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YÜCELTEN, AYŞE DENİZ

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AYŞE DENİZ

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2015 - 201912020 - 20232
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Author: BARIŞ, SAFA ×

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    Potentially Beneficial Effect of Hydroxychloroquine in a Patient with a Novel Mutation in Protein Kinase C delta Deficiency
    (SPRINGER/PLENUM PUBLISHERS, 2015) ÖZEN, AHMET OĞUZHAN; Kiykim, Ayca; Ogulur, Ismail; Baris, Safa; Salzer, Elisabeth; Karakoc-Aydiner, Elif; Ozen, Ahmet Oguzhan; Garncarz, Wojciech; Hirschmugl, Tatjana; Krolo, Ana; Yucelten, Ayse Deniz; Boztug, Kaan; Barlan, Isil B.
    Protein kinase C delta (PRKCD) has essential functions in controlling B-cell proliferation and apoptosis, development of B-cell tolerance and NK-cell cytolitic activity. Human PRKCD deficiency was recently identified to be causative for an autoimmune lymphoproliferative syndrome like disorder with significant B-cell proliferation particularly of immature B cells. Here we report a child with a novel mutation in PRKCD gene who presented with CMV infection and an early onset SLE-like disorder which was successfully treated with hydroxychloroquine.
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    Low Density Granulocytes and Dysregulated Neutrophils Driving Autoinflammatory Manifestations in NEMO Deficiency
    (SPRINGER/PLENUM PUBLISHERS, 2022) ÖZEN, AHMET OĞUZHAN; Yilmaz, Naz Surucu; Eltan, Sevgi Bilgic; Kayaoglu, Basak; Geckin, Busranur; Heredia, Raul Jimenez; Sefer, Asena Pinar; Kiykim, Ayca; Nain, Ercan; Kasap, Nurhan; Dogru, Omer; Yucelten, Ayse Deniz; Cinel, Leyla; Karasu, Gulsun; Yesilipek, Akif; Sozeri, Betul; Kaya, Goksu Gokberk; Yilmaz, Ismail Cem; Baydemir, Ilayda; Aydin, Yagmur; Kahraman, Deniz Cansen; Haimel, Matthias; Boztug, Kaan; Karakoc-Aydiner, Elif; Gursel, Ihsan; Ozen, Ahmet; Baris, Safa; Gursel, Mayda
    NF-kappa B essential modulator (NEMO, IKK-gamma) 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.
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    Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6
    (2023-01-01) BARIŞ, SAFA; YÜCELTEN, AYŞE DENİZ; BOZKURTLAR, EMİNE; CİNEL, ZELİHA LEYLA; AYDINER, ELİF; ÖZEN, AHMET OĞUZHAN; BARIŞ S., Benamar M., Chen Q., Catak M. C., Martínez-Blanco M., Wang M., Fong J., Massaad M. J., Sefer A. P., Kara A., et al.
    Background: Inborn errors of immunity have been implicated in causing immune dysregulation, including allergic diseases. STAT6 is a key regulator of allergic responses. Objectives: This study sought to characterize a novel gain-of-function STAT6 mutation identified in a child with severe allergic manifestations. Methods: Whole-exome and targeted gene sequencing, lymphocyte characterization, and molecular and functional analyses of mutated STAT6 were performed. Results: This study reports a child with a missense mutation in the DNA binding domain of STAT6 (c.1114G>A, p.E372K) who presented with severe atopic dermatitis, eosinophilia, and elevated IgE. Naive lymphocytes from the affected patient displayed increased TH2- and suppressed TH1- and TH17-cell responses. The mutation augmented both basal and cytokine-induced STAT6 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase 1/2 inhibitor ruxolitinib reversed STAT6 hyperresponsiveness to IL-4, normalized TH1 and TH17 cells, suppressed the eosinophilia, and improved the patient\"s atopic dermatitis. Conclusions: This study identified a novel inborn error of immunity due to a STAT6 gain-of-function mutation that gave rise to severe allergic dysregulation. Janus kinase inhibitor therapy could represent an effective targeted treatment for this disorder.