Person: ÖZEN, AHMET OĞUZHAN
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ÖZEN
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AHMET OĞUZHAN
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Publication Open Access Mucus sialylation determines intestinal host-commensal homeostasis(2022-03-31) ÖZEN, AHMET OĞUZHAN; BARIŞ, SAFA; ERTEM ŞAHİNOĞLU, DENİZ; Yao Y., Kim G., Shafer S., Chen Z., Kubo S., Ji Y., Luo J., Yang W., Perner S. P., Kanellopoulou C., et al.Intestinal mucus forms the first line of defense against bacterial invasion while providing nutrition to support microbial symbiosis. How the host controls mucus barrier integrity and commensalism is unclear. We show that terminal sialylation of glycans on intestinal mucus by ST6GALNAC1 (ST6), the dominant sialyltransferase specifically expressed in goblet cells and induced by microbial pathogen-associated molecular patterns, is essential for mucus integrity and protecting against excessive bacterial proteolytic degradation. Glycoproteomic profiling and biochemical analysis of ST6 mutations identified in patients show that decreased sialylation causes defective mucus proteins and congenital inflammatory bowel disease (IBD). Mice harboring a patient ST6 mutation have compromised mucus barriers, dysbiosis, and susceptibility to intestinal inflammation. Based on our understanding of the ST6 regulatory network, we show that treatment with sialylated mucin or a Foxo3 inhibitor can ameliorate IBD.Publication Open Access A boy with a novel homozygous ZAP70 mutation presenting with a dermatological phenotype and postnatal decrease in CD8(+) T cells(2022-03-01) AYDINER, ELİF; ÖZEN, AHMET OĞUZHAN; BARIŞ, SAFA; Babayeva R., Mongellaz C., Karakus I. S., Cansever M., Bilgic Eltan S., Catak M. C., Bulutoglu A., Kendir Demirkol Y., Eser M., Karakoc-Aydiner E., et al.Patients with deficiency of zeta-chain-associated protein kinase 70 (ZAP-70) protein generally present as combined immunodeficiency (CID) with severe recurrent infections and dermatological findings during the first years of life. They also suffer from diarrhea, mainly resulting from viral agents, lymphoproliferation, and autoimmunity (autoimmune cytopenia, bullous pemphigoid, nephrotic syndrome, and adrenal insufficiency). The most striking immunological findings are severely decreased CD3+CD8+ T-cell counts with decreased proliferation. The current definitive treatment of ZAP-70 deficiency is hematopoietic stem cell transplantation (HSCT).1 To date, 52 patients with biallelic mutations in the ZAP70 gene have been described in the literature.1,2 Herein, we report a patient with a novel missense mutation in the ZAP70 who presented with atypical skin lesions and a rapid decrease in CD8+ T-cell counts on immunological evaluations between 6 and 9 months of age. Despite undetectable ZAP-70 protein, the patient did not present severe infections in the first year of life. This description expands the spectrum of disease caused by mutations in thePublication Open Access Clinical and laboratory factors affecting the prognosis of severe combined immunodeficiency(2022-07-01) ÖZTÜRK, ELİF; ÖZEN, AHMET OĞUZHAN; BARIŞ, SAFA; AYDINER, ELİF; Ozturk E., Catak M. C., Kiykim A., Baser D., Bilgic Eltan S., Yalcin K., Kasap N., Nain E., Bulutoglu A., Akgun G., et al.Purpose Severe combined immunodefciency (SCID) is one of the most severe forms of inborn errors of immunity characterized by absence or loss of function in T cells. The long-term outcomes of all forms of SCID have been evaluated in a limited number of studies. We aimed to evaluate the pre- and post-transplant manifestations of SCID patients and determine the factors afecting the survival of patients. Methods We included 54 SCID patients (classical SCID, Omenn syndrome, atypical SCID (AS)) in this study. We evaluated the clinical presentation, infections, and outcome of hematopoietic stem cell transplantation (HSCT). Lymphocyte subsets and T-cell receptor (TCR) repertoire were analyzed by fow cytometry. Results The median age at diagnosis was 5 (range: 3–24) months and follow-up time was 25 (range: 5–61) months. Symptom onset and diagnostic ages were signifcantly higher in AS compared to others (p = 0.001; p < 0.001). The most common SCID phenotype was T-B-NK +, and mutations in