Person: ÖZEN, AHMET OĞUZHAN
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ÖZEN
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AHMET OĞUZHAN
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Publication Open Access Severe Early-Onset Combined Immunodeficiency due to Heterozygous Gain-of-Function Mutations in STAT1(SPRINGER/PLENUM PUBLISHERS, 2016-10) ÖZEN, AHMET OĞUZHAN; Baris, Safa; Alroqi, Fayhan; Kiykim, Ayca; Karakoc-Aydiner, Elif; Ogulur, Ismail; Ozen, Ahmet; Charbonnier, Louis-Marie; Bakir, Mustafa; Boztug, Kaan; Chatila, Talal A.; Barlan, Isil B.Loss and gain-of-function (GOF) mutations in human signal transducer and activator of transcription 1 (STAT1) lead to distinct phenotypes. Although recurrent infections are common to both types of STAT1 mutations, GOF mutations are distinguished by chronic mucocutaneous candidiasis and autoimmunity. However, the clinical spectra of STAT1 GOF mutations continue to expand. We here describe two patients with STAT1 GOF mutations presenting early in life with combined immunodeficiency (CID). Clinical data and laboratory findings including immunophenotyping, level of interferon (IFN)-gamma/IL-17(+) T cells, interferon-induced STAT1 phosphorylation, and JAK inhibitor assays were evaluated. Sequencing of STAT1 gene was performed by Sanger sequencer. Patient 1 (P1) had persistent oral candidiasis and cytomegalovirus (CMV) infection since 2 months of age and later developed cavitary lung lesions due to Mycobacterium tuberculosis. Patient 2 (P2) presented with oral candidiasis and recurrent pneumonia at 4 months of age and subsequently developed CMV pneumonitis. Both patients suffered heterozygous missense mutations in STAT1, leading to deleterious amino acid substitutions in the DNA binding domain (P1: c.1154C > T; p.T385M; P2. c.971G > T; p.C324F). Circulating CD4(+) T cells of both patients exhibited increased interferon-gamma and decreased IL-17 expression as compared to controls. They also exhibited increased IFN-beta and -gamma-induced STAT1 phosphorylation that was reversed upon treatment with the JAK kinase inhibitor ruxolitinib. STAT1 GOF mutations may present early in life with CID, consistent with the clinical heterogeneity of the disease. JAK kinase inhibitors may potentially be useful in some patients as adjunct therapy pending definitive treatment with bone marrow transplantation.Publication Open Access Monogenic early-onset lymphoproliferation and autoimmunity: the natural history of stat3 gof syndrome(2022-10-10) ÖZEN, AHMET OĞUZHAN; Leiding J. W. , Vogel T. P. , Santarlas V. G. J. , Mhaskar R., Smith M. R. , Carisey A., Vargas-Hernandez A., Silva-Carmona M., Heeg M., Rensing-Ehl A., et al.Background: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. Objective: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. Methods: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. 1 Results: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD42CD82) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. Conclusion: : STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome. (J Allergy Clin Immunol 2022Publication Metadata only 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.Publication Open Access Hematopoietic Stem Cell Transplantation in Patients with Heterozygous STAT1 Gain-of-Function Mutation(SPRINGER/PLENUM PUBLISHERS, 2019-01) ÖZEN, AHMET OĞUZHAN; Kiykim, Ayca; Charbonnier, Louis Marie; Akcay, Arzu; Karakoc-Aydiner, Elif; Ozen, Ahmet; Ozturk, Gulyuz; Chatila, Talal A.; Baris, SafaPurposeHuman signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations present with a broad range of manifestations ranging from chronic mucocutaneous candidiasis and autoimmunity to combined immunodeficiency (CID). So far, there is very limited experience with hematopoietic stem cell transplantation (HSCT) as a therapeutic modality in this disorder. Here, we describe two patients with heterozygous STAT1 GOF mutations mimicking CID who were treated with HSCT.MethodsData on the HSC sources, conditioning regimen, graft-versus-host disease (GvHD) and antimicrobial prophylaxis, and the post-transplant course including engraftment, GvHD, transplant-related complications, infections, chimerism, and survival were evaluated. Pre- and post-transplant immunological studies included enumeration of circulating interferon gamma (IFN-)- and interleukin 17 (IL-17)-expressing CD4(+) T cells and analysis of IFN--induced STAT1 phosphorylation in patient 1 (P1)'s T cells.ResultsP1 was transplanted with cord blood from an HLA-identical sibling, and P2 with bone marrow from a fully matched unrelated donor using a reduced toxicity conditioning regimen. While P1 completely recovered from her disease, P2 suffered from systemic CMV disease and secondary graft failure and died due to severe pulmonary involvement and hemorrhage. The dysregulated IFN- production, suppressed IL-17 response, and enhanced STAT1 phosphorylation previously found in the CD4(+) T cells of P1 were normalized following transplantation.ConclusionHSCT could be an alternative and curative therapeutic option for selected STAT1 GOF mutant patients with progressive life-threatening disease unresponsive to conventional therapy. Morbidity and mortality-causing complications included secondary graft failure, infections, and bleeding.Publication Metadata only Stepwise Reversal of Immune Dysregulation Due to STAT1 Gain-of-Function Mutation Following Ruxolitinib Bridge Therapy and Transplantation(SPRINGER/PLENUM PUBLISHERS, 2021) ÖZEN, AHMET OĞUZHAN; Kayaoglu, Basak; Kasap, Nurhan; Yilmaz, Naz Surucu; Charbonnier, Louis Marie; Geckin, Busranur; Akcay, Arzu; Eltan, Sevgi Bilgic; Ozturk, Gulyuz; Ozen, Ahmet; Karakoc-Aydiner, Elif; Chatila, Talal A.; Gursel, Mayda; Baris, SafaPurpose Patients with heterozygous gain-of-function (GOF) mutations in STAT1 frequently exhibit chronic mucocutaneous candidiasis (CMC), immunodeficiency and autoimmune manifestations. Several treatment options including targeted therapies and hematopoietic stem cell transplantation (HSCT) are available for STAT1 GOF patients but modalities and outcomes are not well established. Herein, we aimed to unravel the effect of ruxolitinib as a bridge therapy in a patient with sporadic STAT1 T385M mutation to manage infections and other disease manifestations. Methods Peripheral blood mononuclear cells were isolated from the patient prior to, during ruxolitinib treatment and 6 months after HSCT. IFN-beta-induced STAT1 phosphorylation/dephosphorylation levels and PMA/ionomycin-stimulated intracellular IL-17A/IFN-gamma production in CD4(+) T cells were evaluated. Differentially expressed genes between healthy controls and the patient prior to, during ruxolitinib treatment and post-transplantation were investigated using Nanostring nCounter Profiling Panel. Results Ruxolitinib provided favorable responses by controlling candidiasis and autoimmune hemolytic anemia in the patient. Dysregulation in STAT1 phosphorylation kinetics improved with ruxolitinib treatment and was completely normalized after transplantation. T(H)17 deficiency persisted after ruxolitinib treatment, but normalized following HSCT. Consistent with the impairment in JAK/STAT signaling, multiple immune related pathways were found to be dysregulated in the patient. At baseline, genes related to type I IFN-related pathways, antigen processing, T-cell and B-cell functions were upregulated, while NK-cell function and cytotoxicity related genes were downregulated. Dysregulated gene expression was partially improved with ruxolitinib treatment and normalized after transplantation. Conclusion Our findings suggest that improved disease management and immune dysregulatory profile can be achieved with ruxolitinib treatment before transplantation and this would be beneficial to reduce the risk of adverse outcome of HSCT.