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Öğe Biallelic form of a known CD3E mutation in a patient with severe combined immunodeficiency(Springer/Plenum Publishers, 2020) Erman, Baran; Fırtına, Sinem; Fışgın, Tunç; Bozkurt, Ceyhun; Erol Çipe, FundaT cell receptor (TCR) complex consists of ?? or ?? TCR chains in combination with four CD3 subunits, CD3?, CD3?, CD3?, and CD? [1]. This complex is required for thymocyte development and the initiation of T cell-mediated adaptive immune responses. Although TCR chains bind antigenic peptides presented by MHC molecules, the CD3 subunits provide transduction of signals into the cytosol for the activation and differentiation of T lymphocytes [2]. CD3 deficiencies can cause a rare form of severe combined immunodeficiency (SCID). Although CD3?, CD3?, and CD? mutations usually result in a T- B+ +NK+ SCID phenotype, CD3? deficiency leads to a milder phenotype with autoimmunity [3]. Only 2% of patients with SCID have TCR defects [3]. The T cell antigen receptor epsilon subunit (CD3E) gene is located at 11q23.3 and has been associated with autosomal recessive SCID [4]. Only a few mutations of the CD3E gene have been identified so far [4–8]. Here, we identified the biallelic form of a known CD3E mutation in a patient with a severe T- B+ NK+ phenotypeÖğe Defective kinase activity of IKKα leads to combined immunodeficiency and disruption of immune tolerance in humans(Nature Research, 2024) Çıldır, Gökhan; Aba, Ümran; Pehlivan, Damla; Tvorogov, Denis; Warnock, Nicholas I.; İpşir, Canberk; Arık, Elif; Kok, Chung Hoow; Bozkurt, Ceren; Tekeoğlu, Sidem; İnal, Gaye; Cesur, Mahmut; Küçükosmanoğlu, Ercan; Karahan, İbrahim; Savaş, Berna; Balcı, Deniz; Yaman, Ayhan; Demirbaş, Nazlı Deveci; Tezcan, İlhan; Haskoloğlu, Şule; Doğu, Figen; İkincioğulları, Aydan; Keskin, Özlem; Tümes, Damon J.; Erman, BaranIKKα is a multifunctional serine/threonine kinase that controls various biological processes, either dependent on or independent of its kinase activity. However, the importance of the kinase function of IKKα in human physiology remains unknown since no biallelic variants disrupting its kinase activity have been reported. In this study, we present a homozygous germline missense variant in the kinase domain of IKKα, which is present in three children from two Turkish families. This variant, referred to as IKKαG167R, is in the activation segment of the kinase domain and affects the conserved (DF/LG) motif responsible for coordinating magnesium atoms for ATP binding. As a result, IKKαG167R abolishes the kinase activity of IKKα, leading to impaired activation of the non-canonical NF-κB pathway. Patients carrying IKKαG167R exhibit a range of immune system abnormalities, including the absence of secondary lymphoid organs, hypogammaglobulinemia and limited diversity of T and B cell receptors with evidence of autoreactivity. Overall, our findings indicate that, unlike a nonsense IKKα variant that results in early embryonic lethality in humans, the deficiency of IKKα‘s kinase activity is compatible with human life. However, it significantly disrupts the homeostasis of the immune system, underscoring the essential and non-redundant kinase function of IKKα in humans. © The Author(s) 2024.Öğe Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency(2020) Ghosh, Sujal; Bal, Sevgi Köstel; Edwards, Emily S J; Pillay, Bethany; Jimenez-Heredia, Raúl; Rao, Geetha; Erol Çipe, Funda; Salzer, Elisabeth; Zoghi, Samaneh; Abolhassani, Hassan; Momen, Tooba; Gostick, Emma; Price, David A; Zhang, Yu; Oler, Andrew J; Gonzaga-Jauregui, Claudia; Erman, Baran; Metin, Ayşe; İlhan, İnci; Haskoloğlu, Şule; İslamoğlu, Candan; Baskın, Kübra; Ceylaner, Serdar; Yılmaz, Ebru; Ünal, Ekrem; Karakukcu, Musa; Berghuis, Dagmar; Cole, Theresa; Gupta, Aditya Kumar; Hauck, Fabian; Hoepelman, Andy; Barış, Safa; Karakoç