Autoimmune lymphoproliferative syndrome (alps): clinical, immunologic, and genetic aspects of defective lymphocyte apoptosis

BACKGROUND: Absent Fas protein expression leads to defective lymphocyte apoptosis, expanded TCR α/β CD4-/CD8- (DN) T cells, lymphoproliferation, and autoimmune disease in Ipr mice. A similar disorder termed ALPS was described by Sneller etal (J Gun Invest, 1992) in 2 children, and recently proven to involve heterozygous mutations in human Fas (Fisher etal, Cell, 1995; Rieux-Laucat etal. Science, 1995). Extended studies of 8 NIH kindreds with ALPS have been conducted. MATERIALS AND METHODS: Blood was analyzed for lymphocyte phenotypc, immunoglobulins, autoantibodies, capacity to undergo apoptosis in vitro, and sequencing of Fas cDNA and genomic DNA. RESULTS: ALPS was identified in 8 unrelated children as manifested by moderate to massive splenomegaly and adenopathy, hypergammaglobulioemia, elevated circulating cytokines, expanded DN T cells (>5%; nl <I%), autoimmune hemolysis (n=5), FTP (n=5), neutropenia (n=3), and glomerulitis(n=l). Members of 7 of the 8 families studied lacked these clinical and laboratory findings; in contrast, in one family, some Fas mutation-carrying members had adenopathy, autoimmunity and, in two instances, Hodgkin's Disease. All 8 patients with ALPS, manifested a defect in capacity to undergo apoptosis hiyitro as did some, but not all, of their relatives who carried the same mutations in Fas. Heterozygous Fas mutations were identified in 5 of the ALPS patients and in 9 of their unaffected relatives. In these families Fas mutations are necessary but not sufficient for an apoptosis defect or the development of ALPS. Three ALPS patients with defective apoptosis in vitro did not manifest Fas mutations. CONCLUSIONS: The sine qua non of ALPS is an apoptosis defect which is associated with a Fas gene mutation and/or a mutation in another gene involved in lymphocyte apoptosis. The nature of these other mutations is being determined.