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Single cell transcriptomics reveal type-2 inflammatory gene regulation in airway epithelium driven by allergen-specific immunotherapy

ABSTRACT: Background: Airway epithelium in patients with allergic airway disease actively releases and is subjected to the influence of type-2 cytokines with observable changes in basal epithelial cells. Symptoms that grass pollen-allergic patients experience due to this priming can be controlled by allergen-specific immunotherapy (AIT). However, the impact of AIT on type-2 related mediators of airway epithelial cells is unknown. Methods: Protein levels of type-2 cytokines in nasal secretions of grass pollen-allergic patients were analyzed during 3-year AIT-regimen using multiplex-ELISA. Source and IL-4-dependence of type-2 cytokines were examined in IL-4-primed primary ALI cultures using single-cell transcriptomics. Results: Type-2 cytokines CCL-26 and POSTN oscillated seasonally, derived from basal epithelial cells and were induced by IL-4-priming. In contrast, TSLP and IL-33 derived from basal cells, albeit independently of IL-4. POSTN and IL-24 nasal levels changed corresponding to 3-year AIT progression. Four characteristic epithelial type-2 cytokines stood out: IL-33 changed independent of season, IL-4-exposure, or AIT; CCL-26 was triggered upon IL-4-priming and was induced during pollen season, but not influenced by AIT; IL-24 decreased following three years of AIT; and POSTN, which was increased in IL-4-primed basal epithelial cells and oscillated during pollen season, also responded to long-term AIT. Conclusions: Atopic reprogramming of type-2 epithelial cytokines seems to persist despite long-term AIT, which may be one mechanism explaining why AIT only restores allergen tolerance for seven to ten years. Type-2 related epithelial cytokines are differentially expressed which may relate to the distinct expression of basal as opposed to differentiated secretory or ciliated epithelial cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE203248 | GEO | 2023/03/31

REPOSITORIES: GEO

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Project description:Analysis of gene-expression profiles by microarrays can be very useful to characterize new potential candidate genes, key regulatory networks, and to define phenotypes or molecular signatures to improve the diagnosis or classification of the disease. We have used this approach in the study of one of the major causes of allergic diseases in Mediterranean countries, the olive pollen response, in order to find differential molecular markers among five clinical groups, Non-allergic, Asymptomatic, Allergic but not to olive pollen, Non-treated, olive pollen allergic patients and Olive pollen allergic patients (under specific-immunotherapy). The results of gene-expression by principal components analysis (PCA) clearly showed five clusters of samples that correlated with the five clinical groups. Analysis of differential gene-expression by multiple testing, and functional analysis by KEGG and Gene-Ontology revealed differential genes and pathways among the 5 clinical groups. The study population comprised 28 subjects, selected from a previous immunological study (Aguerri et al. Eur. J. Inflammation 2012, in press), from Andalusia, who were recruited in 2 olive pollen exposure situations: during (April-June) and outside the pollen season (October-December). We established 5 groups, and 6 subjects from each group were selected for gene-expression analysis: Group 1, non-allergic subjects; Group 2, asymptomatic subjects (diagnosed with olive pollen allergy by skin testing, with no seasonal respiratory symptoms [rhinitis and/or asthma], and who consulted for adverse reaction to drugs); Group 3, patients who were allergic, but not to olive pollen; Group 4, non-treated olive pollenM-bM-^@M-^Sallergic; and Group 5, olive pollenM-bM-^@M-^Sallergic patients (receiving olive pollenM-bM-^@M-^Sspecific immunotherapy).The subjects were unrelated and recruited at the Allergy Service of 4 hospitals in Andalusia (Granada, JaM-CM-)n, Sevilla, and MM-CM-!laga). Olive pollenM-bM-^@M-^Sallergic patients fulfilled the following criteria: seasonal rhinitis and/or asthma from April to June, a positive skin prick test result for O. europaea pollen extract (ALK AbellM-CM-3, Madrid, Spain), and no previous immunotherapy. Informed consent was obtained from each subject. Ethical approval for the study was obtained from the Ethical and Research Committee of the participating hospitals. PBMCs were isolated from heparin-containing peripheral blood samples taken during and outside pollen season, by gradient centrifugation on Lymphoprep (Comercial Rafer, Zaragoza, Spain) following the manufacturerM-bM-^@M-^Ys instructions.

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Single cell transcriptomics reveal type-2 inflammatory gene regulation in airway epithelium driven by allergen-specific immunotherapy

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