Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Respir Res. 2023 Jun 9;24(1):153. doi: 10.1186/s12931-023-02453-y.
Among asthmatics, there is significant heterogeneity in the clinical presentation and underlying pathophysiological mechanisms, leading to the recognition of multiple disease endotypes (e.g., T2-high vs. T2-low). This heterogeneity extends to severe asthmatics, who may struggle to control symptoms even with high-dose corticosteroid treatment and other therapies. However, there are limited mouse models available to model the spectrum of severe asthma endotypes. We sought to identify a new mouse model of severe asthma by first examining responses to chronic allergen exposure among strains from the Collaborative Cross (CC) mouse genetics reference population, which contains greater genetic diversity than other inbred strain panels previously used for models of asthma. Mice from five CC strains and the often-used classical inbred strain BALB/cJ were chronically exposed to house dust mite (HDM) allergen for five weeks followed by measurements of airway inflammation. CC strain CC011/UncJ (CC011) exhibited extreme responses to HDM including high levels of airway eosinophilia, elevated lung resistance, and extensive airway wall remodeling, and even fatalities among ~ 50% of mice prior to study completion. Compared to BALB/cJ mice, CC011 mice had stronger Th2-mediated airway responses demonstrated by significantly elevated total and HDM-specific IgE and increased Th2 cytokines during tests of antigen recall, but not enhanced ILC2 activation. Airway eosinophilia in CC011 mice was completely dependent upon CD4 T-cells. Notably, we also found that airway eosinophilia in CC011 mice was resistant to dexamethasone steroid treatment. Thus, the CC011 strain provides a new mouse model of T2-high, severe asthma driven by natural genetic variation likely acting through CD4 T-cells. Future studies aimed at determining the genetic basis of this phenotype will provide new insights into mechanisms underlying severe asthma.
在哮喘患者中，临床表型和潜在病理生理机制存在显著异质性，导致多种疾病表型(endotype)的识别，例如 T2 高与 T2 低。这种异质性也存在于严重哮喘患者中，即使接受高剂量皮质类固醇治疗和其他疗法，他们也可能难以控制症状。然而，目前可用的用于模拟严重哮喘表型谱的小鼠模型有限。我们首先研究了来自于合作交叉（CC）小鼠遗传学参考群体的不同品系对慢性过敏原暴露的反应，以寻找一种新的严重哮喘小鼠模型。该群体比以前用于哮喘模型的其他近交系面板具有更高的遗传多样性。来自五个 CC 品系和常用的经典近交系 BALB/cJ 的小鼠接受为期五周的屋尘螨（HDM）过敏原慢性暴露，然后测量气道炎症。CC011/UncJ（CC011）品系对 HDM 表现出极端的反应，包括气道嗜酸性粒细胞增多、肺阻力升高和广泛的气道壁重塑，甚至在研究完成前有 50%左右的小鼠死亡。与 BALB/cJ 小鼠相比，CC011 小鼠在抗原再刺激试验中表现出更强的 Th2 介导的气道反应，表现为总 IgE 和 HDM 特异性 IgE 显著升高以及 Th2 细胞因子增加，但 ILC2 激活没有增强。CC011 小鼠的气道嗜酸性粒细胞增多完全依赖于 CD4 T 细胞。值得注意的是，我们还发现 CC011 小鼠的气道嗜酸性粒细胞增多对地塞米松类固醇治疗有抗性。因此，CC011 品系提供了一种新的 T2 高、严重哮喘小鼠模型，其由自然遗传变异驱动，可能通过 CD4 T 细胞发挥作用。未来旨在确定这种表型遗传基础的研究将为严重哮喘的机制提供新的见解。
