Chronic neutropenia mediated by Fas ligand

Chronic neutropenia, often associated with rheumatoid arthritis, is a chara cteristic finding in large granular lymphocyte (LGL) leukemia. The mechanis m of neutropenia is not known. Normal neutrophil survival is regulated by t he Pas-Pas ligand apoptotic system. We hypothesized that neutropenia in LGL leukemia is mediated by dysregulated expression of Pas ligand. Levels of P as ligand in serum samples from patients with LGL leukemia were measured wi th a Pas ligand enzyme-linked immunosorbent assay. The effects of serum fro m patients with LGL leukemia on apoptosis of normal neutrophils were determ ined by flow cytometry and morphologic assessment. High levels of circulati ng Pas ligand were detected in 39 of 44 serum samples from patients with LG L leukemia. In contrast, Pas ligand was undetectable in 10 samples from hea lthy donors. Serum from the patients triggered apoptosis of normal neutroph ils that depended partly on the Pas pathway. Resolution of neutropenia was associated with disappearance or marked reduction in Pas ligand levels in 1 0 of 11 treated patients. These data suggest that high levels of Pas ligand are a pathogenetic mechanism in human disease. (C) 2000 by The American So ciety of Hematology.