Study Identifies First Case of Spontaneous Genetic Correction in Severe Immunodeficiency

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. CD137 deficiency is an inborn error of immunity first described in 2019 and caused by a mutation in the TNFRSF9 gene. In patients with CD137 deficiency, CD8 T cells (a type of immune cell) are unable to mount an adequate response to EBV infection, which 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.

The case involved a patient who presented with severe clinical manifestations of EBV infection in 2012, at the age of 13, including the development of lymphoma. While the genetic cause of her condition was unknown, she received 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 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, the patient unexpectedly experienced spontaneous clinical improvement and viral control without substantial changes in treatment. When her immune cells in the blood were analyzed using innovative single-cell sequencing techniques, they discovered two CD8 T-cell lines derived from her brother had naturally corrected the original mutation once inside the patient’s body (post-transplant), known as somatic reversion.

Up to 20 percent 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 Laura Batlle Masó, PhD, 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.

According to the researchers, this discovery is highly relevant from a scientific standpoint, as it provides proof of concept for the viability of future gene therapies.