Cord blood Tregs with stable FOXP3 expression are influenced by prenatal environment and associated with atopic dermatitis at the age of one year
D. Hinz
Department of Environmental Immunology, UFZ – Helmholtz Centre for Environmental Research Leipzig, Leipzig, Germany
Universitätsklinikum, Klinik für Dermatologie, Venerologie und Allergologie, Leipzig, Germany
Search for more papers by this authorM. Bauer
Department of Environmental Immunology, UFZ – Helmholtz Centre for Environmental Research Leipzig, Leipzig, Germany
Search for more papers by this authorS. Röder
Core Facility Studies, UFZ – Helmholtz Centre for Environmental Research Leipzig, Leipzig, Germany
Search for more papers by this authorJ. Huehn
Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
Search for more papers by this authorU. Sack
Institute for Clinical Immunology, University of Leipzig, Leipzig, Germany
Search for more papers by this authorM. Borte
Children's Hospital, Municipal Hospital “St. Georg”, Academic Teaching Hospital of the University of Leipzig, Leipzig, Germany
Search for more papers by this authorJ. C. Simon
Universitätsklinikum, Klinik für Dermatologie, Venerologie und Allergologie, Leipzig, Germany
Search for more papers by this authorCorresponding Author
I. Lehmann
Department of Environmental Immunology, UFZ – Helmholtz Centre for Environmental Research Leipzig, Leipzig, Germany
Correspondence
Dr. Irina Lehmann, Department of Environmental Immunology, UFZ – Helmholtz Centre for Environmental Research, Permoserstrasse 15, 04318 Leipzig, Germany.
Tel.: ++49 341 235 1216
Fax: ++49 341 235 1787
E-mail: [email protected]
Search for more papers by this authorG. Herberth
Department of Environmental Immunology, UFZ – Helmholtz Centre for Environmental Research Leipzig, Leipzig, Germany
Search for more papers by this authorfor the LINA study group
Search for more papers by this authorD. Hinz
Department of Environmental Immunology, UFZ – Helmholtz Centre for Environmental Research Leipzig, Leipzig, Germany
Universitätsklinikum, Klinik für Dermatologie, Venerologie und Allergologie, Leipzig, Germany
Search for more papers by this authorM. Bauer
Department of Environmental Immunology, UFZ – Helmholtz Centre for Environmental Research Leipzig, Leipzig, Germany
Search for more papers by this authorS. Röder
Core Facility Studies, UFZ – Helmholtz Centre for Environmental Research Leipzig, Leipzig, Germany
Search for more papers by this authorJ. Huehn
Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
Search for more papers by this authorU. Sack
Institute for Clinical Immunology, University of Leipzig, Leipzig, Germany
Search for more papers by this authorM. Borte
Children's Hospital, Municipal Hospital “St. Georg”, Academic Teaching Hospital of the University of Leipzig, Leipzig, Germany
Search for more papers by this authorJ. C. Simon
Universitätsklinikum, Klinik für Dermatologie, Venerologie und Allergologie, Leipzig, Germany
Search for more papers by this authorCorresponding Author
I. Lehmann
Department of Environmental Immunology, UFZ – Helmholtz Centre for Environmental Research Leipzig, Leipzig, Germany
Correspondence
Dr. Irina Lehmann, Department of Environmental Immunology, UFZ – Helmholtz Centre for Environmental Research, Permoserstrasse 15, 04318 Leipzig, Germany.
Tel.: ++49 341 235 1216
Fax: ++49 341 235 1787
E-mail: [email protected]
Search for more papers by this authorG. Herberth
Department of Environmental Immunology, UFZ – Helmholtz Centre for Environmental Research Leipzig, Leipzig, Germany
Search for more papers by this authorfor the LINA study group
Search for more papers by this authorEdited by: Hans-Uwe Simon
Abstract
Background:
Regulatory T cells (Tregs) with stable FOXP3 expression are characterized by a specific demethylated region in the FOXP3 gene (Treg-specific demethylated region, TSDR). The aim of this study was to analyse the influence of prenatal factors on cord blood Treg numbers, as detected by changes in the TSDR demethylation, and the subsequent risk for allergic diseases.
Methods:
Analyses were performed within the LINA study in blood samples from pregnant women (34th gestational week) and in cord blood (n = 346 mother–child pairs). Treg numbers were detected via DNA demethylation in the FOXP3 TSDR. At age 1, total and specific IgE was measured in children's blood. In addition, maternal cytokine production (Th1/Th2/Th17) was analysed. Exposure and disease outcomes were assessed by questionnaires.
