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Blood, 15 November 2005, Vol. 106, No. 10, pp. 3483-3489.
Prepublished online as a Blood First Edition Paper on July 14, 2005; DOI 10.1182/blood-2005-05-1980.
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IMMUNOBIOLOGY
Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome
Karin Mazodier,
Valérie Marin,
Daniela Novick,
Catherine Farnarier,
Stéphane Robitail,
Nicolas Schleinitz,
Véronique Veit,
Pascale Paul,
Menachem Rubinstein,
Charles A. Dinarello,
Jean-Robert Harlé, and
Gilles Kaplanski
From the Service de Médecine Interne and Laboratoire d'Exploration des NK and Laboratoire d'Hématologie, Hôpital de la Conception, Marseille, France; Institut National de la Santé et de la Recherche Médicale–Unite Mixté de Recherche 600 (INSERM) UMR600 and Département d'Informatique Médicale, Hôpital Sainte-Marguerite, Marseille, France; Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel; and Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, CO.
Hemophagocytic syndrome (HPS) is characterized by an uncontrolled and poorly understood activation of T-helper 1 (Th-1) lymphocytes and macrophages. We studied 20 patients with HPS secondary to infections, autoimmune disease, lymphoma, or cancer and observed that the concentrations of serum interleukin 18 (IL-18), a strong inducer of Th-1 responses, interferon  (IFN-) production, and stimulation of macrophages and natural killer (NK) cells were highly increased in HPS but not in control patients. In contrast, concentrations of its natural inhibitor, the IL-18 binding protein (IL-18BP), were only moderately elevated, resulting in a high level of biologically active free IL-18 in HPS (4.6-fold increase compared with controls; P < .001). Free IL-18 but not IL-12 concentrations significantly correlated with clinical status and the biologic markers of HPS such as anemia (P < .001), hypertriglyceridemia, and hyperferritinemia (P < .01) and also with markers of Th-1 lymphocyte or macrophage activation, such as elevated concentrations of IFN- and soluble IL-2 and tumor necrosis factor  (TNF-) receptor concentrations. Despite high IL-18 elevation, in vitro NK-cell cytotoxicity was severely impaired in HPS patients, in part due to NK-cell lymphopenia that was observed in a majority of patients but also secondary to an intrinsic NK-cell functional deficiency. We concluded that a severe IL-18/IL-18BP imbalance results in Th-1 lymphocyte and macrophage activation, which escapes control by NK-cell cytotoxicity and may allow for secondary HPS in patients with underlying diseases.
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