title: Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome.
abstract: 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 gamma (IFN-gamma) 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-gamma and soluble IL-2 and tumor necrosis factor alpha (TNF-alpha) 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.
authors: Service de Médecine Interne, Hôpital de la Conception, Marseille, France.
authors: Karin
authors: K
authors: Mazodier
authors: Valérie
authors: V
authors: Marin
authors: Daniela
authors: D
authors: Novick
authors: Catherine
authors: C
authors: Farnarier
authors: Stéphane
authors: S
authors: Robitail
authors: Nicolas
authors: N
authors: Schleinitz
authors: Véronique
authors: V
authors: Veit
authors: Pascale
authors: P
authors: Paul
authors: Menachem
authors: M
authors: Rubinstein
authors: Charles A
authors: CA
authors: Dinarello
authors: Jean-Robert
authors: JR
authors: Harlé
authors: Gilles
authors: G
authors: Kaplanski
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001327:Autoimmune Diseases / Q000097:blood / Q000150:complications / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D016207:Cytokines / Q000097:blood / Q000276:immunology; D005260:Female; D006023:Glycoproteins / Q000097:blood* / Q000276:immunology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18 / Q000097:blood* / Q000276:immunology; D007962:Leukocytes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000097:blood* / Q000209:etiology / Q000276:immunology; D008231:Lymphopenia / Q000097:blood / Q000209:etiology / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000150:complications / Q000276:immunology; D011446:Prospective Studies
chemical_list: D015415:Biomarkers; D016207:Cytokines; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; C118370:interleukin-18 binding protein