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. 2021 Apr 19;7(2):00917-2020.
doi: 10.1183/23120541.00917-2020. eCollection 2021 Apr.

Nasal upregulation of CST1 in dog-sensitised children with severe allergic airway disease

Ulrika Käck  1   2 , Elisabet Einarsdottir  3   4   5 , Marianne van Hage  6 , Anna Asarnoj  7   8 , Anna James  9 , Anna Nopp  1   2 , Kaarel Krjutškov  3   10   11 , Shintaro Katayama  3   5   12 , Juha Kere  3   13 , Gunnar Lilja  1   2 , Cilla Söderhäll  3   7   8   14 , Jon R Konradsen  7   8   14
Affiliations

Nasal upregulation of CST1 in dog-sensitised children with severe allergic airway disease

Ulrika Käck et al. ERJ Open Res. .

Abstract

Background: The clinical presentation of children sensitised to dog dander varies from asymptomatic to severe allergic airway disease, but the genetic mechanisms underlying these differences are not clear. The objective of the present study was to investigate nasal transcriptomic profiles associated with dog dander sensitisation in school children and to reveal clinical symptoms related with these profiles.

Methods: RNA was extracted from nasal epithelial cell brushings of children sensitised to dog dander and healthy controls. Blood sample analyses included IgE against dog dander, dog allergen molecules, other airborne and food allergens, basophil activation and white blood cell counts. Clinical history of asthma and rhinitis was recorded, and lung function was assessed (spirometry, methacholine provocation and exhaled nitric oxide fraction).

Results: The most overexpressed gene in children sensitised to dog dander compared to healthy controls was CST1, coding for Cystatin 1. A cluster of these children with enhanced CST1 expression showed lower forced expiratory volume in 1 s, increased bronchial hyperreactivity, pronounced eosinophilia and higher basophil allergen threshold sensitivity compared with other children sensitised to dog dander. In addition, multi-sensitisation to lipocalins was more common in this group.

Conclusions: Overexpression of CST1 is associated with more severe allergic airway disease in children sensitised to dog dander. CST1 is thus a possible biomarker of the severity of allergic airway disease and a possible therapeutic target for the future treatment of airborne allergy.

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Conflict of interest statement

Conflict of interest: U. Käck reports a lecture fee from Thermo Fisher outside the submitted work. Conflict of interest: E. Einarsdottir has nothing to disclose. Conflict of interest: M. van Hage reports lecture fees from Thermo Fisher Scientific and ALK, and consultancy fees from Biomay AG, Vienna, Austria and Hycor Biomedical LLC, CA, US, outside the submitted work. Conflict of interest: A. Asarnoj has nothing to disclose. Conflict of interest: A. James has nothing to disclose. Conflict of interest: A. Nopp has nothing to disclose. Conflict of interest: K. Krjutškov has nothing to disclose. Conflict of interest: S. Katayama reports grants from the Jane and Aatos Erkko Foundation during the conduct of the study. Conflict of interest: J. Kere has nothing to disclose. Conflict of interest: G. Lilja has nothing to disclose. Conflict of interest: C. Söderhäll has nothing to disclose. Conflict of interest: J.R. Konradsen has received material from Thermo Fisher Scientific to perform IgE analysis in this project.

Figures

FIGURE 1
FIGURE 1
Flow chart from patient inclusion to final study population. Total RNA was obtained from 54 children sensitised to dog dander recruited from outpatient paediatric clinics in the Stockholm area and 20 age-matched healthy controls from the same area recruited through advertising. The sequencing yielded ∼11–12 million reads per sample (supplementary table E1). Five case samples were removed as part of the quality control (QC) analysis (three had too few spike-ins for high-quality normalisation; two showed degraded RNA). Three of the healthy controls showed to be sensitised to dog dander (IgE >0.10 kUA·L−1) and were therefore excluded from further analysis. For each of the technical duplicates passing QC, the sample with the highest number of raw reads was retained. This resulted in a final set of 49 independent cases and 17 healthy controls.
FIGURE 2
FIGURE 2
Expression of CST1 (coding for Cystatin-1) and CCL26 (coding for the C-C motif chemokine ligand 26) among healthy control children (n=17) and dog dander sensitised children. Dog dander sensitised children are separated into CST1 high “cluster cases” (n=10) and low “noncluster cases” (n=39) subgroups.
FIGURE 3
FIGURE 3
Heatmap based on the top 10 most upregulated or downregulated genes in cases versus controls. Hierarchical clustering shows the unsupervised clustering of samples.
FIGURE 4
FIGURE 4
a) Lung function parameters in CST1-high children compared to other dog dander sensitised children. i) Forced expiratory volume in 1 s (FEV1) (% predicted) before reversibility test with short-acting β2-agonist; ii) reversibility: % change in FEV1 after administration of short-acting β2-agonist; iii) bronchial hyperreactivity: dose of methacholine leading to a 20% drop in FEV1 (methacholine PD20); iv) exhaled nitric oxide fraction (FeNO). Two children were excluded due to having FEV1 ≤75% of expected at baseline; two children were excluded due to technical issues; and six children did not reach a drop in FEV1 >20% during the bronchial provocation. b) Blood cell counts among CST1-high children (n=10) compared to other children sensitised to dog dander (n=38): i) neutrophils; ii) eosinophils; iii) dog dander CD-sens levels.
FIGURE 5
FIGURE 5
Proportions of children (%) sensitised to dog allergen molecules among CST1-high (n=10) and other children sensitised to dog dander (n=39).
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