Abstract
Recurrent airway obstruction (RAO) is a common and potentially debilitating lower airway disease in horses, which shares many similarities with human asthma. In susceptible horses RAO exacerbation is caused by environmental allergens and irritants present in hay dust. The objective of this study was the identification of genes and pathways involved in the pathology of RAO by global transcriptome analyses in stimulated peripheral blood mononuclear cells (PBMCs). We performed RNA-seq on PBMCs derived from 40 RAO affected and 45 control horses belonging to three cohorts of Warmblood horses: two half-sib families and one group of unrelated horses. PBMCs were stimulated with hay dust extract, lipopolysaccharides, a recombinant parasite antigen, or left unstimulated. The total dataset consisted of 561 individual samples. We detected significant differences in the expression profiles between RAO and control horses. Differential expression (DE) was most marked upon stimulation with hay dust extract. An important novel finding was a strong upregulation of CXCL13 together with many genes involved in cell cycle regulation in stimulated samples from RAO affected horses, in addition to changes in the expression of several HIF-1 transcription factor target genes. The RAO condition alters systemic changes observed as differential expression profiles of PBMCs. Those changes also depended on the cohort and stimulation of the samples and were dominated by genes involved in immune cell trafficking, development, and cell cycle regulation. Our findings indicate an important role of CXCL13, likely macrophage or Th17 derived, and the cell cycle regulator CDC20 in the immune response in RAO.
Highlights
According to the World Allergy Organization 300 million people suffer from asthma
peripheral blood mononuclear cells (PBMCs) were stimulated with hay dust extract (HDE), LPS, recombinant cyathostomin antigen (RCA) or left unstimulated (4 treatments)
The analysis showed that RCA-stimulated samples were the least distant and the HDE-stimulated samples were the most distant samples from the unstimulated samples (Fig 1)
Summary
According to the World Allergy Organization 300 million people suffer from asthma. There are several types of asthma described, which vary regarding their pathogenesis, molecular mechanisms and clinical phenotype. Cytokine expression profiles and the types of T helper cells implicated in the immune response after allergenic stimulation show considerable variation, as reviewed in [2]. Asthma has an estimated heritability of more than 60% [3,4], but in accordance with the considerable immunological and phenotypical variation, it is genetically heterogenous [5] and more than 200 genes have been shown to be related to asthma [6]. There are important environmental risk factors, including indoor and outdoor allergens, such as mites or pollens, and irritants like lipopolysaccharides (LPS)
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