Human β-Defensin 2 Mutations Are Associated With Asthma and Atopy in Children and Its Application Prevents Atopic Asthma in a Mouse Model
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 ma...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-02-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.636061/full |
| _version_ | 1818944538894401536 |
|---|---|
| author | Natascha S. Borchers Elisangela Santos-Valente Antoaneta A. Toncheva Jan Wehkamp Andre Franke Vincent D. Gaertner Vincent D. Gaertner Peter Nordkild Jon Genuneit Benjamin A. H. Jensen Michael Kabesch |
| author_facet | Natascha S. Borchers Elisangela Santos-Valente Antoaneta A. Toncheva Jan Wehkamp Andre Franke Vincent D. Gaertner Vincent D. Gaertner Peter Nordkild Jon Genuneit Benjamin A. H. Jensen Michael Kabesch |
| author_sort | Natascha S. Borchers |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T07:44:49Z |
| format | Article |
| id | doaj.art-ca341c6fe14e480a99d58a2818523d74 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T07:44:49Z |
| publishDate | 2021-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-ca341c6fe14e480a99d58a2818523d742022-12-21T19:48:01ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-02-011210.3389/fimmu.2021.636061636061Human β-Defensin 2 Mutations Are Associated With Asthma and Atopy in Children and Its Application Prevents Atopic Asthma in a Mouse ModelNatascha S. Borchers0Elisangela Santos-Valente1Antoaneta A. Toncheva2Jan Wehkamp3Andre Franke4Vincent D. Gaertner5Vincent D. Gaertner6Peter Nordkild7Jon Genuneit8Benjamin A. H. Jensen9Michael Kabesch10Department of Pediatric Pneumology and Allergy, University Children’s Hospital Regensburg (KUNO) at Hospital St. Hedwig of the Order of St. John, Regensburg, GermanyDepartment of Pediatric Pneumology and Allergy, University Children’s Hospital Regensburg (KUNO) at Hospital St. Hedwig of the Order of St. John, Regensburg, GermanyDepartment of Pediatric Pneumology and Allergy, University Children’s Hospital Regensburg (KUNO) at Hospital St. Hedwig of the Order of St. John, Regensburg, GermanyDepartment of Internal Medicine II, University Hospital Tübingen, University of Tübingen, Tübingen, GermanyInstitute of Clinical Molecular Biology (IKMB), Kiel University, Kiel, GermanyDepartment of Pediatric Pneumology and Allergy, University Children’s Hospital Regensburg (KUNO) at Hospital St. Hedwig of the Order of St. John, Regensburg, GermanyNewborn Research Zürich, University Hospital and University of Zürich, Zürich, SwitzerlandDefensin Therapeutics ApS, Copenhagen, DenmarkPediatric Epidemiology, Department of Pediatrics, Medical Faculty, Leipzig University, Leipzig, GermanyNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkDepartment of Pediatric Pneumology and Allergy, University Children’s Hospital Regensburg (KUNO) at Hospital St. Hedwig of the Order of St. John, Regensburg, GermanyAsthma 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.https://www.frontiersin.org/articles/10.3389/fimmu.2021.636061/fullhBD-2asthmaatopypreventiondefensin |
| spellingShingle | Natascha S. Borchers Elisangela Santos-Valente Antoaneta A. Toncheva Jan Wehkamp Andre Franke Vincent D. Gaertner Vincent D. Gaertner Peter Nordkild Jon Genuneit Benjamin A. H. Jensen Michael Kabesch Human β-Defensin 2 Mutations Are Associated With Asthma and Atopy in Children and Its Application Prevents Atopic Asthma in a Mouse Model Frontiers in Immunology hBD-2 asthma atopy prevention defensin |
| title | Human β-Defensin 2 Mutations Are Associated With Asthma and Atopy in Children and Its Application Prevents Atopic Asthma in a Mouse Model |
| title_full | Human β-Defensin 2 Mutations Are Associated With Asthma and Atopy in Children and Its Application Prevents Atopic Asthma in a Mouse Model |
| title_fullStr | Human β-Defensin 2 Mutations Are Associated With Asthma and Atopy in Children and Its Application Prevents Atopic Asthma in a Mouse Model |
| title_full_unstemmed | Human β-Defensin 2 Mutations Are Associated With Asthma and Atopy in Children and Its Application Prevents Atopic Asthma in a Mouse Model |
| title_short | Human β-Defensin 2 Mutations Are Associated With Asthma and Atopy in Children and Its Application Prevents Atopic Asthma in a Mouse Model |
| title_sort | human β defensin 2 mutations are associated with asthma and atopy in children and its application prevents atopic asthma in a mouse model |
| topic | hBD-2 asthma atopy prevention defensin |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.636061/full |
| work_keys_str_mv | AT nataschasborchers humanbdefensin2mutationsareassociatedwithasthmaandatopyinchildrenanditsapplicationpreventsatopicasthmainamousemodel AT elisangelasantosvalente humanbdefensin2mutationsareassociatedwithasthmaandatopyinchildrenanditsapplicationpreventsatopicasthmainamousemodel AT antoanetaatoncheva humanbdefensin2mutationsareassociatedwithasthmaandatopyinchildrenanditsapplicationpreventsatopicasthmainamousemodel AT janwehkamp humanbdefensin2mutationsareassociatedwithasthmaandatopyinchildrenanditsapplicationpreventsatopicasthmainamousemodel AT andrefranke humanbdefensin2mutationsareassociatedwithasthmaandatopyinchildrenanditsapplicationpreventsatopicasthmainamousemodel AT vincentdgaertner humanbdefensin2mutationsareassociatedwithasthmaandatopyinchildrenanditsapplicationpreventsatopicasthmainamousemodel AT vincentdgaertner humanbdefensin2mutationsareassociatedwithasthmaandatopyinchildrenanditsapplicationpreventsatopicasthmainamousemodel AT peternordkild humanbdefensin2mutationsareassociatedwithasthmaandatopyinchildrenanditsapplicationpreventsatopicasthmainamousemodel AT jongenuneit humanbdefensin2mutationsareassociatedwithasthmaandatopyinchildrenanditsapplicationpreventsatopicasthmainamousemodel AT benjaminahjensen humanbdefensin2mutationsareassociatedwithasthmaandatopyinchildrenanditsapplicationpreventsatopicasthmainamousemodel AT michaelkabesch humanbdefensin2mutationsareassociatedwithasthmaandatopyinchildrenanditsapplicationpreventsatopicasthmainamousemodel |