recombination-activating genes (RAG1/2) were the prominent genetic defect among patients. The overall survival (OS) rate was 83.3% after HSCT, higher than in nontransplanted patients (p =0.001). Peripheral blood stem cell sources and genotypes other than RAG had a signifcant favorable impact on CD4+ T cells immune reconstitution after transplantation (p=0.044, p=0.035; respectively). Gender matching transplantations from human leukocyte antigen (HLA)–identical and non-identical donors and using peripheral blood stem cell source yielded higher B-cell reconstitution (p=0.002, p=0.028; respectively). Furthermore, receiving a conditioning regimen provided better B-cell reconstitution and chimerism (p = 0.003, p = 0.001). Post-transplant TCR diversity was sufcient in the patients and showed an equal distribution pattern as healthy controls. The OS rate was lower in patients who underwent transplant with active infection or received stem cells from mismatched donors (p=0.030, p=0.015; respectively). Conclusion This study identifes diagnostic and therapeutic approaches predictive of favorable outcomes for patients with SCID.Publication Open Access Expanding the clinical and immunological phenotypes and natural history of MALT1 deficiency(2022-04-01) KOLUKISA, BURCU; BARIŞ, SAFA; ÖZEN, AHMET OĞUZHAN; AYDINER, ELİF; Sefer A. P., Abolhassani H., Ober F., KAYAOĞLU B., Eltan S. B., Kara A., ERMAN B., Yilmaz N. S., Aydogmus C., Aydemir S., et al.Purpose MALT1 deficiency is a combined immune deficiency characterized by recurrent infections, eczema, chronic diarrhea, and failure to thrive. Clinical and immunological characterizations of the disease have not been previously reported in large cohorts. We sought to determine the clinical, immunological, genetic features, and the natural history of MALT-1 deficiency. Methods The clinical findings and treatment outcomes were evaluated in nine new MALT1-deficient patients. Peripheral lymphocyte subset analyses, cytokine secretion, and proliferation assays were performed. We also analyzed ten previously reported patients to comprehensively evaluate genotype/phenotype correlation. Results The mean age of patients and disease onset were 33 +/- 17 and 1.6 +/- 0.7 months, respectively. The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%). Eosinophilia and high IgE were observed in six (67%) and two (22%) patients, respectively. The majority of patients had normal T and NK cells, while eight (89%) exhibited reduced B cells. Immunoglobulin replacement and antibiotics prophylaxis were mostly ineffective in reducing the frequency of infections and other complications. One patient received hematopoietic stem cell transplantation (HSCT) and five patients died as a complication of life-threatening infections. Analyzing this cohort with reported patients revealed overall survival in 58% (11/19), which was higher in patients who underwent HSCT (P = 0.03). Conclusion This cohort provides the largest analysis for clinical and immunological features of MALT1 deficiency. HSCT should be offered as a curative therapeutic option for all patients at the early stage of life.Publication Open Access Comparing the levels of CTLA-4-dependent biological defects in patients with LRBA deficiency and CTLA-4 insufficiency(2022-10-01) BARIŞ, SAFA; AYDINER, ELİF; ÖZEN, AHMET OĞUZHAN; Catak M. C., Akcam B., Bilgic Eltan S., Babayeva R., Karakus I. S., Akgun G., Baser D., Bulutoglu A., Bayram F., Kasap N., et al.Background Lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency and cytotoxic T-lymphocyte protein-4 (CTLA-4) insufficiency are recently described disorders that present with susceptibility to infections, autoimmunity, and lymphoproliferation. Clinical and immunological comparisons of the diseases with long-term follow-up have not been previously reported. We sought to compare the clinical and laboratory manifestations of both diseases and investigate the role of flow cytometry in predicting the genetic defect in patients with LRBA deficiency and CTLA-4 insufficiency. Methods Patients were evaluated clinically with laboratory assessments for lymphocyte subsets, T follicular helper cells (T-FH), LRBA expression, and expression of CD25, FOXP3, and CTLA4 in regulatory T cells (Tregs) at baseline and 16 h post-stimulation. Results