Influence of Vitamin D and Cotinine on T-Regulatory Cells and Asthma Severity in Children

  • Bolesław Kalicki
  • Agata WawrzyniakEmail author
  • Agnieszka Lipińska-Opałka
  • Sławomir Lewicki
  • Robert Zdanowski
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1021)


Asthma is a common chronic respiratory diseases in children. Understanding the immune mechanisms of epigenetic factors may contribute to a better control of asthma. This study seeks to determine the effects of serum vitamin D and urine cotinine on asthma severity and on T regulatory cells (Tregs) and other immune-related factors such as CD3, CD4, CD8, CD19, CD16/56, and anti-CD3 HLA-DR3. The study involved 34 children with asthma. Disease severity was assessed with the Asthma Control Test, spirometry, and the fractional exhaled nitric oxide (FeNO). The control group consisted of 18 healthy children. We found a significantly lower proportion of Tregs in the serum of asthmatic children compared with the control group (p < 0.002). There were no significant differences in the other immunological factors investigated. Nor was there any appreciable association between vitamin D or cotinine and the course of asthma, FeNO, Tregs, and the other immune factors. However, the percentage of Tregs was positively associated with the level of FeNO (p < 0.02). In conclusion, the study shows a role of T regulatory cells in the pathogenesis of asthma in children, but fails to show any influence of serum vitamin D or urine cotinine on disease course.


Asthma Cotinine Exhaled nitric oxide Immune factors Regulatory T-cells Respiratory disease Spirometry Vitamin D 


Conflicts of Interest

The authors declare no conflicts of interest in relation to this study.


