Malignancy and Autoimmune Susceptibility in Adult Patients with Human Inborn Errors of Immunity.

Abstract

Inborn errors of immunity (IEI) are a heterogeneous group of genetic disorders that disrupt the normal development and function of the immune system. These diseases not only increase susceptibility to infections but also significantly elevate the risk of developing malignancies and autoimmune diseases. The interplay between immune dysregulation, chronic inflammation, and altered cellular homeostasis in IEI can lead to aberrant cellular proliferation and self-reactive immune responses. Malignancy in IEI often arises due to the immune system's failure to effectively eliminate transformed cells, predisposing patients to lymphomas, leukemias and solid tumors. Autoimmune diseases in IEI can result from defective T-regulatory cell function, impaired central or peripheral tolerance mechanisms or B-cell dysregulation leading to autoantibody production. This work was a retrospective study of 173 adults with IEI suspicion who underwent genetic sequencing between 2005 and 2023. A significant increase of malignancies was observed in patients with a molecular diagnosis (w_MolDx) compared to those without (wo_MolDx). Notably, hematologic malignancies were predominant in the w_MolDx cohort, whereas solid tumors were more frequently observed in the wo_MolDx group. In contrast, the correlation between autoimmune diseases and molecular diagnosis was less evident when comparing w_MolDx and wo_MolDx patients. Understanding the complex relationship between IEI, malignancies and autoimmunity is crucial for optimizing patient management. Early diagnosis of IEI allows for timely interventions, including hematopoietic stem cell transplantation, gene therapy and targeted immunomodulatory therapies, which can mitigate the risk of both malignancies and autoimmune complications.