Type I IFN-related NETosis in ataxia telangiectasia and Artemis deficiency

dc.contributor.authorGul, Ersin
dc.contributor.authorSayar, Esra Hazar
dc.contributor.authorGungor, Bilgi
dc.contributor.authorEroglu, Fehime Kara
dc.contributor.authorSurucu, Naz
dc.contributor.authorKeles, Sevgi
dc.contributor.authorGuner, Sukru Nail
dc.contributor.authorFindik, Siddika
dc.contributor.authorAlpdundar, Esin
dc.contributor.authorAyanoglu, Ihsan Cihan
dc.contributor.authorKayaoglu, Basak
dc.contributor.authorGeckin, Busra Nur
dc.contributor.authorSanli, Hatice Asena
dc.contributor.authorKahraman, Tamer
dc.contributor.authorYakicier, Cengiz
dc.contributor.authorMuftuoglu, Meltem
dc.contributor.authorOguz, Berna
dc.contributor.authorAyvaz, Deniz Nazire Cagdas
dc.contributor.authorGursel, Ihsan
dc.contributor.authorOzen, Seza
dc.contributor.authorReisli, Ismail
dc.contributor.authorGursel, Mayda
dc.date.accessioned2023-02-21T12:38:53Z
dc.date.available2023-02-21T12:38:53Z
dc.date.issued2018-01-01
dc.description.abstractBackground: Pathological inflammatory syndromes of unknown etiology are commonly observed in ataxia telangiectasia (AT) and Artemis deficiency. Similar inflammatory manifestations also exist in patients with STING-associated vasculopathy in infancy (SAVI). Objective: We sought to test the hypothesis that the inflammation-associated manifestations observed in patients with AT and Artemis deficiency stem from increased type I IFN signature leading to neutrophil-mediated pathological damage. Methods: Cytokine/protein signatures were determined by ELISA, cytometric bead array, or quantitative PCR. Stat1 phosphorylation levels were determined by flow cytometry. DNA species accumulating in the cytosol of patients' cells were quantified microscopically and flow cytometrically. Propensity of isolated polymorhonuclear granulocytes to form neutrophil extracellular traps (NETs) was determined using fluorescence microscopy and picogreen assay. Neutrophil reactive oxygen species levels and mitochondrial stress were assayed using fluorogenic probes, microscopy, and flow cytometry. Results: Type I and III IFNsignatures were elevated in plasma and peripheral blood cells of patients with AT, Artemis deficiency, and SAVI. Chronic IFN production stemmed fromthe accumulation of DNA in the cytoplasm of ATand Artemis-deficient cells. Neutrophils isolated from patients spontaneously produced NETs and displayed indicators of oxidative and mitochondrial stress, supportive of theirNETotic tendencies. Asimilar phenomenonwas also observed in neutrophils from healthy controls exposed to patient plasma samples or exogeneous IFN-alpha. Conclusions: Type I IFN-mediated neutrophil activation and NET formation may contribute to inflammatory manifestations observed in patients with AT, Artemis deficiency, and SAVI. Thus, neutrophils represent a promising target to manage inflammatory syndromes in diseases with active type I IFN signature.
dc.description.issue1
dc.description.issueJUL
dc.description.pages246-257
dc.description.volume142
dc.identifier.doi10.1016/j.jaci.2017.10.030
dc.identifier.urihttps://hdl.handle.net/11443/2439
dc.identifier.urihttp://dx.doi.org/10.1016/j.jaci.2017.10.030
dc.identifier.wosWOS:000437837500027
dc.publisherMOSBY-ELSEVIER
dc.relation.ispartofJOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
dc.subjectPrimary immunodeficiencies
dc.subjectautoinflammation
dc.subjectataxia telangiectasia
dc.subjectArtemis deficiency
dc.subjecttype I IFN
dc.subjectinterferonopathy
dc.subjectneutrophil extracellular traps
dc.subjectNETosis
dc.titleType I IFN-related NETosis in ataxia telangiectasia and Artemis deficiency
dc.typeArticle

Files

Original bundle

Now showing 1 - 1 of 1
Thumbnail Image
Name:
1-s2.0-S0091674917317621-main.pdf
Size:
4.3 MB
Format:
Adobe Portable Document Format

Collections