  1. Barnes P (2008) Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol 8:183–192CrossRefPubMedGoogle Scholar
  2. Boulet LP, FitzGerald JM, Reddel HK (2015) The revised 2014 GINA strategy report: opportunities for change. Curr Opin Pulm Med 21(1):1–7CrossRefPubMedGoogle Scholar
  3. Brehm JM, Acosta-Pérez E, Klei L, Roeder K, Barmada M, Boutaoui N, Forno E, Kelly R, Paul K, Sylvia J, Litonjua AA, Cabana M, Alvarez M, Colon-Semidey A, Canino G, Celedon JC (2012) Vitamin D insufficiency and severe asthma exacerbations in Puerto Rican children. Am J Respir Crit Care Med 186(2):140146CrossRefGoogle Scholar
  4. Damera G, Fogle HW, Lim P, Goncharova EA, Zhao H, Banerjee A, Tliba O, Krymskaya VP, Panettieri RA (2009) Vitamin D inhibits growth of human airway smooth muscle cells through growth factor-induced phosphorylation of retinoblastoma protein and checkpoint kinase 1. J Pharmacol 158(6):1429–1441Google Scholar
  5. ECAP (2016) Epidemiology of allergic disorders in Poland.; Accessed on 29 Dec 2016
  6. Eszes N, Bohács A, Cseh A (2012) Relation of circulating T cell profiles to airway inflammation and asthma control in asthmatic pregnancy. Acta Physiol Hung 99(3):302–310CrossRefPubMedGoogle Scholar
  7. GINA (2014) From global strategy for asthma management and prevention. Updated December 2011.; Accessed on 29 Dec 2016
  8. GINA (2015) From the global strategy for asthma management and prevention, global initiative for asthma.; Accessed on 29 Dec 2016
  9. Gorman S, Judge MA, Burchell JT, Turner DJ, Hart PH (2010) 1,25-dihydroxyvitamin D3 enhances the ability of transferred CD4þ CD25þ cells to modulate T helper type-2-driven asthmatic responses. Immunology 130:181e92CrossRefGoogle Scholar
  10. Gregori S, Giarratana N, Smiroldo S, Uskokovic M, Adorini L (2002) A 1alpha, 25-dihydroxyvitamin D(3) analog enhances regulatory Tcells and arrests autoimmune diabetes in NOD mice. Diabetes 51:1367–1374CrossRefPubMedGoogle Scholar
  11. Halterman JS, Szilagyi PG, Yoos HL, Conn KM, Kaczorowski JM, Holzhauer RJ, Lauver SC, Neely TL, Callahan PM, McConnochie KM (2004) Benefits of a school-based asthma treatment program in the absence of secondhand smoke exposure: results of a randomized clinical trial. Arch Pediatr Adolesc Med 158(5):460–467CrossRefPubMedGoogle Scholar
  12. Hassanzad M, Kalilzadeh S, Nobari SE, Bloursaz M, Sharifi H, Mohajerani SA, Nejad ST, Velayati AA (2015) Cotinine level is associated with asthma severity in passive smoker children. Iran J Allergy Asthma Immunol 14(1):67–73PubMedGoogle Scholar
  13. Hunninghake GW, Crystal RG (1983) Cigarette smoking and lung destruction. Accumulation of neutrophils in the lungs of cigarette smokers. Am Rev Respir Dis 128(5):833–838PubMedGoogle Scholar
  14. Ingram JL, Kraft M (2012) IL-13 in asthma and allergic disease: asthma phenotypes and targeted therapies. J Allergy Clin Immunol 130(4):829–842CrossRefPubMedGoogle Scholar
  15. Ismail A, Aly S, Fayed H, Ahmed SS (2015) Serum 25-hydroxyvitamin D and CD4+CD25+high FoxP3+ regulatory T cell as predictors of severity of bronchial asthma in children. Egypt J Immunol 22(1):9–18PubMedGoogle Scholar
  16. Jiang Y, Du YC, Xu JY (2010) Effect of cigarette smoke exposure on the percentage of CD(4)(+)CD(25)(+) regulatory T cells and the expression of transcription factor Foxp3 in asthmatic rats. Zhonghua Jie He He Hu Xi Za Zhi 33(8):582–586PubMedGoogle Scholar
  17. Josefowicz SZ, Niec RE, Kim HY, Treuting P, Chinen T, Zheng Y, Umetsu DT, Rudensky AY (2012) Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482(7385):395–399CrossRefPubMedPubMedCentralGoogle Scholar
  18. Klein WRG, Kleinjan A, van Nimwegen M, Bergen I, de Bruijn M, Levani Y, Hendriks RW (2012) Pulmonary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma. Eur J Immunol 42(5):1106–1116CrossRefGoogle Scholar
  19. Larsson ML, Frisk M, Hallström J, Kiviloog J, Lundbäck B (2001) Environmental tobacco smoke exposure during childhood is associated with increased prevalence of asthma in adults. Chest 120(3):711–717CrossRefPubMedGoogle Scholar
  20. Lee JH, Yu HH, Wang LC, Yang YH, Lin YT, Chiang BL (2007) The levels of CD4+CD25+ regulatory T cells in paediatric patients with allergic rhinitis and bronchial asthma. Clin Exp Immunol 148:53–63CrossRefPubMedPubMedCentralGoogle Scholar
