Defective Apoptosis in Lymphocytes and the Role of IL-2 in Autoimmune Hematologic Cytopenias

• Published in: Clinical immunology (Orlando, Fla.) Vol. 99; no. 2; pp. 266 - 275
• Main Authors: Shenoy, Shalini, Mohanakumar, T., Chatila, Talal, Tersak, Jean, Duffy, Brian, Wang, Ruduan, Thilenius, Anja R.B., Russell, John H.
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01-05-2001; Elsevier
• Subjects: Adolescent; Anemia, Hemolytic, Autoimmune - genetics; Anemia, Hemolytic, Autoimmune - immunology; Anemia, Hemolytic, Autoimmune - pathology; Apoptosis - drug effects; Apoptosis - immunology; Base Sequence; Biological and medical sciences; Carrier Proteins - metabolism; CASP8 and FADD-Like Apoptosis Regulating Protein; Child; Child, Preschool; DNA Primers - genetics; Fas Ligand Protein; fas Receptor - genetics; fas Receptor - metabolism; Female; Hematologic and hematopoietic diseases; Humans; In Vitro Techniques; Infant; Interleukin-2 - metabolism; Interleukin-2 - pharmacology; Intracellular Signaling Peptides and Proteins; Lymphocyte Activation; Lymphocytes - drug effects; Lymphocytes - immunology; Lymphocytes - pathology; Male; Medical sciences; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mutation; Other diseases. Hematologic involvement in other diseases; Purpura, Thrombocytopenic, Idiopathic - genetics; Purpura, Thrombocytopenic, Idiopathic - immunology; Purpura, Thrombocytopenic, Idiopathic - pathology; Signal Transduction; Immunopathology; Pathogenesis; Cytokine; Autoimmune disease; Hemopathy; Cytopenia; Gene; Interleukin 2; Cell death; Genetics; Mutation; Lymphocyte; Apoptosis; Biological receptor
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1006/clim.2001.5017

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.