Hypercytokinemia in familial hemophagocytic lymphohistiocytosis

Abstract

Familial hemophagocytic lymphohistiocytosis (FHL) is a frequently missed and almost uniformly fatal childhood disorder. It is characterized by fever, hepatosplenomegaly, cytopenia, coagulopathy, and hypertriglyceridemia. The pathogenesis of FHL is not known but the above clinical and laboratory findings are compatible with reported in vitro and in vivo effects of several inflammatory cytokines. We measured circulating interferon-gamma (IFN-gamma), tumor necrosis factor/cachectin (TNF), and interleukin-6 (IL-6) in nine children with FHL. During active disease, elevated IFN-gamma was detected in seven of seven children, TNF in six of six, and IL-6 in two of six children studied. Thus, important inflammatory cytokines are augmented in active FHL and may contribute to the pathogenesis of the disease. Soluble CD8 was also increased in seven of seven children, which suggests a pathophysiologic importance of cytotoxic T lymphocytes. Because FHL appears to be associated with a systemic hypercytokinemia, our results also indicate that studies of FHL may contribute to the understanding of cytokine effects in vivo. Moreover, FHL is a hereditary disorder, suggesting that the hypercytokinemia is caused by a genetic defect in cytokine regulation.

Early diagnostic and prognostic significance of a specific Th1/Th2 cytokine pattern in children with haemophagocytic syndrome

“…This is partially consistent with previous reports (Osugi et al , 1997; Murohashi et al , 2006). Some reports also found that TNF‐α was moderately elevated in most HPS cases, which is consistent with the factor that macrophages are over‐activated in HPS (Henter et al , 1991b; Akashi et al , 1994), but the level was not as high as IFN‐γ and IL‐10. Most cases had reported TNF levels <20 IU/ml (320 pg/ml) (Henter et al , 1991b).…”

“…Numerous well‐differentiated macrophages phagocytosing haematopoietic cells can usually be found in the bone marrow, liver, spleen or lymph nodes (Henter et al , 1991a, 1997, 2007). The clinical presentation of HPS is caused by a hyperinflammatory syndrome resulting from hypercytokinemia of various pro‐inflammatory mediators, such as interferon‐γ (IFN‐γ), tumour necrosis factor‐α (TNF‐α), interleukin (IL)‐6, IL‐8, IL‐12, IL‐18, macrophage–colony‐stimulating factor (M‐CSF), and a number of haematopoietic growth factors released by stimulated lymphocytes and macrophages (Henter et al , 1991b; Akashi et al , 1994; Osugi et al , 1997; Takada et al , 2001; Mazodier et al , 2005).…”

Characterization of PRF1, STX11 and UNC13D genotype‐phenotype correlations in familial hemophagocytic lymphohistiocytosis

“…In addition, many of the patients develop progressive cerebromeningeal symptoms during the course of the disease (Henter & Elinder, 1992; Haddad et al , 1997; Henter & Nennesmo, 1997). Typical for the pathogenesis of HLH is a defect in apoptosis triggering and in natural killer (NK) and cytotoxic T lymphocyte (CTL) cellular cytotoxicity (Arico et al , 1988; Fadeel et al , 1999; Schneider et al , 2002) associated with a prominent overproduction of several inflammatory cytokines (Henter et al , 1991a; Osugi et al , 1997). Without treatment including hematopoietic stem cell transplantation (SCT), FHL is inevitably fatal (Henter et al , 2002; Ouachee‐Chardin et al , 2006).…”

Familial haemophagocytic lymphohistiocytosis: advances in the genetic basis, diagnosis and management

“…Fever and cytopenias are prominent in FHL and may be induced by several cytokines, such as TNF, IL‐6 and IFN‐γ. TNF also has a procoagulant activity, which may account for the hypofibrinogenaemia [17]. The hypertriglyceridaemia is associated with reduced lipoprotein lipase, due to the presence of TNF [18].…”