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Blood, Vol. 95 No. 10 (May 15), 2000: pp. 3219-3222

Chronic neutropenia mediated by Fas ligand

Jin Hong Liu, Sheng Wei, Thierry Lamy, P. K. Epling-Burnette, Gordon Starkebaum, Julie Y. Djeu, and Thomas P. Loughran Jr

From the H. Lee Moffitt Cancer Center and Research Institute, the Veterans Administration Hospital, and the Departments of Internal Medicine, Immunology/Microbiology, and Biochemistry/Molecular Biology; University of South Florida, College of Medicine, Tampa, FL; and the Veterans Administration Puget Sound Health Care System and Department of Medicine, University of Washington School of Medicine, Seattle, WA.

Chronic neutropenia, often associated with rheumatoid arthritis, is a characteristic finding in large granular lymphocyte (LGL) leukemia. The mechanism of neutropenia is not known. Normal neutrophil survival is regulated by the Fas-Fas ligand apoptotic system. We hypothesized that neutropenia in LGL leukemia is mediated by dysregulated expression of Fas ligand. Levels of Fas ligand in serum samples from patients with LGL leukemia were measured with a Fas ligand enzyme-linked immunosorbent assay. The effects of serum from patients with LGL leukemia on apoptosis of normal neutrophils were determined by flow cytometry and morphologic assessment. High levels of circulating Fas ligand were detected in 39 of 44 serum samples from patients with LGL leukemia. In contrast, Fas ligand was undetectable in 10 samples from healthy donors. Serum from the patients triggered apoptosis of normal neutrophils that depended partly on the Fas pathway. Resolution of neutropenia was associated with disappearance or marked reduction in Fas ligand levels in 10 of 11 treated patients. These data suggest that high levels of Fas ligand are a pathogenetic mechanism in human disease.


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