Pathogenesis of hemophagocytic syndrome (HPS)
Introduction
Hemophagocytic syndrome (HPS) is a clinicopathologic entity characterized by high-grade fever, hepatosplenomegaly, cytopenias, high ferritin level, and increased proliferation and activation of benign macrophages with hemophagocytosis throughout the reticuloendothelial system. HPS may be primary, as observed in familial hemophagocytic lymphohistiocytosis (FHL), X-linked lymphoproliferative syndrome (XLP), Chediak-Higashi syndrome (CHS) and Griscelli syndrome (GS), or secondary to malignancy, infections, autoimmune diseases or drugs (hypersensitivity syndrome) [1]. Clinical and biological manifestations result from the secretion of huge amounts of cytokines by activated T cells and macrophages. Genetic defects involving the perforin-dependent cytotoxic process of cytotoxic T lymphocytes (CTL) and natural killer (NK) cells have been identified in a subgroup of primary HPS.
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Macrophages
Although HPS is characterized by proliferation and activation of macrophages with hemophagocytosis, very few studies are aimed at investigating the macrophage itself. Phenotypic markers expressed by macrophages in small series of primary HPS patients comprise complement receptors (CD35, CD21 and CD11b), CD36, and ‘activation’ markers such as CD25 and CD30, while those from patients with secondary HPS or healthy controls do not [2]. It is thus suggested that macrophages differ, at least in their
Familial hemophagocytic lymphohistiocytosis (FHL)
FHL is an autosomal recessive disease of early childhood characterized by a non-malignant accumulation and multivisceral infiltration of activated T-cells, mainly CD8+ T lymphocytes and macrophages following viral infection. Genetic studies mapped the disease associated genes either on chromosome 9q21.3–22 (FHL1 gene), or on chromosome 10q21 (FHL2 gene) but other unidentified genes are also involved [5], [6], [7]. The FHL2 gene codes for perforin, a membranolytic protein expressed in the
Natural killer (NK) cells
NK cell function is defective in FHL patients and in their parents, especially the mothers [23], [24]. This defect is more frequently observed in those with the central nervous system (CNS) involvement. Very young patients with persistently deficient NK cell activity and/or overt CNS disease are at high risk of fatal FHL [24]. In vitro cytolytic function of NK and CTL isolated from 65 patients with FHL were compared to controls. Four distinct defects in cellular cytotoxicity were described and
Cytokines, cytokine receptors and chemokines in HPS
HPS results from uncontrolled T-lymphocyte activation that promote macrophage activation and the formation of a cytokine network (Fig. 1). In patients with active HPS, serum levels of the TH1 cytokines IFN-γ [26], [27], [28], [29], [30], IL-12 [26], [27] and IL-18 [27] are significantly higher than in remission phase of the disease or in healthy controls. IL-18 seem to play a central role in inducing IFN-γ and IL-12 secretion [27] and serum levels of IFN-γ and IL-18 correlate positively with
HPS and autoimmune diseases
HPS may occur during the course of autoimmune and systemic inflammatory diseases (Table 1). In SLE, HPS may initially accompany a disease flare or occur as a consequence of an infectious complication [36]. The occurrence of HPS as part of a disease flare might result from increased IL-18 production, which is able to trigger the inflammatory processes in SLE [37]. IL-18 could also play a prominent role in AOSD, since serum IL-18 modulate ferritin synthesis in vitro by monocyte/macrophage and
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