Sage Sophie E, Leeb Tosso, Jagannathan Vidhya, Gerber Vinzenz
Department of Clinical Veterinary Medicine, Vetsuisse Faculty, Swiss Institute of Equine Medicine, University of Bern, Bern, Switzerland.
Institute of Genetics, Vetsuisse Faculty, Institute of Genetics, University of Bern, Bern, Switzerland.
Immunology. 2024 Apr;171(4):549-565. doi: 10.1111/imm.13745. Epub 2023 Dec 28.
Severe equine asthma (SEA) is a complex respiratory condition characterized by chronic airway inflammation. It shares many clinical and pathological features with human neutrophilic asthma, making it a valuable model for studying this condition. However, the immune mechanisms driving SEA have remained elusive. Although SEA has been primarily associated with a Th2 response, there have also been reports of Th1, Th17, or mixed-mediated responses. To uncover the elusive immune mechanisms driving SEA, we performed single-cell mRNA sequencing (scRNA-seq) on cryopreserved bronchoalveolar cells from 11 Warmblood horses, 5 controls and 6 with SEA. We identified six major cell types, including B cells, T cells, monocytes-macrophages, dendritic cells, neutrophils, and mast cells. All cell types exhibited significant heterogeneity, with previously identified and novel cell subtypes. Notably, we observed monocyte-lymphocyte complexes and detected a robust Th17 signature in SEA, with CXCL13 upregulation in intermediate monocytes. Asthmatic horses exhibited expansion of the B-cell population, Th17 polarization of the T-cell populations, and dysregulation of genes associated with T-cell function. Neutrophils demonstrated enhanced migratory capacity and heightened aptitude for neutrophil extracellular trap formation. These findings provide compelling evidence for a predominant Th17 immune response in neutrophilic SEA, driven by dysregulation of monocyte and T-cell genes. The dysregulated genes identified through scRNA-seq have potential as biomarkers and therapeutic targets for SEA and provide insights into human neutrophilic asthma.
严重马哮喘（SEA）是一种以慢性气道炎症为特征的复杂呼吸道疾病。它与人类嗜中性粒细胞哮喘有许多临床和病理特征，使其成为研究这种疾病的有价值模型。然而，驱动SEA的免疫机制仍然难以捉摸。尽管SEA主要与Th2反应相关，但也有关于Th1、Th17或混合介导反应的报道。为了揭示驱动SEA的难以捉摸的免疫机制，我们对来自11匹温血马（5匹对照和6匹患有SEA）的冷冻保存的支气管肺泡细胞进行了单细胞mRNA测序（scRNA-seq）。我们鉴定出六种主要细胞类型，包括B细胞、T细胞、单核细胞-巨噬细胞、树突状细胞、中性粒细胞和肥大细胞。所有细胞类型均表现出显著的异质性，既有先前已鉴定的细胞亚型，也有新的细胞亚型。值得注意的是，我们观察到单核细胞-淋巴细胞复合物，并在SEA中检测到强大的Th17特征，中间单核细胞中CXCL13上调。哮喘马表现出B细胞群体的扩增、T细胞群体的Th17极化以及与T细胞功能相关基因的失调。中性粒细胞表现出增强的迁移能力和更高的形成中性粒细胞胞外陷阱的倾向。这些发现为嗜中性粒细胞SEA中由单核细胞和T细胞基因失调驱动的主要Th17免疫反应提供了有力证据。通过scRNA-seq鉴定出的失调基因有潜力作为SEA的生物标志物和治疗靶点，并为人类嗜中性粒细胞哮喘提供了见解。
