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Blood, Vol. 95 No. 10 (May 15), 2000:
pp. 3176-3182
Deficiency of the Fas apoptosis pathway without Fas gene
mutations is a familial trait predisposing to development of autoimmune
diseases and cancer
Ugo Ramenghi,
Sara Bonissoni,
Giuseppe Migliaretti,
Simona DeFranco,
Flavia Bottarel,
Caterina Gambaruto,
Daniela DiFranco,
Roberta Priori,
Fabrizio Conti,
Irma Dianzani,
Guido Valesini,
Franco Merletti, and
Umberto Dianzani
Department of Pediatrics and Department of Biomedical Sciences and
Human Oncology, University of Turin, Turin, Italy; Department of
Medical Science, "A. Avogadro" University of Eastern Piedmont,
Novara, Italy; Chair of Allergology and Clinical Immunology, Institute
of Clinical Medicine I, "La Sapienza" University of Rome, Rome,
Italy.
Fas/Apo-1 (CD95) triggers programmed cell death (PCD) and is
involved in immune response control and cell-mediated cytotoxicity. In
the autoimmune/lymphoproliferative syndrome (ALPS), inherited loss-of-function mutations of the Fas gene cause nonmalignant lymphoproliferation and autoimmunity. We have recently identified an
ALPS-like clinical pattern (named autoimmune lymphoproliferative disease [ALD]) in patients with decreased Fas function, but no Fas gene mutation. They also displayed decreased PCD response to ceramide, triggering a death pathway partially overlapping that used
by Fas, which suggests that ALD is caused by downstream alterations of
the Fas signaling pathway. Decreased Fas function is also involved in
tumor development, because somatic mutations hitting the Fas system may
protect neoplastic cells from immune surveillance. This work assessed
the inherited component of the ALD defect by evaluating Fas- and
ceramide-induced T-cell death in both parents and 4 close relatives of
10 unrelated patients with ALD. Most of them (22 of 24) displayed
defective Fas- or ceramide-induced (or both) cell death. Moreover,
analysis of the family histories showed that frequencies of
autoimmunity and cancer were significantly increased in the paternal
and maternal line, respectively. Defective Fas- or ceramide-induced
T-cell death was also detected in 9 of 17 autoimmune patients from 7 families displaying more than a single case of autoimmunity within
first- or second-degree relatives (multiple autoimmune syndrome [MAS] patients). Autoimmune diseases displayed by ALD and MAS families included several organ-specific and systemic forms. These data suggest
that ALD is due to accumulation of several defects in the same subject
and that these defects predispose to development of cancer or
autoimmune diseases other than ALPS/ALD.
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