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

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

Journal: Blood 2021;136(23):2638-2655

PMID: 32603431

Free Full Text on Elsevier Science View on PubMed

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.

Address: Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Germany.; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.; St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.; Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.; St. Vincent's Clinical School, UNSW Sydney, Randwick, NSW, Australia.; Department of Pediatric Allergy and Immunology, Istinye University, Istanbul, Turkey.; St. Anna Children's Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.; Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.; Department of Allergy and Clinical Immunology, Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran.; Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.; Vaccine Research Center.; Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research.; Clinical Genomics Program, and.; Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD.; Regeneron Genetics Center, Tarrytown, NY.; Institute of Child Health, Hacettepe University, Ankara, Turkey.; Can Sucak Research Laboratory for Translational Immunology, Center for Genomics and Rare Diseases, Hacettepe University, Ankara, Turkey.; Division of Pediatric Allergy and Immunology, University of Health Sciences/Ankara City Hospital/Children's Hospital, Ankara, Turkey.; Division of Pediatric Oncology, University of Health Sciences/Ankara City Hospital/Children's Hospital, Ankara, Turkey.; Department of Pediatric Allergy and Immunology, School of Medicine, Ankara University, Ankara, Turkey.; Intergen Genetic Diagnosis and Research Center, Ankara, Turkey.; Department of Pediatrics, Division of Pediatric Hematology & Oncology & Molecular Biology and Genetic Department, Erciyes University, Kayseri, Turkey.; Gevher Nesibe Genom and Stem Cell Institution, GENKOK Genome and Stem Cell Center, Erciyes University, Kayseri, Turkey.; Willem-Alexander Children's Hospital, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.; Department of Allergy and Immunology, The Royal Children's Hospital, Melbourne, VIC, Australia.; Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.; Dr von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany.; Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.; Division of Allergy and Immunology, Marmara University, Istanbul, Turkey.; The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey.; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey.; Department of Pediatric Hematology-Oncology, University of Duisburg-Essen, Essen, Germany.; Vestische Kinder-und Jugendklinik, Witten/Herdecke University, Datteln, Germany.; Department of Pediatric Pulmonology, Immunology, and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.; Institute of Immunity & Transplantation, University College London, Royal Free Hospital, London, United Kingdom.; Unité d'Immuno-Hematologie et Rhumatologie, Département de Pédiatrie Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.; INSERM U1163, Imagine Institute, Université de Paris, Paris, France.; UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.; Department of Pediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital, UMC Utrecht, Utrecht, The Netherlands.; Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.; Department of Pediatrics, Subdivision Infectious Diseases and Immunology, Erasmus MC-Sophia, Rotterdam, The Netherlands.; Department of Immunology, Royal Free London National Health Service (NHS) Foundation Trust, London, United Kingdom.; Department of Pediatrics, Helios Children's Hospital, Krefeld, Germany.; Department of Immunology, Labor Berlin GmbH, Berlin, Germany.; Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany.; Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM U1163, Imagine Institute, Université de Paris, Paris, France.; Hematopoietic Stem Cell Transplantation Unit and Istituto di Ricovero e Cura Pediatrico a Carattere Scientifico (IRCSS) Istituto Giannina Gaslini Research Institute Genova, Italy.; Center for Autoinflammatory Diseases and Immunodeficiency, Istituto di Ricovero e Cura Pediatrico a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genova, Italy.; Department of Biosciences and Nutrition (NEO), Karolinska Institutet, Karolinska, Sweden.; Beijing Genomics Institute (BGI) Shenzhen, Shenzhen, China.; Molecular Development of the Immune System Section, Laboratory of Immune System Biology, NIAID, National Institutes of Health, Bethesda, MD.; Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran; and.; Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

DOI: 10.1182/blood.2020006738