The vitamin D connection to pediatric infections and immune function

Valencia P Walker, Robert L Modlin, Valencia P Walker, Robert L Modlin

Abstract

Over the past 20 y, a resurgence in vitamin D deficiency and nutritional rickets has been reported throughout the world, including the United States. Inadequate serum vitamin D concentrations have also been associated with complications from other health problems, including tuberculosis, cancer (prostate, breast, and colon), multiple sclerosis, and diabetes. These findings support the concept of vitamin D possessing important pleiotropic actions outside of calcium homeostasis and bone metabolism. In children, an association of nutritional rickets with respiratory compromise has long been recognized. Recent epidemiologic studies clearly demonstrate the link between vitamin D deficiency and the increased incidence of respiratory infections. Further research has also elucidated the contribution of vitamin D in the host defense response to infection. However, the mechanism(s) by which vitamin D levels contribute to pediatric infections and immune function has yet to be determined. This knowledge is particularly relevant and timely, because infants and children seem more susceptible to viral rather than bacterial infections in the face of vitamin D deficiency. The connection among vitamin D, infections, and immune function in the pediatric population indicates a possible role for vitamin D supplementation in potential interventions and adjuvant therapies.

Figures

Figure 1
Figure 1
Model of the vitamin D pathway in a macrophage.

