CLINICAL, IMMUNOLOGICAL, AND GENETIC FEATURES OF AN AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME-ASSOCIATED WITH ABNORMAL LYMPHOCYTE APOPTOSIS

Programmed cell death (apoptosis) of activated lymphocytes is critical to immune homeostasis. The cell surface protein Pas (CD95) and its li gand play a pivotal role in regulating lymphocyte apoptosis, and defec tive expression of either Pas or Pas ligand results in marked over acc umulation of mature lymphocytes and autoimmune disease in mice. The re sults of recent studies suggest that defective lymphocyte apoptosis ca used by mutations of the Pas gene can result in a severe autoimmune ly mphoproliferative syndrome (ALPS) in humans. To define the clinical, g enetic, and immunologic spectrum of ALPS, 9 patients and their familie s were extensively evaluated with routine clinical studies, lymphocyte phenotyping, genotyping, and in vitro assays for lymphocyte apoptosis . Individual patients were followed up for 3 months to 6 years. ALPS w as identified in 9 unrelated children as manifested by moderate to mas sive splenomegaly and lymphadenopathy, hypergammaglobulinemia, autoimm unity, B-cell lymphocytosis, and the expansion of an unusual populatio n of CD4(-)CD8(-) T cells that express the alpha/beta T-cell receptor (TCR). All patients showed defective lymphocyte apoptosis in vitro. He terozygous mutations of the Fas gene were detected in 8 patients. One ALPS patient lacked a Pas gene mutation. Healthy relatives with Pas mu tations were identified in 7 of 8 ALPS kindreds. These relatives also showed in vitro abnormalities of Pas-mediated lymphocyte apoptosis, bu t clinical features of ALPS were not present in the vast majority of t hese individuals. ALPS is a unique clinical syndrome in which in vitro abnormalities of lymphocyte apoptosis are associated with abnormal ly mphoproliferation and autoimmunity. These findings provide evidence th at apoptosis of activated lymphocytes is an important mechanism for ma intaining immunologic homeostasis and self-tolerance in humans, Fas ge ne mutations account for impaired lymphocyte apoptosis in only a subse t of patients with ALPS. (C) 1997 by The American Society of Hematolog y.