Abstract
Fas-mediated signaling is important for lymphocyte elimination. We investigated lymphocytes for Fas-signaling defects in 20 pediatric patients with chronic hematologic autoimmunity. In 5 of 20 (25%), there was profound resistance to exogenous FasL-mediated lysis, Fas mAb, and anti-CD3. FasL function, though variable, was not significantly different from that of simultaneously evaluated controls. Only 1 patient had a Fas mutation and manifestations of autoimmune lymphoproliferative syndrome. In contrast, lymphocytes from his clinically normal mother with the same mutation were normally sensitive 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 signaling, independent of Fas mutations, can precipitate hematologic autoimmunity. IL-2 can rescue some lymphocytes from this defect. In IL-2 refractory cases, a persistently defective response to IL-2 continues to confer a lymphocyte survival advantage. Hence, altered Fas pathway signaling with or without defective IL-2 responses should be considered in the etiology of hematologic autoimmunity.