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    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, Kaan
    Biallelic 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.