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Clincial, immunologic, and genetic features of an autoimmune
lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis
MC Sneller, J Wang, JK Dale, W Strober, LA Middelton, Y Choi, TA Fleisher, MS Lim, ES Jaffe, JM Puck, MJ Lenardo and SE Straus
Laboratory of Immunoregulation, National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Bethesda, MD 20892,
USA.
Programmed cell death (apoptosis) of activated lymphocytes is critical to
immune homeostasis. The cell surface protein Fas (CD95) and its ligand play
a pivotal role in regulating lymphocyte apoptosis, and defective expression
of either Fas or Fas ligand results in marked over accumulation of mature
lymphocytes and autoimmune disease in mice. The results of recent studies
suggest that defective lymphocyte apoptosis caused by mutations of the Fas
gene can result in a severe autoimmune lymphoproliferative syndrome (ALPS)
in humans. To define the clinical, genetic, and immunologic spectrum of
ALPS, 9 patients and their families 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 was identified in 9 unrelated children as manifested by
moderate to massive splenomegaly and lymphadenopathy,
hypergammaglobulinemia, autoimmunity, B-cell lymphocytosis, and the
expansion of an unusual population of CD4- CD8- T cells that express the
alpha/beta T-cell receptor (TCR). All patients showed defective lymphocyte
apoptosis in vitro. Heterozygous mutations of the Fas gene were detected in
8 patients. One ALPS patient lacked a Fas gene mutation. Healthy relatives
with Fas mutations were identified in 7 of 8 ALPS kindreds. These relatives
also showed in vitro abnormalities of Fas-mediated lymphocyte apoptosis,
but clinical features of ALPS were not present in the vast majority of
these individuals. ALPS is a unique clinical syndrome in which in vitro
abnormalities of lymphocyte apoptosis are associated with abnormal
lymphoproliferation and autoimmunity. These findings provide evidence that
apoptosis of activated lymphocytes is an important mechanism for
maintaining immunologic homeostasis and self-tolerance in humans. Fas gene
mutations account for impaired lymphocyte apoptosis in only a subset of
patients with ALPS.
Volume 89,
Issue 4,
pp. 1341-1348,
02/15/1997
Copyright © 1997 by The American Society of Hematology
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