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

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      Author(s)
      Surucu Yılmaz, N.
      Bilgic Eltan, S.
      Kayaoğlu, B.
      Geçkin, B.
      Heredia, R. J.
      Sefer, A. P.
      Kiykim, A.
      Nain, E.
      Kasap, N.
      Doğru, Ö.
      Yucelten, A. D.
      Karasu, G.
      Yeşilipek, Y.
      Sözeri, B.
      Cinel, L.
      Kaya, Göksu Gökberk
      Cansen Kahraman, D.
      Yılmaz, İ. C
      Baydemir, İ.
      Aydın, Y.
      Haimel, M.
      Boztuğ, K.
      Karakoc-Aydiner, E.
      Gürsel, İ.
      Özen, A.
      Barış, S.
      Gürsel, M
      Date
      2022-04
      Source Title
      Journal of Clinical Immunology
      Print ISSN
      0271-9142
      Publisher
      Springer
      Volume
      42
      Issue
      3
      Pages
      582 - 596
      Language
      English
      Type
      Article
      Item Usage Stats
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      Abstract
      NF-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.
      Keywords
      Autoinflammation;
      Interferon stimulated genes (ISGs)
      Low-density granulocytes
      NEMO deficiency
      Neutrophil activation related genes
      Permalink
      http://hdl.handle.net/11693/111579
      Published Version (Please cite this version)
      https://doi.org/10.1007/s10875-021-01176-3
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