Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: A molecular and immunological analysis

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 Pas 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 (sIL-2R) and soluble CD30 (sCD30). (C) 1997 by The American Society of Hematology.