Aydıner, Elif; Özen, Ahmet; Kager, Leo; Holzinger, Dirk; Paulussen, Michael; Krüger, Renate; Meisel, Roland; Oommen, Prasad Thomas; Morris, Emma C; Neven, Benedicte; Worth, Austen J J; Montfrans, Joris M van; Fraaij, Pieter; Choo, Sharon; Doğu, Figen; Davies, E Graham; Burns, Siobhan; Dueckers, Gregor; Becker, Ruy Perez; Bernuth, Horst von; Latour, Sylvain; Faraci, Maura; Gattorno, Marco; Su, Helen; Pan-Hammarström, Qiang; Hammarström, Lennart; Lenardo, Michael J; Ma, Cindy S; Niehues, Tim; Aghamohammadi, Asghar; Rezaei, Nima; Ikinciogullari, Aydan; Tangye, Stuart G; Lankester, Arjan C; Boztuğ, KaanBiallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity characterized predominantly by EBV-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation and malignancy. A comprehensive understanding of the natural history, immune characteristics and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected clinical information of 49 patients from 29 families (CD27 n=33, CD70 n=16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority (90%) of patients were EBV+ at diagnosis, but only ~30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one (43%) patients developed autoinflammatory features including uveitis, arthritis and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.Öğe Genetic screening of the patients with primary immunodeficiency by whole-exome sequencing(New Rochelle, 2020) Erman, Baran; Erol Çipe, FundaBackground: Primary immunodeficiencies (PIDs) are a heterogeneous group of congenital disorders characterized by susceptibility to recurrent infections, allergy, malignancies and autoimmunity. The identification of disease-causing genetic defects is critically important for treatment options. In last decade, next-generation sequencing (NGS)-based methods has enabled the rapid genetic screening and the discovery of new genetic defects in PIDs. In this study, we investigated causative mutations in patients with PID by NGS. Methods: We applied whole-exome sequencing in 8 PID patients. Detected mutations by NGS were validated by Sanger sequencing. Results: We made a genetic diagnosis in 5 of 8 (63%) patients, including 3 novel disease-causing variants. The identified mutations were found in RAG1, RAG2, JAK3, RFXANK, and CYBA genes. Conclusions: Our results show that whole-exome sequencing can facilitate the genetic diagnosis of the patients with PID.Öğe IgE and IgG4 binding to lentil epitopes in children with red and green lentil allergy(Wiley, 2020) Saçkesen, Cansın; Erman, Baran; Gimenez, Gustavo; Grishina, Galina; Yılmaz, Özlem; Yavuz, Süleyman T.; Şahiner, Ümit M.; Büyüktiryaki, Betül; Yılmaz, Ebru A.; Çavkaytar, Özlem; Sampson, Hugh A.Background The consumption of lentil is common in the Mediterranean area and is one of the causes of IgE-mediated food allergy in many countries. Len c 1 is a well-defined allergen of lentil and approximately 80% of the patients with lentil allergy recognize the purified Len c 1 protein. We sought to identify IgE and IgG4 sequential epitopes of Len c 1 in patients with red and/or green lentil allergy. We also aimed to determine IgE and IgG4 binding differences between those patients who had outgrown or remained reactive to lentil. Methods Children with IgE-mediated lentil allergy were included in the study. We applied a microarray immunoassay to determine the characterization of positive IgE and IgG4 binding to Len c 1 epitopes in the patients' sera. Results The peptides specifically recognized by IgE and IgG4 antibodies were mainly detected between peptides 107 and 135 of Len c 1. The signal intensities of positive epitopes were significantly greater in reactive patients than tolerant ones (P = .008 for IgE and P = .002 for IgG4). Moreover, IgE and IgG4 antibodies bound largely the same sequential epitopes in patients who remained reactive or outgrew their allergy. Conclusion IgG4-binding epitopes in lentil allergy were identified and IgE and IgG4 binding to epitopes in both red and green lentils was compared. Our data regarding signal intensity differences between reactive and outgrown patients and overlap binding of IgE and IgG4 antibodies may be important for the development of more accurate diagnostic tests and understanding of natural tolerance development.