LRBA-deficient patients (n = 29) showed significantly early age of symptom onset, higher rates of pneumonia, autoimmunity, chronic diarrhea, and failure to thrive compared to CTLA-4 insufficiency (n = 12). In total, 29 patients received abatacept with favorable responses and the overall survival probability was not different between transplanted versus non-transplanted patients in LRBA deficiency. Meanwhile, higher probability of survival was observed in CTLA-4-insufficient patients (p = 0.04). The T-cell subsets showed more deviation to memory cells in CTLA-4-insufficiency, accompanied by low percentages of Treg and dysregulated cT(FH) cells response in both diseases. Cumulative numbers of autoimmunities positively correlated with cT(FH) frequencies. Baseline CTLA-4 expression was significantly diminished in LRBA deficiency and CTLA-4 insufficiency, but significant induction in CTLA-4 was observed after short-term T-cell stimulation in LRBA deficiency and controls, while this elevation was less in CTLA-4 insufficiency, allowing to differentiate this disease from LRBA deficiency with high sensitivity (87.5%) and specificity (90%). Conclusion This cohort provided detailed clinical and laboratory comparisons for LRBA deficiency and CTLA-4 insufficiency. The flow cytometric approach is useful in predicting the defective gene; thus, targeted sequencing can be conducted to provide rapid diagnosis and treatment for these diseases impacting the CTLA-4 pathway.Publication Open Access Defective Treg generation and increased type 3 immune response in leukocyte adhesion deficiency 1(2023-08-01) ÖZEN, AHMET OĞUZHAN; Erdem S., Haskologlu S., Haliloglu Y., Celikzencir H., Arik E., Keskin O., Eltan S. B., Yucel E., Canatan H., Avcilar H., et al.In 15 Turkish LAD-1 patients and controls, we assessed the impact of pathogenic ITGB2 mutations on Th17/Treg differentiation and functions, and innate lymphoid cell (ILC) subsets. The percentage of peripheral blood Treg cells, in vitro-generated induced Tregs differentiated from naive CD4+ T cells were decreased despite the elevated absolute counts of CD4+ cells in LAD-1 patients. Serum IL-23 levels were elevated in LAD-1 patients. Post-curdlan stimulation, LAD-1 patient-derived PBMCs produced more IL-17A. Additionally, the percentages of CD18-deficient Th17 cells expanded from total or naïve CD4+ T cells were higher. The blood ILC3 subset was significantly elevated in LAD-1. Finally, LAD-1 PBMCs showed defects in trans-well migration and proliferation and were more resistant to apoptosis. Defects in de novo generation of Tregs from CD18-deficient naïve T cells and elevated Th17s, and ILC3s in LAD-1 patients\" peripheral blood suggest a type 3-skewed immunity and may contribute to LAD-1-associated autoimmune symptoms.Publication Open Access Increased radiosensitivity and impaired DNA repair in patients with STAT3-LOF and ZNF341 deficiency, potentially contributing to malignant transformations(2022-07-01) AYDINER, ELİF; ÖZEN, AHMET OĞUZHAN; BARIŞ, SAFA; Cekic S., Huriyet H., Hortoglu M., Kasap N., Ozen A. O., Karakoc-Aydiner E., Metin A., Ocakoglu G., Demiroz Abakay C., Temel S. G., et al.STAT3 plays an important role in various complex and sometimes contradictory pathways such as proliferation, differentiation, migration, inflammation, and apoptosis. The transcriptional activity of the STAT3 gene is controlled by a transcription factor called ZNF341. There is insufficient data on radiation sensitivity and post-radiation DNA repair in STAT3- loss-of-function (LOF) patients. We aimed to investigate the radiosensitivity in patients with STAT3-LOF and ZNF341 deficiency. Twelve patients with STAT3-LOF and four ZNF341-deficiency patients were recruited from three clinical immunology centers in Turkey and evaluated for radiosensitivity by the Comet assay, comparing to 14 age- and sex-matched healthy controls. The tail length (TL) (mu m), percentage of DNA in the tail (TDNA%), and olive tail moment (OTM) (arbitrary units) were evaluated at the same time for baseline (spontaneous), initial (immediately after 2 Gy irradiation), and recovery (2 h after irradiation) periods by using a computerized image-analysis system, estimating DNA damage. Except for a patient with ZNF341 deficiency who developed nasal cell primitive