Low density granulocytes and dysregulated neutrophils driving autoinflammatory manifestations in NEMO deficiency

buir.contributor.authorKaya, Göksu Gökberk
dc.citation.epage596en_US
dc.citation.issueNumber3en_US
dc.citation.spage582en_US
dc.citation.volumeNumber42en_US
dc.contributor.authorSurucu Yılmaz, N.
dc.contributor.authorBilgic Eltan, S.
dc.contributor.authorKayaoğlu, B.
dc.contributor.authorGeçkin, B.
dc.contributor.authorHeredia, R. J.
dc.contributor.authorSefer, A. P.
dc.contributor.authorKiykim, A.
dc.contributor.authorNain, E.
dc.contributor.authorKasap, N.
dc.contributor.authorDoğru, Ö.
dc.contributor.authorYucelten, A. D.
dc.contributor.authorKarasu, G.
dc.contributor.authorYeşilipek, Y.
dc.contributor.authorSözeri, B.
dc.contributor.authorCinel, L.
dc.contributor.authorKaya, Göksu Gökberk
dc.contributor.authorCansen Kahraman, D.
dc.contributor.authorYılmaz, İ. C
dc.contributor.authorBaydemir, İ.
dc.contributor.authorAydın, Y.
dc.contributor.authorHaimel, M.
dc.contributor.authorBoztuğ, K.
dc.contributor.authorKarakoc-Aydiner, E.
dc.contributor.authorGürsel, İ.
dc.contributor.authorÖzen, A.
dc.contributor.authorBarış, S.
dc.contributor.authorGürsel, M
dc.date.accessioned2023-02-21T10:47:15Z
dc.date.available2023-02-21T10:47:15Z
dc.date.issued2022-04
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractNF-κB essential modulator (NEMO, IKK-γ) deficiency is a rare combined immunodeficiency caused by mutations in the IKBKG gene. Conventionally, patients are afflicted with life threatening recurrent microbial infections. Paradoxically, the spectrum of clinical manifestations includes severe inflammatory disorders. The mechanisms leading to autoinflammation in NEMO deficiency are currently unknown. Herein, we sought to investigate the underlying mechanisms of clinical autoinflammatory manifestations in a 12-years old male NEMO deficiency (EDA-ID, OMIM #300,291) patient by comparing the immune profile of the patient before and after hematopoietic stem cell transplantation (HSCT). Response to NF-kB activators were measured by cytokine ELISA. Neutrophil and low-density granulocyte (LDG) populations were analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMC) transcriptome before and after HSCT and transcriptome of sorted normal-density neutrophils and LDGs were determined using the NanoString nCounter gene expression panels. ISG15 expression and protein ISGylation was based on Immunoblotting. Consistent with the immune deficiency, PBMCs of the patient were unresponsive to toll-like and T cell receptor-activators. Paradoxically, LDGs comprised 35% of patient PBMCs and elevated expression of genes such as MMP9, LTF, and LCN2 in the granulocytic lineage, high levels of IP-10 in the patient’s plasma, spontaneous ISG15 expression and protein ISGylation indicative of a spontaneous type I interferon (IFN) signature were observed, all of which normalized after HSCT. Collectively, our results suggest that type I IFN signature observed in the patient, dysregulated LDGs and spontaneously activated neutrophils, potentially contribute to tissue damage in NEMO deficiency. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.en_US
dc.identifier.doi10.1007/s10875-021-01176-3en_US
dc.identifier.issn0271-9142
dc.identifier.urihttp://hdl.handle.net/11693/111579
dc.language.isoEnglishen_US
dc.publisherSpringeren_US
dc.relation.isversionofhttps://doi.org/10.1007/s10875-021-01176-3en_US
dc.source.titleJournal of Clinical Immunologyen_US
dc.subjectAutoinflammation;en_US
dc.subjectInterferon stimulated genes (ISGs)en_US
dc.subjectLow-density granulocytesen_US
dc.subjectNEMO deficiencyen_US
dc.subjectNeutrophil activation related genesen_US
dc.titleLow density granulocytes and dysregulated neutrophils driving autoinflammatory manifestations in NEMO deficiencyen_US
dc.typeArticleen_US
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