Defective apoptosis in lymphocytes and the role of IL-2 in autoimmune hematologic cytopenias

Fas-mediated signaling is important for lymphocyte elimination. We investig ated lymphocytes for Pas-signaling defects in 20 pediatric patients with ch ronic hematologic autoimmunity. In 5 of 20 (25%), there was profound resist ance to exogenous Fast-mediated lysis, Fas mAb, and anti-CD3, FasL function , though variable, was not significantly different from that of simultaneou sly evaluated controls. Only 1 patient had a Fas mutation and manifestation s of autoimmune lymphoproliferative syndrome. In contrast, lymphocytes from his clinically normal mother with the same mutation were normally sensitiv e to FasL. In 3 patients, normal Fas-mediated lysis was restored with rhIL- 2. IL-2 had no effect in the other 2 patients. Activation and proliferation functions of IL-2 were normal in all 5, We conclude that altered Fas signa ling, independent of Fas mutations, can precipitate hematologic autoimmunit y. IL-2 can rescue some lymphocytes from this defect. In IL-2 refractory ca ses, a persistently defective response to IL-2 continues to confer a lympho cyte survival advantage. Hence, altered Fas pathway signaling with or witho ut defective IL-2 responses should be considered in the etiology of hematol ogic autoimmunity, (C) 2001 Academic Press.