References

    1. White JH. Vitamin D signaling, infectious diseases, and regulation of innate immunity. Infect Immun. 2008;76:3837–3843.
    1. Sichert-Hellert W, Wenz G, Kersting M. Vitamin intakes from supplements and fortified food in German children and adolescents: results from the DONALD study. J Nutr. 2006;136:1329–1333.
    1. Lehmann B, Knuschke P, Meurer M. A novel pathway for hormonally active calcitriol. Horm Res. 2000;54:312–315.
    1. Diaz L, Sanchez I, Avila E, Halhali A, Vilchis F, Larrea F. Identification of a 25-hydroxyvitamin D3 1alpha-hydroxylase gene transcription product in cultures of human syncytiotrophoblast cells. J Clin Endocrinol Metab. 2000;85:2543–2549.
    1. Mawer EB, Hayes ME, Still PE, Davies M, Lumb GA, Palit J, Holt PJ. Evidence for nonrenal synthesis of 1,25-dihydroxyvitamin D in patients with inflammatory arthritis. J Bone Miner Res. 1991;6:733–739.
    1. Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stewart PM, Hewison M. Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab. 2001;86:888–894.
    1. Lin R, White JH. The pleiotropic actions of vitamin D. Bioessays. 2004;26:21–28.
    1. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999;69:842–856.
    1. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–281.
    1. Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics. 2008;122:398–417.
    1. 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.
    1. Ziegler EE, Hollis BW, Nelson SE, Jeter JM. Vitamin D deficiency in breastfed infants in Iowa. Pediatrics. 2006;118:603–610.
    1. Rajakumar K, Fernstrom JD, Janosky JE, Greenspan SL. Vitamin D insufficiency in preadolescent African-American children. Clin Pediatr (Phila) 2005;44:683–692.
    1. Sullivan SS, Rosen CJ, Halteman WA, Chen TC, Holick MF. Adolescent girls in Maine are at risk for vitamin D insufficiency. J Am Diet Assoc. 2005;105:971–974.
    1. Gordon CM, DePeter KC, Feldman HA, Grace E, Emans SJ. Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med. 2004;158:531–537.
    1. Looker AC, Dawson-Hughes B, Calvo MS, Gunter EW, Sahyoun NR. Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III. Bone. 2002;30:771–777.
    1. Lawson M, Thomas M. Vitamin D concentrations in Asian children aged 2 years living in England: population survey. BMJ. 1999;318:28.
    1. Nicolaidou P, Hatzistamatiou Z, Papadopoulou A, Kaleyias J, Floropoulou E, Lagona E, Tsagris V, Costalos C, Antsaklis A. Low vitamin D status in mother-newborn pairs in Greece. Calcif Tissue Int. 2006;78:337–342.
    1. Fuleihan G El-Hajj, Nabulsi M, Choucair M, Salamoun M, Shahine C Hajj, Kizirian A, Tannous R. Hypovitaminosis D in healthy schoolchildren. Pediatrics. 2001;107:E53.
    1. Du X, Greenfield H, Fraser DR, Ge K, Trube A, Wang Y. Vitamin D deficiency and associated factors in adolescent girls in Beijing. Am J Clin Nutr. 2001;74:494–500.
    1. Lehtonen-Veromaa M, Mottonen T, Irjala K, Karkkainen M, Lamberg-Allardt C, Hakola P, Viikari J. Vitamin D intake is low and hypovitaminosis D common in healthy 9- to 15-year-old Finnish girls. Eur J Clin Nutr. 1999;53:746–751.
    1. Ward LM, Gaboury I, Ladhani M, Zlotkin S. Vitamin D-deficiency rickets among children in Canada. CMAJ. 2007;177:161–166.
    1. Huh SY, Gordon CM. Vitamin D deficiency in children and adolescents: epidemiology, impact and treatment. Rev Endocr Metab Disord. 2008;9:161–170.
    1. Zipitis CS, Markides GA, Swann IL. Vitamin D deficiency: prevention or treatment? Arch Dis Child. 2006;91:1011–1014.
    1. Bener A, Alsaied A, Al-Ali M, Al-Kubaisi A, Basha B, Abraham A, Guiter G, Mian M. High prevalence of vitamin D deficiency in type 1 diabetes mellitus and healthy children. Acta Diabetol. 2008 (in press)
    1. Zittermann A, Dembinski J, Stehle P. Low vitamin D status is associated with low cord blood levels of the immunosuppressive cytokine interleukin-10. Pediatr Allergy Immunol. 2004;15:242–246.
    1. Davies PD, Brown RC, Woodhead JS. Serum concentrations of vitamin D metabolites in untreated tuberculosis. Thorax. 1985;40:187–190.
    1. Wilkinson RJ, Llewelyn M, Toossi Z, Patel P, Pasvol G, Lalvani A, Wright D, Latif M, Davidson RN. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet. 2000;355:618–621.
    1. Bryce J, Boschi-Pinto C, Shibuya K, Black RE. WHO estimates of the causes of death in children. Lancet. 2005;365:1147–1152.
    1. Williams B, Williams AJ, Anderson ST. Vitamin D deficiency and insufficiency in children with tuberculosis. Pediatr Infect Dis J. 2008;27:941–942.
