Human β-Defensin 2 Mutations Are Associated With Asthma and Atopy in Children and Its Application Prevents Atopic Asthma in a Mouse Model.

Autor:	Borchers NS; Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO) at Hospital St. Hedwig of the Order of St. John, Regensburg, Germany., Santos-Valente E; Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO) at Hospital St. Hedwig of the Order of St. John, Regensburg, Germany., Toncheva AA; Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO) at Hospital St. Hedwig of the Order of St. John, Regensburg, Germany., Wehkamp J; Department of Internal Medicine II, University Hospital Tübingen, University of Tübingen, Tübingen, Germany., Franke A; Institute of Clinical Molecular Biology (IKMB), Kiel University, Kiel, Germany., Gaertner VD; Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO) at Hospital St. Hedwig of the Order of St. John, Regensburg, Germany.; Newborn Research Zürich, University Hospital and University of Zürich, Zürich, Switzerland., Nordkild P; Defensin Therapeutics ApS, Copenhagen, Denmark., Genuneit J; Pediatric Epidemiology, Department of Pediatrics, Medical Faculty, Leipzig University, Leipzig, Germany., Jensen BAH; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Kabesch M; Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO) at Hospital St. Hedwig of the Order of St. John, Regensburg, Germany.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2021 Feb 25; Vol. 12, pp. 636061. Date of Electronic Publication: 2021 Feb 25 (Print Publication: 2021).
DOI:	10.3389/fimmu.2021.636061
Abstrakt:	Asthma and allergies are complex, chronic inflammatory diseases in which genetic and environmental factors are crucial. Protection against asthma and allergy development in the context of farming environment is established by early animal contact, unpasteurized milk consumption and gut microbiota maturation. The human β-defensin 2 (hBD-2) is a host defense peptide present almost exclusively in epithelial tissues, with pronounced immunomodulatory properties, which has recently been shown to ameliorate asthma and IBD in animal models. We hypothesized that adequate hBD-2 secretion plays a role in the protection against asthma and allergy development and that genetic variations in the complex gene locus coding for hBD-2 may be a risk factor for developing these diseases, if as a consequence, hBD-2 is insufficiently produced. We used MALDI-TOF MS genotyping, sequencing and a RFLP assay to study the genetic variation including mutations, polymorphisms and copy number variations in the locus harboring both genes coding for hBD-2 ( DEFB4A and DEFB4B) . We administered hBD-2 orally in a mouse model of house dust mite (HDM)-asthma before allergy challenge to explore its prophylactic potential, thereby mimicking a protective farm effect. Despite the high complexity of the region harboring DEFB4A and DEFB4B we identified numerous genetic variants to be associated with asthma and allergy in the GABRIELA Ulm population of 1,238 children living in rural areas, including rare mutations, polymorphisms and a lack of the DEFB4A . Furthermore, we found that prophylactic oral administration of hBD-2 significantly curbed lung resistance and pulmonary inflammation in our HDM mouse model. These data indicate that inadequate genetic capacity for hBD-2 is associated with increased asthma and allergy risk while adequate and early hBD-2 administration (in a mouse model) prevents atopic asthma. This suggests that hBD-2 could be involved in the protective farm effect and may be an excellent candidate to confer protection against asthma development. Competing Interests: PN is employed by Defensin Therapeutics. PN and JW hold shares of Defensin Therapeutics. Defensin Therapeutics holds patents on treatment with defensins. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Borchers, Santos-Valente, Toncheva, Wehkamp, Franke, Gaertner, Nordkild, Genuneit, Jensen and Kabesch.)
Databáze:	MEDLINE
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