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Increased regulatory T-cell numbers are associated with farm milk exposure and lower atopic sensitization and asthma in childhood.
J Allergy Clin Immunol. 2014 Feb; 133(2):551-9.JA

Abstract

BACKGROUND

European cross-sectional studies have suggested that prenatal and postnatal farm exposure decreases the risk of allergic diseases in childhood. Underlying immunologic mechanisms are still not understood but might be modulated by immune-regulatory cells early in life, such as regulatory T (Treg) cells.

OBJECTIVE

We sought to assess whether Treg cells from 4.5-year-old children from the Protection against Allergy: Study in Rural Environments birth cohort study are critical in the atopy and asthma-protective effect of farm exposure and which specific exposures might be relevant.

METHODS

From 1133 children, 298 children were included in this study (149 farm and 149 reference children). Detailed questionnaires until 4 years of age assessed farming exposures over time. Treg cells were characterized as upper 20% CD4(+)CD25(+) forkhead box protein 3 (FOXP3)(+) (intracellular) in PBMCs before and after stimulation (with phorbol 12-myristate 13-acetate/ionomycin or LPS), and FOXP3 demethylation was assessed. Atopic sensitization was defined by specific IgE measurements; asthma was defined by a doctor's diagnosis.

RESULTS

Treg cells were significantly increased in farm-exposed children after phorbol 12-myristate 13-acetate/ionomycin and LPS stimulation. Exposure to farm milk was defined as a relevant independent farm-related exposure supported by higher FOXP3 demethylation. Treg cell (upper 20% CD4(+)CD25(+), FOXP3(+) T cells) numbers were significantly negatively associated with doctor-diagnosed asthma (LPS stimulated: adjusted odds ratio, 0.26; 95% CI, 0.08-0.88) and perennial IgE (unstimulated: adjusted odds ratio, 0.21; 95% CI, 0.08-0.59). Protection against asthma by farm milk exposure was partially mediated by Treg cells.

CONCLUSIONS

Farm milk exposure was associated with increased Treg cell numbers on stimulation in 4.5-year-old children and might induce a regulatory phenotype early in life, potentially contributing to a protective effect for the development of childhood allergic diseases.

Authors+Show Affiliations

LMU Munich, University Children's Hospital, Munich, Germany.LMU Munich, University Children's Hospital, Munich, Germany.University Hospital of Besançon and Plateforme de Biomonitoring, CIC-BT506, EFS Bourgogne Franche-Comté, INSERM UMR1098, University of Franche-Comté, Besançon, France.University Hospital of Besançon and Plateforme de Biomonitoring, CIC-BT506, EFS Bourgogne Franche-Comté, INSERM UMR1098, University of Franche-Comté, Besançon, France.LMU Munich, University Children's Hospital, Munich, Germany.LMU Munich, University Children's Hospital, Munich, Germany.University Children's Hospital Eastern Bavaria (KUNO), Department of Pediatric Pneumology and Allergy, University of Regensburg, Regensburg, Germany.Laboratory for Epigenetics and Environment (LEE), Centre National de Genotypage, CEA-Institut de Genomique, Evry, France.LMU Munich, University Children's Hospital, Munich, Germany; Second Hospital of JI LIN University, Department of Respiratory Medicine, Chang Chun, China.Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany.Department of Clinical Chemistry and Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany.Department of Environmental Science, University of Eastern Finland, Kuopio, Finland.LMU Munich, University Children's Hospital, Munich, Germany.Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland.Children's Hospital Schwarzach, Schwarzach, Austria.Christine Kühne-Center for Allergy Research and Education, Hochgebirgklinik Davos, Davos-Wolfgang, Switzerland.University Hospital of Besançon, Research Unit Health and Rural Environment, University of Franche-Comté, Besançon, France.University Hospital of Besançon, Research Unit Health and Rural Environment, University of Franche-Comté, Besançon, France.Department of Environmental Health, National Institute for Health and Welfare, Kuopio, Finland; Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.LMU Munich, University Children's Hospital, Munich, Germany.LMU Munich, University Children's Hospital, Munich, Germany. Electronic address: Bianca.Schaub@med.uni-muenchen.de.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23993223

