Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome

• Published in: Blood 2005-11, Vol.106 (10), p.3483-3489
• Main Authors: Mazodier, Karin, Marin, Valérie, Novick, Daniela, Farnarier, Catherine, Robitail, Stéphane, Schleinitz, Nicolas, Veit, Véronique, Paul, Pascale, Rubinstein, Menachem, Dinarello, Charles A., Harlé, Jean-Robert, Kaplanski, Gilles
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Autoimmune Diseases - blood; Autoimmune Diseases - complications; Autoimmune Diseases - immunology; Biomarkers - blood; Cytokines - blood; Cytokines - immunology; Female; Glycoproteins - blood; Glycoproteins - immunology; Humans; Immunobiology; Intercellular Signaling Peptides and Proteins; Interleukin-18 - blood; Interleukin-18 - immunology; Leukocytes - immunology; Lymphocyte Activation - immunology; Lymphohistiocytosis, Hemophagocytic - blood; Lymphohistiocytosis, Hemophagocytic - etiology; Lymphohistiocytosis, Hemophagocytic - immunology; Lymphopenia - blood; Lymphopenia - etiology; Lymphopenia - immunology; Macrophage Activation - immunology; Male; Middle Aged; Neoplasms - blood; Neoplasms - complications; Neoplasms - immunology; Prospective Studies
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-05-1980

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 γ (IFN-γ) 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-γ and soluble IL-2 and tumor necrosis factor α (TNF-α) 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.