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

Autoimmune lymphoproliferative syndrome (ALPS) is a primary immune regulatory disorder characterized by benign or malignant lymphoproliferation and autoimmunity. Classically, ALPS is due to mutations in FAS and 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 in FAS often show an incomplete penetrance, and certain genotypes have been associated to a dominant or recessive inheritance pattern. FAS mutations may also be acquired or could become pathogenic when associated to variants in other genes, delineating a possible digenic type of inheritance. Intriguingly, variants in FAS and increased TCR alpha beta 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.

Automated summary

Autoimmune lymphoproliferative syndrome (ALPS) is a primary immune regulatory disorder characterized by lymphoproliferation and autoimmunity. ALPS classification and diagnostic criteria have changed, and other ALPS-like disorders have been identified. Mutations in FAS may show incomplete penetrance and can be associated with different inheritance patterns. Variants in FAS and increased TCR alpha beta double-negative T cells (a hallmark of ALPS) have been found in multifactorial autoimmune diseases, suggesting a possible role of FAS in carcinogenesis.