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Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency.


ABSTRACT: 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.

SUBMITTER: Ghosh S 

PROVIDER: S-EPMC7735164 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency.

Ghosh Sujal S   Köstel Bal Sevgi S   Edwards Emily S J ESJ   Pillay Bethany B   Jiménez Heredia Raúl R   Erol Cipe Funda F   Rao Geetha G   Salzer Elisabeth E   Zoghi Samaneh S   Abolhassani Hassan H   Momen Tooba T   Gostick Emma E   Price David A DA   Zhang Yu Y   Oler Andrew J AJ   Gonzaga-Jauregui Claudia C   Erman Baran B   Metin Ayse A   Ilhan Inci I   Haskologlu Sule S   Islamoglu Candan C   Baskin Kubra K   Ceylaner Serdar S   Yilmaz Ebru E   Unal Ekrem E   Karakukcu Musa M   Berghuis Dagmar D   Cole Theresa T   Gupta Aditya K AK   Hauck Fabian F   Kogler Hubert H   Hoepelman Andy I M AIM   Baris Safa S   Karakoc-Aydiner Elif E   Ozen Ahmet A   Kager Leo L   Holzinger Dirk D   Paulussen Michael M   Krüger Renate R   Meisel Roland R   Oommen Prasad T PT   Morris Emma E   Neven Benedicte B   Worth Austen A   van Montfrans Joris J   Fraaij Pieter L A PLA   Choo Sharon S   Dogu Figen F   Davies E Graham EG   Burns Siobhan S   Dückers Gregor G   Becker Ruy Perez RP   von Bernuth Horst H   Latour Sylvain S   Faraci Maura M   Gattorno Marco M   Su Helen C HC   Pan-Hammarström Qiang Q   Hammarström Lennart L   Lenardo Michael J MJ   Ma Cindy S CS   Niehues Tim T   Aghamohammadi Asghar A   Rezaei Nima N   Ikinciogullari Aydan A   Tangye Stuart G SG   Lankester Arjan C AC   Boztug Kaan K  

Blood 20201201 23


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 coll  ...[more]

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