A study recently published in the renowned journal Blood, led by Kaan Boztug, Scientific Director of the St. Anna Children’s Cancer Research Institute, the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Adjunct Principal Investigator at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and Associate Professor at the Medical University of Vienna, together with scientists from Israel, Germany, Turkey, Colombia, Argentina and the USA, investigated four patients from independent families with malignancy, autoimmunity and immunodeficiency. All four patients had a germline mutation in the gene encoding CD137, which led to a dysfunction of the co-receptor protein CD137.
‘CD137 deficiency is a novel inborn error of immunity with immune dysregulation and EBV-related lymphomagenesis.’
This dysfunction impaired crucial factors for immune surveillance, in particular for the prevention of viral infections and the development of lymphoma associated with Epstein-Barr virus (EBV) infection.
“Not only did we discover a new tumor predisposition syndrome particularly for childhood lymphomas in this study, we also learned more about the basic function of CD137 in the immune system,” says Kaan Boztug, joint corresponding and last author, together with colleagues Raz Somech from the Chaim Sheba Medical Center in Tel Aviv and Christoph Klein from the Dr. von Hauner Children’s Hospital of the LMU Munich.
The disease mechanism in detail:
Co-receptors play a fundamental role in regulating and fine-tuning the signal strength of so-called antigen receptors, which help immune cells to recognize foreign bodies. An impaired function of these immune receptors can lead to an increased susceptibility to infections, autoimmune disorders, and cancer. CD137 or 4-1BB is a co-stimulatory molecule which is frequently expressed on activated T cells to ensure a proper T cell function. Recent studies have also investigated CD137 as an attractive target for cancer immunotherapy.
EBV is a herpes virus that infects more than 90% of all people and remains latent in the body for life. In individuals with impaired T-cell function, EBV infection can lead to lymphoproliferative disorders all the way to malignant lymphomas. Co-first author Marini Thian states: “For me as a biologist and Ph.D. student in the lab, it’s exciting to see how we bridge the gap from deep genetic analysis to understanding the disrupted immune response, in particular to EBV virus infection.”
Diseases caused by a defect in a single gene, e.g., for CD137, provide unique opportunities to investigate the consequences of such errors for the whole organism. Thus, we can gain mechanistic insights into the signal pathways necessary for robust immune surveillance of the host against EBV.
In summary, this study demonstrates the key role of CD137 in the control of EBV virus by the immune system. If the body fails to keep the virus under control, it can lead to the development of lymphomas. In the future, scientists want to use their findings to develop and use targeted therapeutics that can stop this dangerous disease process.