neuroendocrine tumor and papillary thyroid cancer during the follow-up, there was no cancer in both groups. During the recovery period of irradiation, TL, TDNA%, and OTM values of healthy controls decreased rapidly toward the baseline, while these values of patients with STAT3-LOF and ZNF341 deficiency continued to increase, implying impaired DNA repair mechanisms. Increased radiosensitivity and impaired DNA repair were demonstrated in patients diagnosed with STAT3-LOF and ZNF341 deficiency, potentially explaining the susceptibility to malignant transformation.Publication Open Access 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.Publication Open Access Expanding the clinical and immunological phenotypes and natural history of MALT1 deficiency(2022-04-01) KOLUKISA, BURCU; ÖZEN, AHMET OĞUZHAN; BARIŞ, SAFA; Sefer A. P., Abolhassani H., KAYAOĞLU B., Ober F., Bilgic-Eltan S., Kara A., ERMAN B., Surucu-Yilmaz N., Aydogmus C., AYDEMİR S., et al.Purpose MALT1 defciency is a combined immune defciency characterized by recurrent infections, eczema, chronic diarrhea, and failure to thrive. Clinical and immunological characterizations of the disease have not been previously reported in large cohorts. We sought to determine the clinical, immunological, genetic features, and the natural history of MALT-1 defciency. Methods The clinical fndings and treatment outcomes were evaluated in nine new MALT1-defcient patients. Peripheral lymphocyte subset analyses, cytokine secretion, and proliferation assays were performed. We also analyzed ten previously reported patients to comprehensively evaluate genotype/phenotype correlation. Results The mean age of patients and disease onset were 33±17 and 1.6±0.7 months, respectively. The main clinical fndings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%). Eosinophilia and high IgE were observed in six (67%) and two (22%) patients, respectively. The majority of patients had normal T and NK cells, while eight (89%) exhibited reduced B cells. Immunoglobulin replacement and antibiotics prophylaxis were mostly inefective in reducing the frequency of infections and other complications. One patient received hematopoietic stem cell transplantation (HSCT) and fve patients died as a complication of life-threatening infections. Analyzing this cohort with reported patients revealed overall survival in 58% (11/19), which was higher in patients who underwent HSCT (P=0.03). Conclusion This cohort provides the largest analysis for clinical and immunological features of MALT1 defciency. HSCT should be ofered as a curative therapeutic option for all patients at the early stage of life. Keywords Inborn errors of immunity · primary immunodefciency · MALT1 · combined immune defciency · immune dysregulation · recurrent infections · skin involvement · failure to thrive · hematopoietic stem cell transplantationPublication Open Access Immunologists’ Perspectives on Monogenic Inflammatory Bowel Diseases(2024-01-01) ÖZEN, AHMET OĞUZHAN; Osman M. J. A., Aydoğdu E. S., Mackeh R., ÖZEN A. O., Lo B.Inflammatory bowel diseases (IBD) encompass a group of chronic inflammatory disorders primarily impacting the gastrointestinal system, and they may also affect other organ systems. While common forms of IBD typically arise from multifactorial causes, there exists a subset of patients with single gene defects known as monogenic IBD (mIBD). Over 100 genes have been associated with mIBD, spanning various biological pathways which affect various tissues; the immune system is the most commonly involved, but more rarely, the intestinal epithelium is the primarily affected compartment. Timely diagnosis hinges on awareness and the application of contemporary molecular techniques. Due to the diverse range of causes, managing mIBD requires a multidisciplinary approach. Conventional treatments often fall short, necessitating a personalized strategy that considers the multifaceted nature of mIBD presentations and the diverse etiologic factors. In recent times, novel therapies have emerged, targeting specific causative genes or affected pathways. This discussion delves into the fundamental aspects of mIBD, with particular emphasis on recent breakthroughs in the field, encompassing newly identified gene defects and innovative management strategies.