Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency
Authors: 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 
Published: June 2020

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.