Öğe Immune reconstitution in the patients with talasemia major after hematopoietic stem cell transplantation(Turkish Society of Immunology, 2020) Erman, Baran; Adaklı Aksoy, BaşakGiriş: Beta?talasemi (??TM) otozomal resesif kalıtım gösteren, dünyada en yaygın hematolojik hastalıklardan birdir. Hematopoietik kök hücre transplantasyonu (HKHT) tek tedavi edici yöntem olduğundan transplantasyon sonrası hücresel immün yeniden yapılanmanın belirlenmesi başarılı klinik sonuçların anlaşılması için kritik öneme sahiptir. Bu çalışmada kök hücre transplantasyonu yapılan pediatrik yaş grubu talasemi major hastalarında lenfoid seri hücrelerin yeniden yapılanması değerlendirilmiştir. Gereçler ve Yöntemler: Kök hücre transplantasyonu yapılan 20 beta talasemili hasta çalışmaya dahil edilmiştir. Hastaların klinik ve laboratuvar bilgileri geçmişe yönelik değerlendirilmiştir. Bulgular: Transplantasyondan bir sene sonra, tüm hastalar sağ ve kan transfüzyonuna gerek duymayan bir durumdadır. Hastaların büyük çoğunluğunda CD4+ T hücre yapılanması düşüktür ve CD4+ /CD8+ hücre oranları bozulmuştur. Diğer lenfoid seri hücrelerinin yüzde ve sayıları 12 ay içinde genel olarak normal değerlere ulaştı. On yedi hastada tam donör kimerizmi görülürken yalnızca 3 hastada karışık donör kimerizmi saptandı ve yüzdeleri %55–86 arasında değişmekte idi. Sonuç: Başarılı klinik sonuçlar ve immün yeniden yapılanmaya rağmen hastaların dikkatli takip edilmesi gerekmektedir. Çünkü CD4+ T hücrelerin yapılanmasının düşük olması hastalarda ciddi enfeksiyon riski yaratabilir.Öğe Invasive saprochaete capitata Infection in a patient with autosomal recessive CARD9 deficiency and a review of the literature(Springer/Plenum Publishers, 2020) Erman, Baran; Fırtına, Sinem; Aksoy, Başak Adaklı; Aydoğdu, Selime; Genç, Gonca Erköse; Doğan, Öner; Bozkurt, Ceyhun; Fışgın, Tunç; Erol Çipe, FundaPurpose Autosomal recessive (AR) CARD9 deficiency is an inherited immune disorder which results in impaired innate immunity against various fungi. Superficial and invasive fungal infections, mainly caused by Candida or Trichophyton species, are the hallmark of CARD9 deficiency. Together with the increasing number of CARD9-deficient patients reported, different pathogenic fungal species have been described such as Phialophora, Exophiala, Corynespora, Aureobasidium, and Ochroconis. Saprochaete capitata is an opportunistic infectious agent in immunocompromised patients and is a common cause of invasive fungal disease in patients with hematological malignancies. In this study, we investigated the causative genetic defect in a patient with S. capitata fungal infection which disseminated to lymph nodes and common bile duct. Methods The identification of the isolated yeast strain was made by direct microscopic examination and confirmed by internal transcribed spacer (ITS) sequencing. We applied whole exome sequencing to search for the disease-causing mutation. Sanger sequencing was used to validate the mutation in the patient and his parents. Results S. capitata was isolated from the biopsy specimen as the causative microorganism responsible for the invasive fungal disease in the patient. Whole exome sequencing revealed a homozygous c.883C > T, (p.Q295*) mutation in CARD9, confirmed by Sanger sequencing. Conclusions This is the first report of invasive Saprochaete infection associated with autosomal recessive (AR) CARD9 deficiency in the literature and thereby further extends the spectrum of fungal diseases seen in these patients.
