Researchers from the National Center for Genomic Analysis (CNAG), located at the Barcelona Science Park, have participated in a study led by the Infection and Immunity in Pediatric Patients group at VHIR, in collaboration with Hospital Sant Joan de Déu, Hospital de la Santa Creu i Sant Pau, and the Blood and Tissue Bank, which for the first time identifies a case of spontaneous correction of a genetic mutation in a patient with CD137 deficiency, a rare immunodeficiency that causes vulnerability to Epstein–Barr virus (EBV) infection.

Congenital errors of immunity are disorders caused by genetic mutations that affect the functioning of the immune system. CD137 deficiency is one of these conditions, first described in 2019 and caused by a mutation in the TNFRSF9 gene. In these patients, CD8 T lymphocytes, a type of immune cell, are unable to mount an adequate response to Epstein–Barr virus infection. This infection is very common in the general population and usually does not cause serious consequences, but in patients with this deficiency, it can persist for years and may even lead to certain types of lymphoma.

A unique case of spontaneous improvement after a transplant

The patient described in the study first presented with severe clinical manifestations of Epstein–Barr virus (EBV) infection in 2012, at the age of 13, including the development of lymphoma. At that time, the genetic cause of her condition was still unknown, and she was therefore referred to Hospital de Sant Pau to undergo a bone marrow transplant from her brother, who was compatible and apparently healthy. The transplant enabled most T cells in her blood to originate from her brother; however, the patient continued to present high levels of the virus for years without clinical improvement. In 2019, her inclusion in a research project led by the Translational Immunology Group using high-throughput sequencing techniques enabled the genetic diagnosis of her condition: CD137 deficiency. It was also discovered that her brother carried the same mutation, despite being clinically asymptomatic, which explained why the patient had not improved after the transplant.

A few years after the transplant, and unexpectedly, the patient experienced spontaneous clinical improvement and viral control without substantial changes in treatment. When the VHIR team, together with CNAG, analysed her immune cells in the blood using innovative single-cell sequencing techniques, they discovered that two CD8 T-cell lines derived from her brother had naturally corrected the original mutation once inside the patient’s body (post-transplant).

“This approach allowed us to determine that the cells with the corrected mutation originated from the donor, not the patient, and to observe that some of these cells were proliferating preferentially. This indicated that these cells had acquired a functional advantage within the immune system and that the phenomenon was not random,” says Dr Anna Esteve, author of the study and Leader of the Functional Genomics Team at CNAG.

This phenomenon is known as somatic reversion. In total, up to 20% of T cells in the blood showed this genetic reversion. “At some point after the transplant, these somatic mutations emerged and corrected the original genetic defects. This partially restored the immune response against the virus and improved the patient’s clinical condition,” explains Dr Laura Batlle Masó, postdoctoral researcher in the Translational Immunology Group at VHIR. “This phenomenon had previously been described in other inborn errors of immunity, but this is the first time it has been detected in this particular disorder and, moreover, after a transplant,” she adds.

Over the years, the number of corrected cells has decreased, although they remain detectable in the patient’s body. This decrease has coincided with an increase in viral load, making her medium-term clinical prognosis uncertain.

This discovery is highly relevant from a scientific standpoint, as it provides proof of concept for the viability of future gene therapies. “The somatic reversion observed in this patient indicates that even a small proportion of corrected cells can improve the immune response to EBV, resulting in significant clinical benefit. This finding opens the door to the development of gene therapy for this disease. Since current gene therapies do not correct all target cells, demonstrating that partial restoration of immune function can translate into meaningful clinical benefit is essential,” explains Dr Roger Colobran, head of the Translational Immunology Group at VHIR.

» Article of reference: Batlle-Masó, Laura, et al. ‘Somatic Reversion in CD137 Deficiency Correlating with Epstein-Barr Virus Control and Clinical Improvement’. Npj Genomic Medicine, vol. 10, no. 1, Nov. 2025, p. 78. https://doi.org/10.1038/s41525-025-00535-y.

» Access to the news: CNAG website [+]