Increased regulatory T-cell numbers are associated with farm milk exposure and lower atopic sensitization and asthma in childhood - 30/01/14

Doi : 10.1016/j.jaci.2013.06.034

Anna Lluis, PhD ^a,^{^{∗
These authors contributed equally to this work.}}, Martin Depner, PhD ^a,^{^{∗
These authors contributed equally to this work.}}, Beatrice Gaugler, PhD ^b, Philippe Saas, PhD ^b, Vera Isabel Casaca, MSc ^a, Diana Raedler ^a, Sven Michel, MSc ^c, Jorg Tost, PhD ^d, Jing Liu, MD ^a,^e, Jon Genuneit, MD ^f, Petra Pfefferle, PhD ^g, Marjut Roponen, PhD ^h, Juliane Weber, MD ^a, Charlotte Braun-Fahrländer, MD ^i,^j, Josef Riedler, MD ^k, Roger Lauener, MD ^l, Dominique Angèle Vuitton, PhD ^m, Jean-Charles Dalphin, MD, PhD ^m, Juha Pekkanen, MD ^n,^o, Erika von Mutius, MD, MSc ^a, Bianca Schaub, MD ^a,^⁎
and the
Protection Against Allergy: Study in Rural Environments Study Group
A. Hyvärinen ⁿ, A. Karvonen ⁿ, M.R. Hirvonen ⁿ, P. Tiittanen ⁿ, S. Remes ⁿ, V. Kaulek ^b, M.L. Dalphin ^b, M. Ege M ^a, G. Büchele ^f, S. Bitter ^i,^j, G. Loss ^i,^j, C. Roduit ^l, R. Frei ^l, H. Renz ^g, M. Kabesch ^c, G. Doekes ^p
^a LMU Munich, University Children's Hospital, Munich, Germany
^b University Hospital of Besançon and Plateforme de Biomonitoring, CIC-BT506, EFS Bourgogne Franche-Comté, INSERM UMR1098, University of Franche-Comté, Besançon, France
^c University Children's Hospital Eastern Bavaria (KUNO), Department of Pediatric Pneumology and Allergy, University of Regensburg, Regensburg, Germany
^f Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany
^g Department of Clinical Chemistry and Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany
ⁱ Swiss Tropical and Public Health Institute, Basel, Switzerland
^j University of Basel, Basel, Switzerland
^l Christine Kühne-Center for Allergy Research and Education, Hochgebirgklinik Davos, Davos-Wolfgang, Switzerland
ⁿ Department of Environmental Health, National Institute for Health and Welfare, Kuopio, Finland
^p Institute for Risk Assessment Sciences (IRAS), Division of Environmental Epidemiology, Utrecht University, Utrecht, The Netherlands

^a LMU Munich, University Children's Hospital, Munich, Germany
^b University Hospital of Besançon and Plateforme de Biomonitoring, CIC-BT506, EFS Bourgogne Franche-Comté, INSERM UMR1098, University of Franche-Comté, Besançon, France
^c University Children's Hospital Eastern Bavaria (KUNO), Department of Pediatric Pneumology and Allergy, University of Regensburg, Regensburg, Germany
^d Laboratory for Epigenetics and Environment (LEE), Centre National de Genotypage, CEA-Institut de Genomique, Evry, France
^e Second Hospital of JI LIN University, Department of Respiratory Medicine, Chang Chun, China
^f Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany
^g Department of Clinical Chemistry and Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany
^h Department of Environmental Science, University of Eastern Finland, Kuopio, Finland
ⁱ Swiss Tropical and Public Health Institute, Basel, Switzerland
^j University of Basel, Basel, Switzerland
^k Children's Hospital Schwarzach, Schwarzach, Austria
^l Christine Kühne-Center for Allergy Research and Education, Hochgebirgklinik Davos, Davos-Wolfgang, Switzerland
^m University Hospital of Besançon, Research Unit Health and Rural Environment, University of Franche-Comté, Besançon, France
ⁿ Department of Environmental Health, National Institute for Health and Welfare, Kuopio, Finland
^o Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland

^∗Corresponding author: Bianca Schaub, MD, LMU Munich, University Children's Hospital, Lindwurmstrasse 4, D 80337, Munich, Germany.

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.

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Key words : Asthma, atopic sensitization, farming, FOXP3 demethylation, innate, milk, peripheral blood mononuclear cells, regulatory T cells

Abbreviations used : ALEX, EFRAIM, FITC, FOXP3, OR, PARSIFAL, PASTURE, PE, PI, SIC, TLR, Treg

Plan

Supported by EFRAIM EU FP7- KBBE-2007-1, the Bavarian Research Association (to J.L.), SFB TR22 (to B.S. and A.L.), a Marie Curie Grant (MEST-CT-2005-020524-GALTRAIN; to A.L.), and the Comprehensive Pneumology Centre (to B.S.).

Disclosure of potential conflict of interest: M. Depner has received research support from the European Research Council. J. Tost has received conference fees paid by Roche. M. Roponen has received research support from the European Union and the Academy of Finland. J. Weber has received research support from the European Commission. R. Lauener has received research support from the Kühne Foundation and European Union. D. A. Vuitton has received consulting fees from the URGO Foundation, France. J. Pekkanen has received research support from the European Union, Academy of Finland, and the Ministry of Social Affairs and Health. E. von Mutius has received consultancy fees from GlaxoSmithKline, ProtectImmun, Novartis, Astellas Pharma, Europe Ltd, and ALK-Abelló; has received lecture fees from InfectoPharma and Nestlé Research; has received research support from the European Commission; and has provided legal consultation/expert witness testimony for the UK Research Excellence Framework. B. Schaub has received research support from the DFG and the European Union. M. Ege has received grants from the European Commission and Deutsch Forschungsgemeinschaft and is an inventor for a patent regarding a pharmaceutical composition for protection from allergies and inflammatory disorders. M. Kabesch has received grants from the European Union, the German Ministry of Education and Research, and the German Research Foundation and has received payment for lectures from the European Respiratory Society, the European Academy of Allergology and Clinical Immunology, the American Thoracic Society, Novartis, and GlaxoSmithKline. G. Doekes has received research support from the European Commission and the Netherlands Asthma Fund. The rest of the authors declare that they have no relevant conflicts of interest.

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Vol 133 - N° 2

P. 551 - février 2014 Retour au numéro

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Increased regulatory T-cell numbers are associated with farm milk exposure and lower atopic sensitization and asthma in childhood - 30/01/14

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