Abstract
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.
Highlights
Exposure to a diversity of microbes is crucial for the development and maturation of the human immune system [1,2,3]
Polymorphisms and Copy Number Variants in the Human b-defensin 2 (hBD-2) Region Are Associated With Asthma and Atopy in Children
The genes DEFB4A and DEFB4B, both coding for hBD-2, are located on chromosome 8 in close vicinity to five other b-defensins (DEFB103, DEFB104, DEFB105, DEFB106, DEFB107), all of which are aligned in a peculiar, mirror-like cluster with their respective gene copies (Figure 1A)
Summary
Exposure to a diversity of microbes is crucial for the development and maturation of the human immune system [1,2,3]. Contact of microorganisms with human surfaces induce epithelial barrier defense mechanisms and the release of host defense peptides (HDPs), such as b-defensins [14,15,16] These are capable of eliminating a broad range of microorganisms and fine-tune the elicited immune response in multiple diseases, including IBD, cystic fibrosis, and rhinovirus infections [17,18,19]. Genetic and/or environmental disturbances in the secretory capacity of functional HDPs may facilitate bacterial translocation [20] and simultaneously disrupt microbial homeostasis [21], collectively fueling systemic inflammation Both aberrant inflammation and early airway colonization with microbial pathogens may predispose for childhood asthma [22]. HBD-2 has recently been shown to ameliorate asthma and IBD in animal models [17,18,19,20,21,22,23,24,25,26,27]
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