    1. Muhe L, Lulseged S, Mason KE, Simoes EA. Case-control study of the role of nutritional rickets in the risk of developing pneumonia in Ethiopian children. Lancet. 1997;349:1801–1804.
    1. Najada AS, Habashneh MS, Khader M. The frequency of nutritional rickets among hospitalized infants and its relation to respiratory diseases. J Trop Pediatr. 2004;50:364–368.
    1. Wayse V, Yousafzai A, Mogale K, Filteau S. Association of subclinical vitamin D deficiency with severe acute lower respiratory infection in Indian children under 5 y. Eur J Clin Nutr. 2004;58:563–567.
    1. Karatekin G, Kaya A, Salihoglu O, Balci H, Nuhoglu A. Association of subclinical vitamin D deficiency in newborns with acute lower respiratory infection and their mothers. Eur J Clin Nutr. 2007 (in press)
    1. Green D, Carson K, Leonard A, Davis JE, Rosenstein B, Zeitlin P, Mogayzel P., Jr Current treatment recommendations for correcting vitamin D deficiency in pediatric patients with cystic fibrosis are inadequate. J Pediatr. 2008;153:554–559.
    1. Yim S, Dhawan P, Ragunath C, Christakos S, Diamond G. Induction of cathelicidin in normal and CF bronchial epithelial cells by 1,25-dihydroxyvitamin D(3) J Cyst Fibros. 2007;6:403–410.
    1. Villamor E. A potential role for vitamin D on HIV infection? Nutr Rev. 2006;64:226–233.
    1. Janssen R, Bont L, Siezen CL, Hodemaekers HM, Ermers MJ, Doornbos G, van ’t Slot R, Wijmenga C, Goeman JJ, Kimpen JL, van Houwelingen HC, Kimman TG, Hoebee B. Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes. J Infect Dis. 2007;196:826–834.
    1. Roth DE, Jones AB, Prosser C, Robinson JL, Vohra S. Vitamin D status is not associated with the risk of hospitalization for acute bronchiolitis in early childhood. Eur J Clin Nutr. 2007 (in press)
    1. Roth DE, Jones AB, Prosser C, Robinson JL, Vohra S. Vitamin D receptor polymorphisms and the risk of acute lower respiratory tract infection in early childhood. J Infect Dis. 2008;197:676–680.
    1. Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, Garland CF, Giovannucci E. Epidemic influenza and vitamin D. Epidemiol Infect. 2006;134:1129–1140.
    1. Pelletier AJ, Mansbach JM, Camargo CA., Jr Direct medical costs of bronchiolitis hospitalizations in the United States. Pediatrics. 2006;118:2418–2423.
    1. Devereux G, Litonjua AA, Turner SW, Craig LC, McNeill G, Martindale S, Helms PJ, Seaton A, Weiss ST. Maternal vitamin D intake during pregnancy and early childhood wheezing. Am J Clin Nutr. 2007;85:853–859.
    1. Camargo CA, Jr, Rifas-Shiman SL, Litonjua AA, Rich-Edwards JW, Weiss ST, Gold DR, Kleinman K, Gillman MW. Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age. Am J Clin Nutr. 2007;85:788–795.
    1. Arkkola T, Uusitalo U, Kronberg-Kippila C, Mannisto S, Virtanen M, Kenward MG, Veijola R, Knip M, Ovaskainen ML, Virtanen SM. Seven distinct dietary patterns identified among pregnant Finnish women--associations with nutrient intake and sociodemographic factors. Public Health Nutr. 2008;11:176–182.
    1. Fronczak CM, Baron AE, Chase HP, Ross C, Brady HL, Hoffman M, Eisenbarth GS, Rewers M, Norris JM. In utero dietary exposures and risk of islet autoimmunity in children. Diabetes Care. 2003;26:3237–3242.
    1. Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet. 2001;358:1500–1503.
    1. Brekke HK, Ludvigsson J. Vitamin D supplementation and diabetes-related autoimmunity in the ABIS study. Pediatr Diabetes. 2007;8:11–14.
    1. Willer CJ, Dyment DA, Sadovnick AD, Rothwell PM, Murray TJ, Ebers GC, Canadian Collaborative Study Group Timing of birth and risk of multiple sclerosis: population based study. BMJ. 2005;330:120.
    1. Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296:2832–2838.
    1. Adams JS, Gacad MA, Singer FR, Sharma OP. Production of 1,25-dihydroxyvitamin D3 by pulmonary alveolar macrophages from patients with sarcoidosis. Ann N Y Acad Sci. 1986;465:587–594.
    1. Adams JS, Singer FR, Gacad MA, Sharma OP, Hayes MJ, Vouros P, Holick MF. Isolation and structural identification of 1,25-dihydroxyvitamin D3 produced by cultured alveolar macrophages in sarcoidosis. J Clin Endocrinol Metab. 1985;60:960–966.
    1. Adams JS, Gacad MA. Characterization of 1 alpha-hydroxylation of vitamin D3 sterols by cultured alveolar macrophages from patients with sarcoidosis. J Exp Med. 1985;161:755–765.
    1. Barnes PF, Modlin RL, Bikle DD, Adams JS. Transpleural gradient of 1,25-dihydroxyvitamin D in tuberculous pleuritis. J Clin Invest. 1989;83:1527–1532.
