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Missense mutations in the Fas gene resulting in autoimmune
lymphoproliferative syndrome: a molecular and immunological analysis
A Bettinardi, D Brugnoni, E Quiros-Roldan, A Malagoli, S La Grutta, A Correra and LD Notarangelo
Consorzio per le Biotecnologie, Servizio di Immunologia Clinica, Spedali
Civili di Brescia, Italy.
Programmed cell death (or apoptosis) is a physiological process essential
to the normal development and homeostatic maintenance of the immune system.
The Fas/Apo-1 receptor plays a crucial role in the regulation of apoptosis,
as demonstrated by lymphoproliferation in MRL- lpr/lpr mice and by the
recently described autoimmune lymphoproliferative syndrome (ALPS) in
humans, both of which are due to mutations in the Fas gene. We describe a
novel family with ALPS in which three affected siblings carry two distinct
missense mutations on both the Fas gene alleles and show lack of
Fas-induced apoptosis. The children share common clinical features
including splenomegaly and lymphadenopathy, but only one developed severe
autoimmune manifestations. In all three siblings, we demonstrated the
presence of anergic CD3+CD4-CD8- (double negative, [DN]) T cells; moreover,
a chronic lymphocyte activation was found, as demonstrated by the presence
of high levels of HLA-DR expression on peripheral CD3+ cells and by the
presence of high levels of serum activation markers such as soluble
interleukin-2 receptor (slL-2R) and soluble CD30 (sCD30).
Volume 89,
Issue 3,
pp. 902-909,
02/01/1997
Copyright © 1997 by The American Society of Hematology
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