The autoimmune lymphoproliferative syndrome: A rare disorder providing clues about normal tolerance.

The autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic, non-malignant lymphoproliferation, autoimmunity often manifesting as multilineage cytopenias, and an increased risk of lymphoma. While considered a rare disease, there are currently over 250 patients with ALPS being followed at the National Institutes of Health in Bethesda, Maryland. Most of these patients have a mutation in the gene for the TNF receptor-family member Fas (CD 95, Apo-1), and about one-third have an unknown defect or mutations affecting function of other signaling proteins involved in the apoptotic pathway. While ALPS is one of the few autoimmune diseases with a known genetic defect, there remain unanswered questions regarding how a defect in apoptosis results in the observed phenotype. In addition to shedding light on the pathophysiology of this rare and fascinating condition, studying ALPS may improve our understanding of normal tolerance and more common, sporadic autoimmune disorders.