Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency.
Клиническое исследованиеСтатьяМногоцентровое исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Ghosh Sujal, Köstel Bal Sevgi, Edwards Emily S J, Pillay Bethany, Jiménez Heredia Raúl, Erol Cipe Funda, Rao Geetha, Salzer Elisabeth, Zoghi Samaneh, Abolhassani Hassan, Momen Tooba, Gostick Emma, Price David A, Zhang Yu, Oler Andrew J, Gonzaga-Jauregui Claudia, Erman Baran, Metin Ayse, Ilhan Inci, Haskologlu Sule, Islamoglu Candan, Baskin Kubra, Ceylaner Serdar, Yilmaz Ebru, Unal Ekrem, Karakukcu Musa, Berghuis Dagmar, Cole Theresa, Gupta Aditya K, Hauck Fabian, Kogler Hubert, Hoepelman Andy I M, Baris Safa, Karakoc-Aydiner Elif, Ozen Ahmet, Kager Leo, Holzinger Dirk, Paulussen Michael, Krüger Renate, Meisel Roland, Oommen Prasad T, Morris Emma, Neven Benedicte, Worth Austen, van Montfrans Joris, Fraaij Pieter L A, Choo Sharon, Dogu Figen, Davies E Graham, Burns Siobhan, Dückers Gregor, Becker Ruy Perez, von Bernuth Horst, Latour Sylvain, Faraci Maura, Gattorno Marco, Su Helen C, 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, Boztug Kaan
Аннотация
Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (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 the 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 of patients (90%) 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 patients (43%) 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.