) Google Scholar, 36Mora 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: 685-698Crossref PubMed Scopus (1070) Google Scholar 1,25(OH)2D influences integration of host-microbe signaling pathways by modulating expression of the microbial pattern-recognition molecules, such as NOD2,45Wang T.T. Dabbas B. Laperriere D. Bitton A.J. Soualhine H. Tavera-Mendoza L.E. et al.Direct and indirect induction by 1,25-dihydroxyvitamin D3 of the NOD2/CARD15-defensin beta2 innate immune pathway defective in Crohn disease.J Biol Chem. 2010; 285: 2227-2231Crossref PubMed Scopus (301) Google Scholar CD14, and Toll-like receptor 2.46Schauber 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 (558) Google Scholar VDD appears to predispose to a wide variety of infections, including tuberculosis and respiratory tract viruses.11Ginde A.A. Mansbach J.M. Camargo Jr., C.A. Vitamin D, respiratory infections, and asthma.Curr Allergy Asthma Rep. 2009; 9: 81-87Crossref PubMed Scopus (144) Google Scholar We speculate that VDD might similarly predispose to more frequent infections, more severe infections, or both caused by common gastrointestinal pathogens. In addition, VDD (through altered production of antimicrobial peptides) and intestinal infections might promote persistent abnormal microbial ecology or "dysbiosis."47Frank D.N. Pace N.R. Gastrointestinal microbiology enters the metagenomics era.Curr Opin Gastroenterol. 2008; 24: 4-10Crossref PubMed Scopus (312) Google Scholar Support for this proposal has recently been observed in a murine model in which VDD predisposed to colitis through dysregulated colonic antimicrobial activity and impaired homeostasis of enteric bacteria.48Lagishetty V. Misharin A.V. Liu N.Q. Lisse T.S. Chun R.F. Ouyang Y. et al.Vitamin D deficiency in mice impairs colonic antibacterial activity and predisposes to colitis.Endocrinology. 2010; 151: 2423-2432Crossref PubMed Scopus (186) Google ScholarRecent data illustrate potential mechanisms by which VDD might directly compromise barrier function in addition to increasing susceptibility to infections. Experimentally, 1,25(OH)2D has been shown to have protective roles in maintenance of mucosal barrier function (regulation of tight junction proteins, including ZO-1, claudin 1, claudin 2, and E-cadherin) and response to mucosal damage.39Kong J. Zhang Z. Musch M.W. Ning G. Sun J. Hart J. et al.Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier.Am J Physiol Gastrointest Liver Physiol. 2008; 294: G208-G216Crossref PubMed Scopus (487) Google Scholar Additionally, Schauber et al46S

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