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 Metadata only Lymphocyte Subset Abnormalities in Pediatric-Onset Common Variable Immunodeficiency(KARGER, 2020) ÖZEN, AHMET OĞUZHAN; Ogulur, Ismail; Kiykim, Ayca; Baser, Dilek; Karakoc-Aydiner, Elif; Ozen, Ahmet; Baris, SafaIntroduction: Common variable immunodeficiency (CVID) is characterized by recurrent infections, autoimmunity, lymphoproliferation, hypogammaglobulinemia, and defective antibody production. In CVID, B-cell abnormalities were described to predict end organ involvement and prognosis. Pediatric-onset CVID is much rarer than adult CVID, and lymphocyte subset abnormalities have not been thoroughly evaluated. Objective: We sought to determine lymphocyte subset abnormalities and their association with end organ involvement in pediatric-onset CVID patients. Methods: The clinical manifestations and laboratory findings including absolute numbers and percentages of B-, T-, and NK cell populations were assessed in pediatric-onset CVID patients and compared to age-matched healthy controls. The patients were divided into 2 groups according to age at assessment (pediatric CVID patients: 10-16 years, n = 9; and adult CVID patients: >16 years, n = 13). The comparisons between lymphocyte subsets and organ involvement were also evaluated. Results: Mean age at symptom onset was 18 (3-204) months. All CVID patients with pediatric onset had decreased levels of total and memory B cells, CD4(+) T cells, CD4(+)CD45RA(+) naive T cells, and recent thymic emigrant (RTE) cells. On the other hand, they had increases in CD8(+)CD45RO(+) memory T cells. Interestingly, adult CVID patients demonstrated high frequencies of activated and double-negative T cells, which were unique only for this group of patients. Specific cellular abnormalities associated with the reduction in B and NK cells and increase in CD8(+) T cells were found in patients with bronchiectasis. Moreover, in pediatric CVID patients, low serum IgA levels and decreased numbers of naive T and RTE cells were determined as risk factors for chronic diarrhea. Conclusions: Specific abnormalities in B- and T-lymphocyte compartments were identified in pediatric-onset CVID patients and appear to be associated with end organ manifestations.Publication Metadata only Parents of ataxia-telangiectasia patients display a distinct cellular immune phenotype mimickingATM-mutated patients(WILEY, 2021) ÖZEN, AHMET OĞUZHAN; Ogulur, Ismail; Ertuzun, Tugce; Kocamis, Burcu; Kendir Demirkol, Yasemin; Uyar, Emel; Kiykim, Ayca; Baser, Dilek; Yesil, Gozde; Akturk, Hacer; Somer, Ayper; Ozen, Ahmet; Karakoc-Aydiner, Elif; Muftuoglu, Meltem; Baris, SafaBackground Heterozygous relatives of ataxia-telangiectasia (AT) patients are at an increased risk for certain AT-related manifestations. We also show that there is an increase of infection frequency in parents of AT patients. Thus, we hypothesized that the parents might exhibit immune alterations similar to their affected children. Methods Lymphocyte phenotyping to enumerate T- and B-cell subsets was performed. Functional analyses included in vitro quantified gamma-H2AX, poly (ADP-ribose) polymerase (PARP) and caspase-9 proteins. Chromosomal instability was determined by comet assay. Results We analyzed 20 AT patients (14F/6M), 31 parents (16F/15M), and 35 age-matched healthy controls. The AT patients' parents exhibited low frequency of naive CD4(+)T- (n = 14, 45%) and recent thymic emigrants (n = 11, 35%) in comparison with the age-matched healthy donors. Interestingly, parents with low naive T cells also demonstrated high rate of recurrent infections (9/14, 64%). In comparison with age-matched controls, parents who had recurrent infections and low naive T cells showed significantly higher baseline gamma-H2AX levels and H2O2-induced DNA damage as well as increased cleaved caspase-9 and PARP proteins. Conclusion Parents of AT patients could present with recurrent infections and display cellular defects that mimic AT patients. The observed immunological changes could be associated with increased DNA double-strand breaks.Publication Open Access Immune system defects in DiGeorge syndrome and association with clinical course(WILEY, 2019-11) ÖZEN, AHMET OĞUZHAN; Nain, Ercan; Kiykim, Ayca; Ogulur, Ismail; Kasap, Nurhan; Karakoc-Aydiner, Elif; Ozen, Ahmet; Baris, SafaWe evaluated 18 DiGeorge syndrome (DGS) patients and aimed to investigate the immunological changes in this population. DGS patients with low naive CD4(+)T and CD8(+)T cells were defined as high-risk (HR) patients, whereas patients with normal numbers of naive CD4(+) and CD8(+)T cells were defined as standard risk (SR) patients. Level of serum IgM, CD3(+) T cell counts and percentages of class-switched memory B cells were significantly low in HR group compared to SR ones. Severe infections and persistent hypoparathyroidism were detected significantly higher in HR group. Patients with reduced percentages of class-switched B cells had earlier onset of infection, lower blood IgM, lower CD4(+) and CD8(+)T counts than patients with normal class-switched memory B cells. Decreased levels of IgM were associated with low numbers of naive CD4(+) and recent thymic emigrants T cells. Monitoring the immune changes of patients with DGS would be useful to predict the severe phenotype of disease.Publication Open Access Gastrointestinal Manifestations in Children with Primary Immunodeficiencies: Single Center: 12 Years Experience(KARGER, 2019) ÖZEN, AHMET OĞUZHAN; Akkelle, Bilge S.; Tutar, Engin; Volkan, Burcu; Sengul, Ozlem K.; Ozen, Ahmet; Celikel, Cigdem A.; Ertem, DenizBackground: