TY - JOUR
T1 - Defective apoptosis in lymphocytes and the role of IL-2 in autoimmune hematologic cytopenias
AU - Shenoy, Shalini
AU - Mohanakumar, T.
AU - Chatila, Talal
AU - Tersak, Jean
AU - Duffy, Brian
AU - Wang, Ruduan
AU - Thilenius, Anja R.B.
AU - Russell, John H.
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
KW - Activation-induced cell death
KW - Apoptosis
KW - Autoimmune cytopenia
KW - Fas signaling
KW - IL-2
UR - http://www.scopus.com/inward/record.url?scp=0035867843&partnerID=8YFLogxK
U2 - 10.1006/clim.2001.5017
DO - 10.1006/clim.2001.5017
M3 - Article
C2 - 11318598
AN - SCOPUS:0035867843
VL - 99
SP - 266
EP - 275
JO - Clinical Immunology
JF - Clinical Immunology
SN - 1521-6616
IS - 2
ER -