Journal
BLOOD
Volume 106, Issue 10, Pages 3483-3489Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2005-05-1980
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Funding
- NHLBI NIH HHS [HL-68743] Funding Source: Medline
- NIAID NIH HHS [AI-15614] Funding Source: Medline
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Hemophagocytic syndrome (HIPS) is characterized by an uncontrolled and poorly understood activation of T-helper 1 (Th-1) lymphocytes and macrophages. We studied 20 patients with HIPS 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 HIPS 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 HIPS 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 HIPS 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 HIPS in patients with underlying diseases.
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