Human β-Defensin 2 Mutations Are Associated With Asthma and Atopy in Children and Its Application Prevents Atopic Asthma in a Mouse Model.
Human β-Defensin 2 Mutations Are Associated With Asthma and Atopy in Children and Its Application Prevents Atopic Asthma in a Mouse Model.
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人类β-防御素2突变与儿童哮喘和特应性哮喘相关及其在小鼠模型中的应用预防特应性哮喘。
DOI：
10.3389/fimmu.2021.636061
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发表时间：
2021
影响因子：
7.3
通讯作者：
Kabesch M
中科院分区：
文献类型：
--
作者：
Borchers NS;Santos-Valente E;Toncheva AA;Wehkamp J;Franke A;Gaertner VD;Nordkild P;Genuneit J;Jensen BAH;Kabesch M
哮喘和过敏是复杂的慢性炎症性疾病，其中遗传和环境因素至关重要。在农业环境背景下，通过早期动物接触、未经巴氏消毒的牛奶消费和肠道微生物群成熟来预防哮喘和过敏发展。人β-防御素2（human β-defensin 2，hBD-2）是一种几乎只存在于上皮组织中的宿主防御肽，具有显著的免疫调节特性，最近在动物模型中显示其可改善哮喘和IBD。我们假设，足够的hBD-2分泌发挥了作用，在保护免受哮喘和过敏的发展，在复杂的基因位点编码的hBD-2的遗传变异可能是发展这些疾病的危险因素，如果作为一个结果，hBD-2是不充分的生产。我们使用MALDI-TOF MS基因分型，测序和RFLP分析，以研究遗传变异，包括突变，多态性和拷贝数的变化，在基因座窝藏两个基因编码的hBD-2（DEFB 4A和DEFB 4 B）。在过敏激发前，我们在屋尘螨（HDM）-哮喘小鼠模型中口服hBD-2，以探索其预防潜力，从而模拟保护性农场效应。尽管携带DEFB 4A和DEFB 4 B的区域高度复杂，但我们在GABRIELA乌尔姆农村地区的1，238名儿童中发现了许多与哮喘和过敏相关的遗传变异，包括罕见的突变，多态性和缺乏DEFB 4A。此外，我们发现预防性口服hBD-2显著抑制了我们的HDM小鼠模型中的肺阻力和肺部炎症。这些数据表明，hBD-2的遗传能力不足与哮喘和过敏风险增加有关，而适当和早期的hBD-2给药（在小鼠模型中）可预防特应性哮喘。这表明hBD-2可能参与了保护性农场效应，可能是一个很好的候选人，以提供保护，防止哮喘的发展。
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.
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影响因子：
9.8
作者：
Fellermann, Klaus;Stange, Daniel E.;Stange, Eduard F.
通讯作者：
Stange, Eduard F.
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1016/j.jcf.2003.12.008
发表时间：
2004-03-01
期刊：
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
影响因子：
--
作者：
Chen, Christiane I-U;Schaller-Bals, Susanne;Bals, Robert
通讯作者：
Bals, Robert
影响因子：
2.1
作者：
Hua X;Yuan X;Tang X;Li Z;Pflugfelder SC;Li DQ
通讯作者：
Li DQ
影响因子：
7.3
作者：
Koeninger, Louis;Armbruster, Nicole S.;Wehkamp, Jan
通讯作者：
Wehkamp, Jan