International Immunology, Vol 10, 195-202, Copyright © 1998 by Oxford University Press
Y Kasahara, T Wada, Y Niida, A Yachie, H Seki, Y Ishida, T Sakai, F Koizumi, S Koizumi, T Miyawaki and N Taniguchi
Fas is an apoptosis-signaling receptor important for homeostasis of the
immune system. In this study, Fas-mediated apoptosis and Fas mutations were
analyzed in three Japanese children from two families with a
lymphoproliferative disorder characterized by lymphadenopathy,
hepatosplenomegaly, pancytopenia, hypergammaglobulinemia and an increase in
TCR alphabeta+ CD4- CD8- T cells. Apoptosis induced by anti- Fas mAb was
defective in both activated T cells and B cells, and granulocytes from
these patients. Truncated Fas receptor lacking the cytoplasmic death domain
caused by a point mutation in the splice region of intron 7 were
demonstrated in two siblings. A homozygous point mutation in the splice
acceptor of intron 3 was found in the Fas gene of the third patient, which
resulted in the skipping of exon 4 and complete loss of Fas expression.
Corresponding to these mutations, soluble Fas concentrations were decreased
and reciprocally soluble Fas ligands were increased in patients' sera.
Interestingly, co-stimulation by immobilized anti-Fas mAb in T cells from
the two siblings was comparable to that seen in normal T cells. These
results suggest that Fas-mediated apoptosis plays a pivotal role in
immunological homeostasis in vivo, especially regarding clonal deletion of
immune cells in humans.
ARTICLES
Novel Fas (CD95/APO-1) mutations in infants with a lymphoproliferative disorder
Department of Pediatrics, School of Medicine, Kanazawa University, Ishikawa, Japan.
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