Results:
Boys had lower Treg numbers compared with girls (P < 0.001). Parental atopy history, particularly maternal hay fever and paternal asthma were related to lower Treg numbers in cord blood (adj. MR = 0.81, 95% CI = 0.68–0.97; adj. MR = 0.60, 95% CI = 0.45–0.81). Maternal cytokines (IL-13, IL-17E and IFN-γ) and maternal smoking/exposure to tobacco smoke during pregnancy were also associated with decreased cord blood Treg numbers (adj. MR = 0.89, 95% CI = 0.97–1.00). Children with lower Treg numbers at birth had a higher risk to develop atopic dermatitis (adj. OR = 1.55, 95% CI = 1.00–2.41) and sensitization to food allergens (adj. OR = 1.55, 95% CI = 1.06–2.25) during the first year of life.
Conclusions:
These results indicate that both genetic and environmental factors presumably influence the development of foetal Tregs. Low cord blood Treg numbers may predict early atopic dermatitis.
Supporting Information
| Filename | Description |
|---|---|
| all2767-sup-0001-figs1.docxWord document, 34.5 KB | Figure S1. Flow chart of the LINA study population with the analysed subcohort. |
| all2767-sup-0002-figs2.docxWord document, 138.4 KB | Figure S2. Regression model with all factors possibly influencing cord blood Treg numbers. |
| all2767-sup-0003-tables1.docxWord document, 17.2 KB | Table S1. Relationship between parental history of atopy and Treg numbers in cord blood as detected by demethylation of TSDR in the FOXP3 gene. |
| all2767-sup-0004-tables2.docxWord document, 16.1 KB | Table S2. Relationship between maternal prenatal exposure and Treg numbers in cord blood as detected by demethylation of TSDR in the FOXP3 gene. |
| all2767-sup-0005-tables3.docxWord document, 16.5 KB | Table S3. Relationship between PHA-/LPS-stimulated cytokine production in maternal blood during pregnancy and number of Tregs in cord blood as detected by demethylation of TSDR in the FOXP3 gene. |
| all2767-sup-0006-tables4.docxWord document, 15.3 KB | Table S4. Cytokine production during pregnancy in PHA-/LPS-stimulated blood samples. Values are presented as medians and the interquartile range. |
| all2767-sup-0007-tables5.docxWord document, 16.5 KB | Table S5. Relationship between Treg numbers in cord blood as detected by demethylation of TSDR in the FOXP3 gene and the development of allergy as well as sensitisation to food or inhalant specific allergens in the first year of life. |
| all2767-sup-0008-tables6.docxWord document, 19.2 KB | Table S6. (a) Association between maternal history of atopy and PHA induced maternal cytokine production in pregnancy. Cytokine concentrations are presented as medians and interquartile range (IQR). (b) Association between maternal history of atopy and PHA induced maternal cytokine production in pregnancy. Cytokine concentrations are presented as medians and interquartile range (IQR). |
| all2767-sup-0009-tables7.docxWord document, 20.7 KB | Table S7. (a) Association between exposures during pregnancy and maternal cytokine production upon PHA-stimulation. Cytokine concentrations are presented as medians and interquartile range (IQR). (b) Association between exposures during pregnancy and maternal cytokine production upon PHA-stimulation. Cytokine concentrations are presented as medians and interquartile range (IQR). (c) Association between exposures during pregnancy and maternal cytokine production upon PHA-stimulation. Cytokine concentrations are presented as medians and interquartile range (IQR). |
| all2767-sup-0010-Suppl_Material.docWord document, 415.5 KB | Appendix S1. Methods and Results. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Jones CA, Kilburn SA, Warner JA, Warner JO. Intrauterine environment and fetal allergic sensitization. Clin Exp Allergy 1998; 28: 655–659.
- 2Prescott SL. Early immune development: the role of intrauterine influences. Early Hum Dev 2007; 83: S41–S41.
- 3Martino D, Prescott S. Epigenetics and prenatal influences on asthma and allergic airways disease. Chest 2011; 139: 640–647.
- 4Palomares O, Yaman G, Azkur AK, Akkoc T, Akdis M, Akdis CA. Role of Treg in immune regulation of allergic diseases. Eur J Immunol 2010; 40: 1232–1240.
- 5Haddeland U, Karstensen AB, Farkas L, Bo KO, Pirhonen J, Karlsson M et al. Putative regulatory T cells are impaired in cord blood from neonates with hereditary allergy risk. Pediatr Allergy Immunol 2005; 16: 104–112.
- 6Schaub B, Liu J, Hoppler S, Haug S, Sattler C, Lluis A et al. Impairment of T-regulatory cells in cord blood of atopic mothers. J Allergy Clin Immunol 2008; 121: 1491–1499, 1499 e1–e13.
- 7Rindsjo E, Joerink M, Johansson C, Bremme K, Malmstrom V, Scheynius A. Maternal allergic disease does not affect the phenotype of T and B cells or the immune response to allergens in neonates. Allergy 2010; 65: 822–830.
- 8Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 2005; 22: 329–341.
- 9Walker MR, Kasprowicz DJ, Gersuk VH, Benard A, Van Landeghen M, Buckner JH et al. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25− T cells. J Clin Invest 2003; 112: 1437–1443.
