A study led by the Translational Immunology Group at the Vall d’Hebron Research Institute (VHIR) has identified, for the first time, 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. The study, published in npj Genomic Medicine, was carried out in collaboration with the Infection and Immunity in the Paediatric Patient Group at VHIR, the National Centre for Genomic Analysis (CNAG), Sant Joan de Déu Hospital, Hospital de la Santa Creu i Sant Pau and the Blood and Tissue Bank.

Inborn 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 cells, 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 lead to severe consequences, but in patients with this deficiency, it may persist for years and can 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 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.

Vall d’Hebron, a reference centre in immunodeficiencies

Vall d’Hebron has played a key role in this finding as a reference centre for primary immunodeficiencies. It is a national reference centre (CSUR) for primary immunodeficiencies, a member of the European network ERN-RITA, and part of the Jeffrey Modell Foundation, which also enables advances in research to improve the diagnosis and treatment of patients with these disorders.

This research was directly funded by the Instituto de Salud Carlos III through projects PI20/00761 and PI23/00161, co-funded by the European Regional Development Fund (ERDF), with support from the Jeffrey Modell Foundation. It also received support from the European Reference Network for Rare Immunological, Autoinflammatory and Autoimmune Diseases (ERN-RITA). Dr Laura Batlle-Masó is supported by a “Sara Borrell” postdoctoral fellowship (CD24/00011) from the Instituto de Salud Carlos III.

Other funding agencies linked to this study include: Ministry of Science and Innovation (project PID2021-125106OB-C32), the Catalan Agency for Management of University and Research Grants (AGAUR) (2021SGR01093). The National Centre for Genomic Analysis (CNAG) receives institutional support from the Ministry of Science and Innovation through the Instituto de Salud Carlos III, and from the Government of Catalonia through the Department of Health and the Department of Research and Universities.