It has been reported that 5-50% of patients with primary immune deficiencies (PID) may present with or develop gastrointestinal (GI) manifestations. Objective: This study was aimed at analyzing GI and related endoscopic, histopathological findings in children with PID. Methods: Children with PID who were evaluated by endoscopy between 2005 and 2016 were enrolled in this study. Demographic data, growth parameters, signs and symptoms at diagnosis were obtained. Results: Of 425 children with PID, 195 had GI manifestations. Forty-seven of 195 children required endoscopic investigation, 30 (63.8%) were male, and the mean age was 7.7 +/- 5 years. The rate of consanguinity was 61.7%, and the most common symptom was chronic diarrhea (57.4%). Seventy-two percent of the patients were malnourished. Giardia intestinalis was detected in 4, and Helicobacter pylori was confirmed in 8/45 (17.7%) patients. Non-celiac villous flatting was discovered in 15.5% of patients. Twelve patients were diagnosed as having immunodeficiency associated inflammatory bowel disease (IBD)-like colitis. Conclusions: PID may present with GI manifestations or develop during the course of the disease. Investigating immunodeficiency in patients with atypical GI symptoms can provide an appropriate therapeutic option, and an improved quality of life, particularly in populations with a high rate of consanguinity.Publication Open Access Can Atopic Diseases be Differentiated from Hyper IgE Syndrome by Serum IgE and Blood Eosinophil Levels?(BILIMSEL TIP YAYINEVI, 2017-08-25) ÖZEN, AHMET OĞUZHAN; Kiykim, Ayca; Yuce, Ezgi Gizem; Baris, Ezgi; Nain, Ercan; Keles, Sevgi; Akturk, Hacer; Bakir, Mustafa; Ozen, Ahmet; Baris, Safa; Karakoc Aydiner, ElifObjective: High serum IgE and eosinophil counts are laboratory features of severe atopic dermatitis (AD), persistent food allergies and severe allergic asthma as well as some primary immune deficiencies (PID), especially hyperIgE syndrome (HIES). Our objective was to define cut-off values to discriminate atopic diseases and HIES by comparing serum IgE, eosinophil levels, allergen sensitizations among patients with AD, IgE-mediated food allergy, allergic asthma and/or rhinitis, chronic granulomatous disease and HIES. Materials and Methods: A total of 315 patients were enrolled into the study. We evaluated serum IgE (IU/L) and eosinophil (/mm3) values, allergen sensitizations and the age range of patients. ROC curve analysis was performed in order to define an optimal cut-off value for serum IgE levels and blood eosinophil counts. Results: The median levels of serum IgE and eosinophils were 2542 (min:1, max:55400) and 1000 (min:0, max:37880), respectively in the PID group. In the atopy group, the median serum IgE was 265 (min:4, max:7122), and median eosinophil count was 400 (min:0, max:6050). Serum IgE and blood eosinophil levels were significantly higher in PID patients compared to those with atopic diseases (p<0.001 and p<0.001, respectively). IgE was statistically higher in the food allergy group compared to only house dust mite sensitized and/or grass co-sensitized patients (p=0.008 and p=0.01, respectively). If the IgE cut-off values for HIES are considered to be equal to 2000 IU/l, the sensitivity accounted for 74% and the specificity for 96% (PPV:74%, NPV:96%). When serum IgE=5000 IU/l was considered as the cut-off, the sensitivity decreased to 56% in contrast to the specificity increasing to 99% (PPV:91%, NPV:94%). Similarly, for eosinophils=1500/mm3, the sensitivity was %51 and the specificity 96% (PPV:61%, NPV:93%) and for eosinophils=2500/mm3, the sensitivity was 41% while the specificity was 98% (PPV:76%, NPV: 92%) to discriminate HIES from atopic diseases. Conclusion: It is possible to discriminate atopic diseases from HIES when the cut-off values are used are 2500 IU/l for IgE and 1500/mm3 for eosinophils with ROC curve analysis. An atopic disease is the most likely underlying condition below these values. Moreover, patients with serum IgE higher than 5000 IU/l and/or blood eosinophils higher than 2500/mm3 should be managed as HIES unless otherwise proven.Publication Metadata only Evaluation of Hyperimmunoglobulin M Syndrome by Flow Cytometry(TURKISH SOC IMMUNOLOGY, 2015) ÖZEN, AHMET OĞUZHAN; Cinar, Suzan; Gelmez, Metin Yusuf; Baris, Safa; Aydiner, Elif Karakoc; Ozen, Ahmet Oguzhan; Akturk, Hacer; Barlan, Isil; Camcioglu, Yildiz; Deniz, GunnurObjectives: In this study, we discuss CD40 and CD40L expression findings in hyperimmunoglobuline M (HIGM) syndrome suspected patients obtained by flow cytometry. Patients and methods: Between May 2009 and February 2014, CD40 analysis was performed in 12 male (range, 4 months to 20 years) and eight female patients (range, 2 months to 28 years) and CD40 ligand (CD40L) analysis in eight male patients (range, 11 months to 20 years). Peripheral blood mononuclear cell (PBMC) samples were stained with anti-CD19, -CD45, -CD20 and -CD40 monoclonal antibodies and CD19(+)CD40(+) cells were detected in the flow cytometer. For the diagnosis of X-linked HIGM syndrome, isolated PBMCs were cultured in phorbol myristate acetate and ionomycin for four hours and then CD3(+)CD4(+)CD8(-)CD40L(+) cells were analyzed by flow cytometry. Results: Compared to the healthy controls, low CD40 expression in one female patient (0.09%) and low CD40L expression in three male patients (0.03%, 2.7% and 4%, respectively) were observed. Conclusion: Although flow cytometry is a quick and reliable method in the diagnosis of HIGM syndrome, additional genetic testing is required to establish the definite diagnosis.