Identification of a new key player in the immune control of Epstein-Barr virus infection

In their work published on 20 March 2024 in the scientific journal Nature, the team led by Sylvain Latour, CNRS researcher at Institut Imagine (Inserm, Université Paris Cité, AP-HP), has just identified an inherited genetic disease responsible for poor immune control during primary infection by the Epstein-Barr virus, leading to severe mononucleosis. They have also demonstrated the major role played by the inflammatory cytokine IL-27 and its receptor in the immune response to this infection.

Published on 20.03.2024

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Infection with the Epstein-Barr virus (EBV) can lead to serious lymphoproliferative diseases, including cancers of the B lymphocytes, the key cells in the immune response and the main target of the infection. However, the initial infection often remains asymptomatic, or causes only infectious mononucleosis, a limited lymphoproliferative disorder. Selective vulnerability to EBV has been reported in association with inherited mutations. In this work published in the journal Nature, the "Lymphocyte activation and susceptibility to Epstein-Barr virus" team, led by Sylvain Latour, CNRS researcher at Institut Imagine, reports a new inherited disease affecting the immune response to primary EBV infection. This work was initiated by Sarah Winter, a PhD student in the team, who identified the first mutations in the IL27RA gene. Following her departure, the work was continued by Emmanuel Martin, researcher.

The mutations identified affect the IL27RA gene, which encodes a subunit of the receptor for IL-27 (interleukin-27), a cytokine whose role in the immune response to EBV infection was previously unknown. When first infected with EBV, patients with this mutation suffered a severe mononucleosis syndrome associated with significant symptoms (persistent fever, hepatitis and splenomegaly), which led to hospitalisation and persisted for several months. Nevertheless, the outcome remained favourable and the patients did not develop B-cell cancer, a complication frequently observed when infection is poorly controlled.

The team therefore sought to understand how mutation of the IL27RA gene affected the effectiveness of the IL-27 receptor and increased susceptibility to infection by the virus. In the absence of IL27RA, the team showed that the effector T lymphocytes responsible for eliminating EBV-infected B lymphocytes amplify poorly and their cytotoxic function is impaired. This deficiency in the T lymphocytes responsible for eliminating infected B cells would explain the abnormal response to the initial EBV infection, which is not properly controlled in patients.

In parallel, the team observed that IL-27 is produced by B lymphocytes when they are infected by EBV. However, the team also showed that a signalling loop involving IL27RA and IL-27 is necessary for the maintenance of EBV-transformed B lymphocytes. In the absence of IL27RA in patients with the mutation, the maintenance of this population of EBV-transformed cells is likely to be impaired. This could explain the favourable outcome of EBV-induced viral disease in IL27RA-deficient patients.

Finally, the team also detected IL-27 neutralising autoantibodies in most people who developed sporadic infectious mononucleosis. The presence of these neutralising autoantibodies confirms the critical role of IL27RA-IL-27 immunity against EBV.

From a therapeutic point of view, these observations open up the possibility of manipulating the IL-27 pathway. Inactivation of the IL-27 pathway could represent a new therapeutic avenue for the treatment of EBV-related lymphoproliferative disorders, as in the case of patients receiving immunosuppressive treatment.

 

Reference : Role of IL-27 in Epstein-Barr virus infection revealed by IL27RA deficiency’. Emmanuel MArtin et. al, Nature, march 20 2024

Corresponding author : Sylvain Latour

DOI : https://doi.org/10.1038/s41586-019-0000-0