Somatic reversion in CD137 deficiency correlating with Epstein-Barr virus control and clinical improvement
Year: 2025
Type: article
Study design: Case Report
Abstract: Epstein-Barr virus (EBV) is an oncogenic virus ubiquitous in human populations. CD8 T cells play a crucial role in establishing a strong anti-EBV immune response. Among the various inborn errors of immunity (IEI) showing a restricted vulnerability to EBV, TNFRSF9 (CD137, 4-1BB) deficiency was described in 2019 in patients with chronic EBV viremia and EBV-associated lymphoproliferative diseases. We here investigated a patient with a history of chronic EBV infection and CD137 deficiency who had previously undergone transplantation from her HLA-identical brother. We found that the brother was also a homozygous carrier of the same TNFRSF9 variant, explaining the patient's inability to control EBV after transplantation. Remarkably, during a period of spontaneous clinical improvement and EBV control, we detected two somatic variants in the patient, which resulted in the emergence of two independent revertant CD8 T cell clones that accounted for up to 20% of CD8 T cells in peripheral blood. Using single cell RNA sequencing we demonstrated that both revertant clones originated post-transplant from donor-derived cells. We report here the first described case of a somatic reversion phenomenon in TNFRSF9 deficiency, correlating with clinical improvement and paving the way for future gene therapy strategies for this IEI.
Source: npj Genomic Medicine
Authors: Laura Batlle-Masó, Joan Padrosa Pulido, Anna Esteve-Codina, Janire Perurena-Prieto, Clara Franco-Jarava, Aina Aguiló-Cucurull, Mónica Martínez-Gallo, Cristina Cea, Marta Rodriguez-Aliberas, Pere Soler-Palacín, Ferran Casals, Sara Redondo Velao, Montserrat Torrent, Laia Alsina, Roger Colobran
Institutions: Vall d'Hebron Institut de Recerca, Vall d'Hebron Hospital Universitari, Centre for Biomedical Network Research on Rare Diseases, Hospital Clínic de Barcelona, Centro Nacional de Análisis Genómico, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de Barcelona, Universitat Autònoma de Barcelona, Hospital Universitari Joan XXIII de Tarragona, Institut Català de la Salut, Banc de Sang i Teixits, Instituto de Salud Carlos III, Institut de Recerca Sant Joan de Déu, Institut de Biomedicina de la Universitat de Barcelona, Hospital de Sant Pau, Josep Carreras Leukaemia Research Institute, Hospital Sant Joan de Déu Barcelona
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,190
Awards: G1208641939, G121809054, G1568148067, G1622782223, G2660406951, G3480869486, G4596800910, Identificación y caracterización funcional de variantes genéticas estructurales en pacientes con errores congénitos de la inmunidad., G6219869690, Integración de perfiles genómicos y transcriptómicos para la identificación de nuevas bases genéticas en las inmunodeficiencias primarias., G7084143925
OpenAlex ID: W4416794200