ALPS, FAS, and beyond: from inborn errors of immunity to acquired immunodeficiencies

Abstract

AbstractAutoimmune lymphoproliferative syndrome (ALPS) is a primary immune regulatory disorder characterized by benign or malignant lymphoproliferation and autoimmunity. Classically, ALPS is due to mutations inFASand other related genes; however, recent research revealed that other genes could be responsible for similar clinical features. Therefore, ALPS classification and diagnostic criteria have changed over time, and several ALPS-like disorders have been recently identified. Moreover, mutations inFASoften show an incomplete penetrance, and certain genotypes have been associated to a dominant or recessive inheritance pattern.FASmutations may also be acquired or could become pathogenic when associated to variants in other genes, delineating a possible digenic type of inheritance. Intriguingly, variants inFASand increased TCR αβ double-negative T cells (DNTs, a hallmark of ALPS) have been identified in multifactorial autoimmune diseases, while FAS itself could play a potential role in carcinogenesis. These findings suggest that alterations of FAS-mediated apoptosis could trespass the universe of inborn errors of immunity and that somatic mutations leading to ALPS could only be the tip of the iceberg of acquired immunodeficiencies.