Autoimmunity and inborn errors of immunity: a complex coexistence

Inborn errors of immunity (IEI) and autoimmune diseases represent two major consequences of immune system dysregulation. Although recurrent infections are a hallmark of IEI, autoimmune manifestations are also highly prevalent in affected patients. Nevertheless, identifying an underlying IEI in individuals presenting primarily with autoimmune disorders remains challenging, as these manifestations can be highly heterogeneous. Many pediatricians and specialists managing autoimmune conditions do not systematically consider an early immunological evaluation, often underestimating the likelihood of an underlying immunodeficiency. As a result, the diagnosis of a genetic immunodeficiency is frequently delayed. The pathogenesis of autoimmune manifestations in IEI is complex and largely related to defects in central and peripheral immune tolerance, leading to the persistence of autoreactive T and B lymphocytes. Consistently, pathogenic variants in genes that play a critical role in the establishment and maintenance of immune tolerance have been identified in patients with IEI. Through this narrative review, we aim to raise awareness among clinicians and laboratory specialists about the close interplay between autoimmunity and IEI, and to emphasize that autoimmune manifestations may represent an early warning sign of an underlying immunodeficiency. We also highlight key elements to guide the diagnostic approach to autoimmunity in this clinical context.