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Understanding allergic multimorbidity within the non-eosinophilic interactome.

ABSTRACT: BACKGROUND:The mechanisms explaining multimorbidity between asthma, dermatitis and rhinitis (allergic multimorbidity) are not well known. We investigated these mechanisms and their specificity in distinct cell types by means of an interactome-based analysis of expression data. METHODS:Genes associated to the diseases were identified using data mining approaches, and their multimorbidity mechanisms in distinct cell types were characterized by means of an in silico analysis of the topology of the human interactome. RESULTS:We characterized specific pathomechanisms for multimorbidities between asthma, dermatitis and rhinitis for distinct emergent non-eosinophilic cell types. We observed differential roles for cytokine signaling, TLR-mediated signaling and metabolic pathways for multimorbidities across distinct cell types. Furthermore, we also identified individual genes potentially associated to multimorbidity mechanisms. CONCLUSIONS:Our results support the existence of differentiated multimorbidity mechanisms between asthma, dermatitis and rhinitis at cell type level, as well as mechanisms common to distinct cell types. These results will help understanding the biology underlying allergic multimorbidity, assisting in the design of new clinical studies.

SUBMITTER: Aguilar D

PROVIDER: S-EPMC6834334 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Understanding allergic multimorbidity within the non-eosinophilic interactome.

Aguilar Daniel D Lemonnier Nathanael N Koppelman Gerard H GH Melén Erik E Oliva Baldo B Pinart Mariona M Guerra Stefano S Bousquet Jean J Anto Josep M JM

PloS one 20191106 11

<h4>Background</h4>The mechanisms explaining multimorbidity between asthma, dermatitis and rhinitis (allergic multimorbidity) are not well known. We investigated these mechanisms and their specificity in distinct cell types by means of an interactome-based analysis of expression data.<h4>Methods</h4>Genes associated to the diseases were identified using data mining approaches, and their multimorbidity mechanisms in distinct cell types were characterized by means of an in silico analysis of the t ...[more]

PMID: 31693680

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Project description:BACKGROUND:Severe non-allergic eosinophilic asthma (SNEA) is a rare asthma phenotype associated with severe clinical course, frequent exacerbations, and resistance to therapy, including high steroid doses. The key feature is type 2 inflammation with predominant airway eosinophilia. Eosinophil maturation, activation, survivability, and recruitment are mainly induced by interleukin (IL)-3, IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) through their receptors on eosinophil surface and related with integrins activation states. The aim of the study was to estimate the expression of eosinophil ? chain-signaling cytokines receptors, outer-membrane integrins, and serum-derived type 2 inflammation biomarkers in SNEA. METHODS:We examined 8 stable SNEA patients with high inhaled steroid doses, 12 steroid-free patients with non-severe allergic asthma (AA), 12 healthy subjects (HS). Blood eosinophils were isolated using Ficol gradient centrifugation and magnetic separation. Eosinophils were lysed, and mRNA was isolated. Gene expressions of IL-5R?, IL-3R?, GM-CSFR?, and ?4?1, ?M?2 integrins were analyzed using quantitative real-time reverse transcription polymerase chain reaction. Type 2 inflammation activity was evaluated measuring exhaled nitric oxide concentration (FeNO) collected with the electrochemical sensing device. Serum IL-5, IL-3, GM-CSF, periostin, chemokine ligand (CCL) 17 and eotaxin concentrations were assessed by enzyme-linked immunosorbent assay. RESULTS:Eosinophils from SNEA patients demonstrated significantly increased gene expression of IL-3R?, IL-5R? and GM-CSFR? as well as ?4, ?1 and ?M integrin subunits compared with the AA group. The highest IL-5 serum concentration was in the SNEA group; it significantly differed compared with AA and HS. GM-CSF serum levels were similar in the SNEA and AA groups and were significantly lower in the HS group. No differences in serum IL-3 concentration were found among all groups. Furthermore, serum levels of eotaxin, CCL17 and FeNO, but not periostin, differed in all groups, with the highest levels in SNEA patients. CONCLUSIONS:Eosinophil demonstrated higher expression of IL-3, IL-5, GM-CSF ?-chain receptors and ?4, ?1, ?M integrins subunits in SNEA compared with the AA group. Additionally, SNEA patients had increased serum levels of IL-5, eotaxin and CCL-17. TRIAL REGISTRATION:ClinicalTrials.gov Identifier NCT03388359.

Dataset Information

Understanding allergic multimorbidity within the non-eosinophilic interactome.

Publications

Understanding allergic multimorbidity within the non-eosinophilic interactome.

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