Anna Lluis1, Martin Depner1, Beatrice Gaugler2, Philippe Saas2, Vera Isabel Casaca1, Diana Raedler1, Sven Michel3, Jorg Tost4, Jing Liu5, Jon Genuneit6, Petra Pfefferle7, Marjut Roponen8, Juliane Weber1, Charlotte Braun-Fahrländer9, Josef Riedler10, Roger Lauener11, Dominique Angèle Vuitton12, Jean-Charles Dalphin12, Juha Pekkanen13, Erika von Mutius1, Bianca Schaub14. 1. LMU Munich, University Children's Hospital, Munich, Germany. 2. University Hospital of Besançon and Plateforme de Biomonitoring, CIC-BT506, EFS Bourgogne Franche-Comté, INSERM UMR1098, University of Franche-Comté, Besançon, France. 3. University Children's Hospital Eastern Bavaria (KUNO), Department of Pediatric Pneumology and Allergy, University of Regensburg, Regensburg, Germany. 4. Laboratory for Epigenetics and Environment (LEE), Centre National de Genotypage, CEA-Institut de Genomique, Evry, France. 5. LMU Munich, University Children's Hospital, Munich, Germany; Second Hospital of JI LIN University, Department of Respiratory Medicine, Chang Chun, China. 6. Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany. 7. Department of Clinical Chemistry and Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany. 8. Department of Environmental Science, University of Eastern Finland, Kuopio, Finland. 9. Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland. 10. Children's Hospital Schwarzach, Schwarzach, Austria. 11. Christine Kühne-Center for Allergy Research and Education, Hochgebirgklinik Davos, Davos-Wolfgang, Switzerland. 12. University Hospital of Besançon, Research Unit Health and Rural Environment, University of Franche-Comté, Besançon, France. 13. Department of Environmental Health, National Institute for Health and Welfare, Kuopio, Finland; Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland. 14. LMU Munich, University Children's Hospital, Munich, Germany. Electronic address: Bianca.Schaub@med.uni-muenchen.de.
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.
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.
Keywords:
ALEX; Allergy and Endotoxin Study; Asthma; EFRAIM; FITC; FOXP3; FOXP3 demethylation; Fluorescein isothiocyanate; Forkhead box protein 3; Mechanisms of Early Protective Exposures on Allergy Development; OR; Odds ratio; PARSIFAL; PASTURE; PE; PI; Phorbol 12-myristate 13-acetate/ionomycin; Phycoerythrin; Prevention of Allergy—Risk Factors for Sensitization In Children Related to Farming and Anthroposophic Lifestyle; Protection Against Allergy: Study in Rural Environments; Regulatory T; SIC; Specific IgE class; TLR; Toll-like receptor; Treg; atopic sensitization; farming; innate; milk; peripheral blood mononuclear cells; regulatory T cells
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