Cytokine Production Regulating Th1 and Th2 Cytokines in Hemophagocytic Lymphohistiocytosis

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is caused by the hyperactivation of T cells and macrophages. The clinical characteristics associated with this disease result from overproduction of Th1 cytokines including interferon-γ (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor-α (TNF-α). In this study, we analyzed the production of IL-12 and IL-4, which determine Th1 and Th2 response, respectively, and IL-10, which antagonizes Th1 cytokines, in 11 patients with HLH. IL-12 was detected in plasma in all patients (mean peak value, 30.0 ± 5.0 pg/mL), while IFN-γ was massively produced in nine patients (mean peak value, 79.2 ± 112.0 U/mL). IL-4 was not detected in any of the patients. Plasma IL10 levels were elevated in all patients (mean peak value, 2,698.0 ± 3,535.0 pg/mL). There was a positive correlation between the levels of IFN-γ and IL-10 (P < .01). The plasma concentrations of these cytokines were initially high, before decreasing after the acute phase. However, the decrease in IL-10 levels was slower than that of IFN-γ. Although the concentration of IL-12 was high at the acute phase, in some patients, a peak in the level was delayed until the chronic phase. Thus, in HLH, production of cytokines that promote development of Th1 cells appears to be predominant over that for Th2 cell development. Overproduction of IL-10 was also observed indicating that a mechanism suppressing hyperactivation of Th1 cells and monocytes/macrophages functions in patients with this disease.

Gene expression profiling of peripheral blood mononuclear cells from children with active hemophagocytic lymphohistiocytosis

“…43 Osugi et al reported no increase in IFN-␥ levels in patients with FHL, regardless of the level of IL-10 in serum. 44 In another study by Nagasawa et al, 2 of 4 patients with FHL showed no elevated levels of plasma IFN-␥. 45 Serum level of IFN-␥ was not elevated in 2 of 5 patients with FHL.…”

Viral infections associated with haemophagocytic syndrome

“…The persistent activation of lymphocytes is the result of an uncontrolled immune response causing a hypersecretion of pro-inflammatory cytokines such as IFN [17], TNF [18], IL-6 [19], IL-8, IL-10 [18], IL-16 [20], IL-18 [21] and macrophage-colony-stimulating factor (M-CSF). IL-18 appears to play a crucial role particularly in autoimmune related HPS.…”

Use of a mouse model to identify a blood biomarker for IFNγ activity in pediatric secondary hemophagocytic lymphohistiocytosis

“…21 Produced by cells of the innate and adaptive immune systems, including natural killer (NK) cells, natural killer T cells, T cells, neutrophils and dendritic cells, 16,22,23 IFNg is well place to serve as the instigating mediator of cytokine release syndromes. Indeed, substantially elevated levels of IFNg are measured in patients with Severe Acute Respiratory Syndrome 24,25 and HLH, [26][27][28] both cytokine driven diseases. Furthermore, overexpression of IFNg in transgenic mice is sufficient to drive systemic and organ inflammation, 29 and in animal models of pHLH 30,31 and sHLH, 16,17 cytokine neutralization studies revealed the pivotal role of IFNg.…”