  21. Lin YL, Shieh CC, Wang JY (2008) The functional insufficiency of human CD4+CD25 high T-regulatory cells in allergic asthma is subjected to TNF-alpha modulation. Allergy 63:67–74CrossRefPubMedGoogle Scholar
  22. Mai XM, Langhammer A, Camargo CA Jr, Chen Y (2012) Serum 25-hydroxyvitamin D levels and incident asthma in adults: the HUNT study. Am J Epidemiol 176(12):1169–1176CrossRefPubMedGoogle Scholar
  23. Meehan MA, Kerman RH, Lemire JM (1992) 1,25-dihydroxyvitamin D3 enhances the generation of nonspecific suppressor cells while inhibiting the induction of cytotoxic cells in a human MLR. Cell Immunol 140:400–409CrossRefPubMedGoogle Scholar
  24. Meng JJ, Zhong XN, Bai J, He ZY, Zhang JQ, Huang QP (2012) Changes of CD(4)(+)Foxp3(+) regulatory T cells and CD(4)(+)IL-17(+)T cells in cigarette smoke-exposed rats. Zhonghua Jie He He Hu Xi Za Zhi 35(1):55–60PubMedGoogle Scholar
  25. Menon J, Maranda L, Nwosu BU (2012) Serum 25-hydroxyvitamin D levels do not correlate with asthma severity in a casecontrolled study of children and adolescents. J Pediatr Endocrinol Metab 25(7–8):673–679PubMedGoogle Scholar
  26. NAEPP (2007) Expert panel report 3: guidelines for the diagnosis and management of asthma.; Accessed on 29 Dec 2016
  27. Ohta M, Okabe T, Urabe A, Takaku F (1985) 1,25-dihydroxyvitamin D3 (calcitriol) stimulates proliferation of human circulating monocytes in vitro. FEBS Lett 185:9–13CrossRefPubMedGoogle Scholar
  28. Pellegrino R et al. (2005) Interpretative strategies for lung function tests. Series ‘ATS/ERS Task force: standardisation of lung function testing’. V. Brusasco V, Crapo R, Viegi G (Eds). Eur Respir J 26:948–968Google Scholar
  29. Ryan JW, Anderson PH, Turner AG, Morris HA (2013) Vitamin D activities and metabolic bone disease. Clin Chim Acta 425:148–152CrossRefPubMedGoogle Scholar
  30. Schick SF, van den Vossenberg G, Luo A, Whitlatch A, Jacob P 3rd, Balmes J, Shusterman D (2013) Thirty minute-exposure to aged cigarette smoke increases nasal congestion in nonsmokers. J Toxicol Environ Health A 76(10):601–613CrossRefPubMedGoogle Scholar
  31. Schwartz J, Weiss ST (1994) Cigarette smoking and peripheral blood leukocyte differentials. Ann Epidemiol 4(3):236–242CrossRefPubMedGoogle Scholar
  32. Seccareccia F, Zuccaro P, Pacifici R, Meli P, Pannozzo F, Freeman KM, Santaquilani A, Giampaoli S (2003) Serum cotinine as a marker of environmental tobacco smoke exposure in epidemiological studies: the experience of the MATISS project. Eur J Epidemiol 18(6):487–492CrossRefPubMedGoogle Scholar
  33. Shi HZ, Qin XJ (2005) CD4CD25 regulatory T lymphocytes in allergy and asthma. Allergy 60:986–995CrossRefPubMedGoogle Scholar
  34. Urry Z, Chambers ES, Xystrakis E, Dimeloe S, Richards DF, Gabryšová L, Christensen J, Gupta A, Saglani S, Bush A, O’Garra A, Brown Z, Hawrylowicz CM (2012) The role of 1α,25-dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+ and IL-10+ CD4+ T cells. Eur J Immunol 42(10):2697–2708CrossRefPubMedPubMedCentralGoogle Scholar
  35. Xue K, Zhou Y, Xiong S, Xiong W, Tang T (2007) Analysis of CD4+ CD25+ regulatory T cells and Foxp3 mRNA in the peripheral blood of patients with asthma. J Huazhong Univ Sci Technolog Med Sci 27:31–33CrossRefPubMedGoogle Scholar
  36. Xystrakis E, Kusumakar S, Boswell S, Peek E, Urry Z, Richards DF, Adikibi T, Pridgeon C, Dallman M, Loke TK, Robinson DS, Barrat FJ, O’Garra A, Lavender P, Lee TH, Corrigan C, Hawrylowicz CM (2006) Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest 116:146–155CrossRefPubMedGoogle Scholar
  37. Yang YL, Pan YQ, He BS, Zhong TY (2013) Regulatory T cells and Th1/Th2 in peripheral blood and their roles in asthmatic children. Transl Pediatr 2(1):27–33PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • Bolesław Kalicki
    • 1
  • Agata Wawrzyniak
    • 1
    Email author
  • Agnieszka Lipińska-Opałka
    • 1
  • Sławomir Lewicki
    • 2
  • Robert Zdanowski
    • 2
  1. 1.Department of Pediatrics, Nephrology and AllergologyMilitary Institute of MedicineWarsawPoland
  2. 2.Military Institute of Hygiene and EpidemiologyWarsawPoland

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