Deficiency of the Fas apoptosis pathway without Fas gene mutations is a familial trait predisposing to development of autoimmune diseases and cancer

Fas/Apo-1 (CD95) triggers programmed cell death (PCD) and is involved in im mune response control and cell-mediated cytotoxicity. in the autoimmune/ ly mphoproliferative syndrome (ALPS), inherited loss-of-function mutations of the Fas gene cause nonmalignant lymphoproliferation and autoimmunity. We ha ve recently identified an ALPS-like clinical pattern (named autoimmune lymp hoproliferative disease [ALD]) in patients with decreased Fas function, but no Fas gene mutation. They also displayed decreased PCD response to cerami de, triggering a death pathway partially overlapping that used by Fas, whic h suggests that ALD is caused by downstream alterations of the Fas signalin g pathway, Decreased Fas function is also involved in tumor development, be cause somatic mutations hitting the Fas system may protect neoplastic cells from immune surveillance. This work assessed the inherited component of th e ALD defect by evaluating Fas- and ceramide-induced T-cell death in both p arents and 4 close relatives of 10 unrelated patients with ALD. Most of the m (22 of 24) displayed defective Fas- or ceramide-induced (or both) cell de ath. Moreover, analysis of the family histories showed that frequencies of autoimmunity and cancer were significantly increased in the paternal and ma ternal 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 rel atives (multiple autoimmune syndrome [MAS] patients), Autoimmune diseases d isplayed by ALD and MAS families included several organ-specific and system ic forms, These data suggest that ALD is due to accumulation of several def ects in the same subject and that these defects predispose to development o f cancer or autoimmune diseases other than ALPS/ALD. (C) 2000 by The Americ an Society of Hematology.