Citation

Lluis, Anna, et al. "Increased Regulatory T-cell Numbers Are Associated With Farm Milk Exposure and Lower Atopic Sensitization and Asthma in Childhood." The Journal of Allergy and Clinical Immunology, vol. 133, no. 2, 2014, pp. 551-9.
Lluis A, Depner M, Gaugler B, et al. Increased regulatory T-cell numbers are associated with farm milk exposure and lower atopic sensitization and asthma in childhood. J Allergy Clin Immunol. 2014;133(2):551-9.
Lluis, A., Depner, M., Gaugler, B., Saas, P., Casaca, V. I., Raedler, D., Michel, S., Tost, J., Liu, J., Genuneit, J., Pfefferle, P., Roponen, M., Weber, J., Braun-Fahrländer, C., Riedler, J., Lauener, R., Vuitton, D. A., Dalphin, J. C., Pekkanen, J., ... Schaub, B. (2014). Increased regulatory T-cell numbers are associated with farm milk exposure and lower atopic sensitization and asthma in childhood. The Journal of Allergy and Clinical Immunology, 133(2), 551-9. https://doi.org/10.1016/j.jaci.2013.06.034
Lluis A, et al. Increased Regulatory T-cell Numbers Are Associated With Farm Milk Exposure and Lower Atopic Sensitization and Asthma in Childhood. J Allergy Clin Immunol. 2014;133(2):551-9. PubMed PMID: 23993223.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Increased regulatory T-cell numbers are associated with farm milk exposure and lower atopic sensitization and asthma in childhood. AU - Lluis,Anna, AU - Depner,Martin, AU - Gaugler,Beatrice, AU - Saas,Philippe, AU - Casaca,Vera Isabel, AU - Raedler,Diana, AU - Michel,Sven, AU - Tost,Jorg, AU - Liu,Jing, AU - Genuneit,Jon, AU - Pfefferle,Petra, AU - Roponen,Marjut, AU - Weber,Juliane, AU - Braun-Fahrländer,Charlotte, AU - Riedler,Josef, AU - Lauener,Roger, AU - Vuitton,Dominique Angèle, AU - Dalphin,Jean-Charles, AU - Pekkanen,Juha, AU - von Mutius,Erika, AU - Schaub,Bianca, AU - ,, Y1 - 2013/08/28/ PY - 2012/09/01/received PY - 2013/06/06/revised PY - 2013/06/10/accepted PY - 2013/9/3/entrez PY - 2013/9/3/pubmed PY - 2014/5/14/medline KW - ALEX KW - Allergy and Endotoxin Study KW - Asthma KW - EFRAIM KW - FITC KW - FOXP3 KW - FOXP3 demethylation KW - Fluorescein isothiocyanate KW - Forkhead box protein 3 KW - Mechanisms of Early Protective Exposures on Allergy Development KW - OR KW - Odds ratio KW - PARSIFAL KW - PASTURE KW - PE KW - PI KW - Phorbol 12-myristate 13-acetate/ionomycin KW - Phycoerythrin KW - Prevention of Allergy—Risk Factors for Sensitization In Children Related to Farming and Anthroposophic Lifestyle KW - Protection Against Allergy: Study in Rural Environments KW - Regulatory T KW - SIC KW - Specific IgE class KW - TLR KW - Toll-like receptor KW - Treg KW - atopic sensitization KW - farming KW - innate KW - milk KW - peripheral blood mononuclear cells KW - regulatory T cells SP - 551 EP - 9 JF - The Journal of allergy and clinical immunology JO - J Allergy Clin Immunol VL - 133 IS - 2 N2 - BACKGROUND: European cross-sectional studies have suggested that prenatal and postnatal farm exposure decreases the risk of allergic diseases in childhood. Underlying immunologic mechanisms are still not understood but might be modulated by immune-regulatory cells early in life, such as regulatory T (Treg) cells. OBJECTIVE: We sought to assess whether Treg cells from 4.5-year-old children from the Protection against Allergy: Study in Rural Environments birth cohort study are critical in the atopy and asthma-protective effect of farm exposure and which specific exposures might be relevant. METHODS: From 1133 children, 298 children were included in this study (149 farm and 149 reference children). Detailed questionnaires until 4 years of age assessed farming exposures over time. Treg cells were characterized as upper 20% CD4(+)CD25(+) forkhead box protein 3 (FOXP3)(+) (intracellular) in PBMCs before and after stimulation (with phorbol 12-myristate 13-acetate/ionomycin or LPS), and FOXP3 demethylation was assessed. Atopic sensitization was defined by specific IgE measurements; asthma was defined by a doctor's diagnosis. RESULTS: Treg cells were significantly increased in farm-exposed children after phorbol 12-myristate 13-acetate/ionomycin and LPS stimulation. Exposure to farm milk was defined as a relevant independent farm-related exposure supported by higher FOXP3 demethylation. Treg cell (upper 20% CD4(+)CD25(+), FOXP3(+) T cells) numbers were significantly negatively associated with doctor-diagnosed asthma (LPS stimulated: adjusted odds ratio, 0.26; 95% CI, 0.08-0.88) and perennial IgE (unstimulated: adjusted odds ratio, 0.21; 95% CI, 0.08-0.59). Protection against asthma by farm milk exposure was partially mediated by Treg cells. CONCLUSIONS: Farm milk exposure was associated with increased Treg cell numbers on stimulation in 4.5-year-old children and might induce a regulatory phenotype early in life, potentially contributing to a protective effect for the development of childhood allergic diseases. SN - 1097-6825 UR - https://www.unboundmedicine.com/medline/citation/23993223/Increased_regulatory_T_cell_numbers_are_associated_with_farm_milk_exposure_and_lower_atopic_sensitization_and_asthma_in_childhood_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0091-6749(13)01050-6 DB - PRIME DP - Unbound Medicine ER -