- 10Wang J, Ioan-Facsinay A, van der Voort EI, Huizinga TW, Toes RE. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol 2007; 37: 129–138.
- 11Pillai V, Ortega SB, Wang CK, Karandikar NJ. Transient regulatory T-cells: a state attained by all activated human T-cells. Clin Immunol 2007; 123: 18–29.
- 12Baron U, Floess S, Wieczorek G, Baumann K, Grutzkau A, Dong J et al. DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells. Eur J Immunol 2007; 37: 2378–2389.
- 13Huehn J, Polansky JK, Hamann A. Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage? Nat Rev Immunol 2009; 9: 83–89.
- 14Toker A, Huehn J. To be or not to be a T-reg cell: lineage decisions controlled by epigenetic mechanisms. Sci Signal 2011; 4: pe4.
- 15Wieczorek G, Asemissen A, Model F, Turbachova I, Floess S, Liebenberg V et al. Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue. Cancer Res 2009; 69: 599–608.
- 16Liu J, Lluis A, Illi S, Layland L, Olek S, von Mutius E et al. T regulatory cells in cord blood-FOXP3 demethylation as reliable quantitative marker. PLoS ONE 2010; 5: e13267.
- 17Hinz D, Simon JC, Maier-Simon C, Milkova L, Roder S, Sack U et al. Reduced maternal regulatory T cell numbers and increased T helper type 2 cytokine production are associated with elevated levels of immunoglobulin E in cord blood. Clin Exp Allergy 2010; 40: 419–426.
- 18Liappis N, Schlebusch H, Niesen M. [Reference values for IgE concentration in serum of children. Method: ImmunoCAP-FEIA system]. Monatsschr Kinderheilkd 1992; 140: 300–302.
- 19Perneger TV. What's wrong with Bonferroni adjustments. BMJ 1998; 316: 1236–1238.
- 20Reece P, Thanendran A, Crawford L, Tulic MK, Thabane L, Prescott SL et al. Maternal allergy modulates cord blood hematopoietic progenitor Toll-like receptor expression and function. J Allergy Clin Immunol 2011; 127: 447–453.
- 21Schaub B, Liu J, Hoppler S, Schleich I, Huehn J, Olek S et al. Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells. J Allergy Clin Immunol 2009; 123: 774–782 e5.
- 22Schaub B, Campo M, He HZ, Perkins D, Gillman MW, Gold DR et al. Neonatal immune responses to TLR2 stimulation: influence of maternal atopy on Foxp3 and IL-10 expression. Respir Res 2006; 7: 40.
- 23Osman M. Therapeutic implications of sex differences in asthma and atopy. Arch Dis Child 2003; 88: 587–590.
- 24Uekert SJ, Akan G, Evans MD, Li Z, Roberg K, Tisler C et al. Sex-related differences in immune development and the expression of atopy in early childhood. J Allergy Clin Immunol 2006; 118: 1375–1381.
- 25Chen W, Mempel M, Schober W, Behrendt H, Ring J. Gender difference, sex hormones, and immediate type hypersensitivity reactions. Allergy 2008; 63: 1418–1427.
- 26Kopp MV, Zehle C, Pichler J, Szepfalusi Z, Moseler M, Deichmann K et al. Allergen-specific T cell reactivity in cord blood: the influence of maternal cytokine production. Clin Exp Allergy 2001; 31: 1536–1543.
- 27Herberth G, Hinz D, Roder S, Schlink U, Sack U, Diez U et al. Maternal immune status in pregnancy is related to offspring's immune responses and atopy risk. Allergy 2011; 66: 1065–1074.
- 28Wei J, Duramad O, Perng OA, Reiner SL, Liu YJ, Qin FX. Antagonistic nature of T helper 1/2 developmental programs in opposing peripheral induction of Foxp3+ regulatory T cells. Proc Natl Acad Sci USA 2007; 104: 18169–18174.
- 29Noakes PS, Holt PG, Prescott SL. Maternal smoking in pregnancy alters neonatal cytokine responses. Allergy 2003; 58: 1053–1058.
- 30Noakes PS, Hale J, Thomas R, Lane C, Devadason SG, Prescott SL. Maternal smoking is associated with impaired neonatal toll-like-receptor-mediated immune responses. Eur Respir J 2006; 28: 721–729.
- 31Breton CV, Byun HM, Wenten M, Pan F, Yang A, Gilliland FD. Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation. Am J Respir Crit Care Med 2009; 180: 462–467.
- 32Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25(high) regulatory cells in human peripheral blood. J Immunol 2001; 167: 1245–1253.
- 33Smith M, Tourigny MR, Noakes P, Catherine A, Tulic MK, Prescott SL. Children with egg allergy have evidence of reduced neonatal CD4(+)CD25(+)CD127(lo/−) regulatory T cell function. J Allergy Clin Immunol 2008; 121: 1460–1466.
Citing Literature
