Autoimmune lymphoproliferative syndrome: molecular basis of disease and clinical phenotype

Autoimmune lymphoproliferative syndrome (ALPS) is a variable clinical condition manifest by lymphoproliferative disease, autoimmune cytopenias and susceptibility to malignancy. Central to the cellular pathogenesis is defective FAS-induced apoptosis, which in turn leads to dysregulation of lymphocyte homeostasis. The majority of patients have heterozygous mutations in the FAS (TNFRSF6) gene, but the condition is genetically heterogeneous and mutations in FAS ligand and caspase-8 and caspase-10, all of which are involved in Fas mediated signalling, have also been identified. This review provides a detailed insight into the pathophysiology of lymphocyte apoptosis and how this relates to the variable and complex clinical manifestations of ALPS.