    1. Fagan DL, Prehn JL, Adams JS, Jordan SC. The human myelomonocytic cell line U-937 as a model for studying alterations in steroid-induced monokine gene expression: marked enhancement of lipopolysaccharide-stimulated interleukin-1 beta messenger RNA levels by 1,25-dihydroxyvitamin D3. Mol Endocrinol. 1991;5:179–186.
    1. Hewison M, Dabrowski M, Faulkner L, Hughson E, Vadher S, Rut A, Brickell PM, O’Riordan JL, Katz DR. Transfection of vitamin D receptor cDNA into the monoblastoid cell line U937. The role of vitamin D3 in homotypic macrophage adhesion. J Immunol. 1994;153:5709–5719.
    1. Hewison M, Dabrowski M, Vadher S, Faulkner L, Cockerill FJ, Brickell PM, O’Riordan JL, Katz DR. Antisense inhibition of vitamin D receptor expression induces apoptosis in monoblastoid U937 cells. J Immunol. 1996;156:4391–4400.
    1. Hewison M, Freeman L, Hughes SV, Evans KN, Bland R, Eliopoulos AG, Kilby MD, Moss PA, Chakraverty R. Differential regulation of vitamin D receptor and its ligand in human monocyte-derived dendritic cells. J Immunol. 2003;170:5382–5390.
    1. Jordan SC, Lemire JM, Sakai RS, Toyoda M, Adams JS. Exogenous interleukin-2 does not reverse the immunoinhibitory effects of 1,25-dihydroxyvitamin D3 on human peripheral blood lymphocyte immunoglobulin production. Mol Immunol. 1990;27:95–100.
    1. Lemire JM, Adams JS, Kermani-Arab V, Bakke AC, Sakai R, Jordan SC. 1,25-Dihydroxyvitamin D3 suppresses human T helper/inducer lymphocyte activity in vitro. J Immunol. 1985;134:3032–3035.
    1. Lemire JM, Adams JS, Sakai R, Jordan SC. 1 alpha,25-dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J Clin Invest. 1984;74:657–661.
    1. Prehn JL, Fagan DL, Jordan SC, Adams JS. Potentiation of lipopolysaccharide-induced tumor necrosis factor-alpha expression by 1,25-dihydroxyvitamin D3. Blood. 1992;80:2811–2816.
    1. D’Ambrosio D, Cippitelli M, Cocciolo MG, Mazzeo D, Di LP, Lang R, Sinigaglia F, Panina-Bordignon P. Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. J Clin Invest. 1998;101:252–262.
    1. Piemonti L, Monti P, Sironi M, Fraticelli P, Leone BE, Dal Cin E, Allavena P, Di Carlo V. Vitamin D3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells. J Immunol. 2000;164:4443–4451.
    1. Yang S, Smith C, Prahl JM, Luo X, DeLuca HF. Vitamin D deficiency suppresses cell-mediated immunity in vivo. Arch Biochem Biophys. 1993;303:98–106.
    1. Lathers DM, Clark JI, Achille NJ, Young MR. Phase 1B study to improve immune responses in head and neck cancer patients using escalating doses of 25-hydroxyvitamin D3. Cancer Immunol Immunother. 2004;53:422–430.
    1. Krutzik SR, Tan B, Li H, Ochoa MT, Liu PT, Sharfstein SE, Graeber TG, Sieling PA, Liu YJ, Rea TH, Bloom BR, Modlin RL. TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells. Nat Med. 2005;11:653–660.
    1. Rook GA, Steele J, Fraher L, Barker S, Karmali R, O’Riordan J, Stanford J. Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology. 1986;57:159–163.
    1. Crowle AJ, Ross EJ, May MH. Inhibition by 1,25(OH)2-vitamin D3 of the multiplication of virulent tubercle bacilli in cultured human macrophages. Infect Immun. 1987;55:2945–2950.
    1. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zugel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311:1770–1773.
    1. Dowling GB. The present status of vitamin D2 in the treatment of lupus vulgaris. Dermatologica. 1957;115:491–495.
    1. Morcos MM, Gabr AA, Samuel S, Kamel M, el Baz M, el Beshry M, Michail RR. Vitamin D administration to tuberculous children and its value. Boll Chim Farm. 1998;137:157–164.
    1. Nursyam EW, Amin Z, Rumende CM. The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion. Acta Med Indones. 2006;38:3–5.
    1. Wagner CL, Greer FR. Prevention of rickets and vitamin d deficiency in infants, children, and adolescents. Pediatrics. 2008;122:1142–1152.
    1. Hollis BW, Pittard WB., 3rd Evaluation of the total fetomaternal vitamin D relationships at term: evidence for racial differences. J Clin Endocrinol Metab. 1984;59:652–657.
    1. Canadian Paediatric Society Vitamin D supplementation: Recommendations for Canadian mothers and infants. Paediatr Child Health. 2007;12:583–598.
    1. Kovacs CS. Vitamin D in pregnancy and lactation: maternal, fetal, and neonatal outcomes from human and animal studies. Am J Clin Nutr. 2008;88:520S–528S.

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