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

Sujal Ghosh , Sevgi Köstel Bal , Emily Edwards , Bethany Pillay , Raúl Jiménez Heredia , Funda Erol Cipe , Geetha Rao , Elisabeth Salzer , Samaneh Zoghi , Hassan Abolhassani , Tooba Momen , Emma Gostick , David Price , Yu Zhang , Andrew Oler , Claudia Gonzaga-Jauregui , Baran Erman , Ayse Metin , Inci Ilhan , Sule Haskologlu , Candan Islamoglu , Kubra Baskin , Serdar Ceylaner , Ebru Yilmaz , Ekrem Unal , Musa Karakukcu , Dagmar Berghuis , Theresa Cole , Aditya Gupta , Fabian Hauck , Hubert Kogler , Andy Hoepelman , Safa Baris , Elif Karakoc-Aydiner , Ahmet Ozen , Leo Kager , Dirk Holzinger , Michael Paulussen , Renate Krüger , Roland Meisel , Prasad Oommen , Emma Morris , Benedicte Neven , Austen Worth , Joris van Montfrans , Pieter Fraaij , Sharon Choo , Figen Dogu , E. Graham Davies , Siobhan Burns , Gregor Dückers , Ruy Perez Becker , Horst von Bernuth , Sylvain Latour (1) , Maura Faraci , Marco Gattorno , Helen Su , Qiang Pan-Hammarström , Lennart Hammarström , Michael Lenardo , Cindy Ma , Tim Niehues , Asghar Aghamohammadi , Nima Rezaei , Aydan Ikinciogullari , Stuart Tangye , Arjan Lankester , Kaan Boztug

1 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)

Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity characterized predominantly by EBVassociated 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 CD27and 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.

Domaines: Sciences du Vivant [q-bio]

Sujal Ghosh, Sevgi Köstel Bal, Emily Edwards, Bethany Pillay, Raúl Jiménez Heredia, et al.. Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency. Blood, 2020, 136 (23), pp.2638-2655. ⟨10.1182/blood.2020006738⟩. ⟨hal-03066024⟩