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J Allergy Clin Immunol. 2019 Aug 2. pii: S0091-6749(19)30978-9. doi: 10.1016/j.jaci.2019.07.029. [Epub ahead of print]

TNFAIP3 is a key player in childhood asthma development and environment-mediated protection.

Author information

1
Pediatric Allergology, Department of Pediatrics, Dr. von Hauner Children´s Hospital, University Hospital, LMU Munich; Member of German Center for Lung Research - DZL, LMU Munich, Germany.
2
Pediatric Allergology, Department of Pediatrics, Dr. von Hauner Children´s Hospital, University Hospital, LMU Munich.
3
Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, China.
4
Institute of Pathology, Medical Faculty, LMU Munich, Munich, Germany; German Cancer Consortium (DKTK), partner site Munich, Munich, Germany.
5
Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.
6
Children's Hospital Schwarzach, Schwarzach, Austria, Teaching Hospital of Paracelsus Medical Private University Salzburg.
7
University Hospital of Besançon, UMR CNRS 6249 Chrono-Environnement, University of Franche-Comté, Besançon, France.
8
Department of Health Security, National Institute for Health and Welfare (THL), P.O. Box 95 FIN-70701 Kuopio, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland.
9
Christine Kühne Center for Allergy Research and Education (CK-CARE), Davos, Switzerland; Childrens Hospital of Eastern Switzerland, St. Gallen, Switzerland.
10
Department of Environmental and Biological Sciences, University of Eastern Finland, P.O. Box 1627, Kuopio, Finland.
11
Guangzhou Institute of Respiratory Health, The first Affiliated Hospital of Guangzhou Medical University, Department of Allergy and Clinical Immunology, Guangzhou, China.
12
Department of Chemical Pathology, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China.
13
Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong. Electronic address: Bianca.Schaub@med.uni-muenchen.de.
14
Pediatric Allergology, Department of Pediatrics, Dr. von Hauner Children´s Hospital, University Hospital, LMU Munich; Member of German Center for Lung Research - DZL, LMU Munich, Germany. Electronic address: Bianca.Schaub@med.uni-muenchen.de.
15
University of California, San Diego, School of Medicine, Department of Pediatrics, 9500 Gilman Drive, La Jolla, CA 92093-0831,U.S.A.
16
Department of Clinical Chemistry and Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany.
17
Member of German Center for Lung Research - DZL, LMU Munich, Germany; Comprehensive Biomaterial Bank Marburg CBBM, Fachbereich Medizin der Philipps Universität Marburg, Zentrum für Tumor und Immunbiologie ZTI, Hans-Meerweinstr. 3, D-35043 Marburg, Germany.
18
KUNO Childrens University Hospital Regensburg, Department of Pediatric Pneumology and Allergy Campus St. Hedwig, Steinmetzstr. 1-3, D-93049 Regensburg, Germany.
19
Ulm University, Institute of Epidemiology and Medical Biometry, Helmholtzstr. 22, D-89081 Ulm, Germany.
20
Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland.
21
Swiss Tropical and Public Health Institute, Socinstr. 57, P.O. Box, CH-4002 Basel, Switzerland; University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland.
22
Department of Public Health, University of Helsinki, Helsinki, Finland; Children's Hospital, University of Zürich, Zürich, Switzerland.
23
University Hospital of Besançon, UMR CNRS 6249 Chrono-Environnement, University of Franche-Comté, Besançon, France; Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
24
University of Besanҫ;on, Department of Pediatrics, University Hospital, 25030 Besanҫon, France.
25
Utrecht University, Institute for Risk Assessment Sciences (IRAS), Division of Environmental Epidemiology, PO Box 80178, 3508TD, Utrecht, NL.

Abstract

BACKGROUND:

Childhood asthma prevalence is significantly higher in urban areas compared to rural/farm environments. Murine studies have shown that TNFAIP3 (TNF-α-induced protein 3, A20), an anti-inflammatory regulator of NF-κB signaling, mediates environmental-induced asthma protection.

OBJECTIVE:

We aimed to determine the role of TNFAIP3 for asthma development in childhood and immune modulatory effects of environmental factors.

METHODS:

In a representative selection of 250 out of 2,168 children from two prospective birth cohort and two cross-sectional studies, we analyzed blood cells of healthy and asthmatic children from urban and rural/farm environments from Europe and China. PBMCs were stimulated ex vivo with dust from "asthma-protective" farms or LPS. NF-κB signaling-related gene and protein expression was assessed in PBMCs and multiplex gene expression assays (NanoString) in isolated dendritic cells of school-children and in CBMCs from newborns.

RESULTS:

Anti-inflammatory TNFAIP3 gene and protein expression was consistently decreased while pro-inflammatory TLR4 expression was increased in urban asthmatics (p<0.05), reflecting their elevated inflammatory status. Ex vivo farm dust or LPS-stimulation restored TNFAIP3 expression to healthy levels in asthmatics and shifted NF-κB signaling associated gene expression towards an anti-inflammatory state (p<0.001). Farm/rural children showed lower expression indicating tolerance induction by continuous environmental exposure. Newborns with asthma at school-age showed reduced TNFAIP3 expression at birth, suggesting TNFAIP3 as a possible biomarker predicting subsequent asthma.

CONCLUSION:

Our data indicate TNFAIP3 as key regulator during childhood asthma development and its environment-mediated protection. Since environmental dust exposure conferred anti-inflammatory effects, it may represent a promising future agent for asthma prevention and treatment.

KEYWORDS:

A20; LPS; TNFAIP3; asthma; childhood; environment; farming; immune development; inflammatory; protection

PMID:
31381928
DOI:
10.1016/j.jaci.2019.07.029

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