Ishii, E. et al. Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions. Blood 105, 3442-3448

Department of Pediatrics, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan.
Blood (Impact Factor: 10.45). 06/2005; 105(9):3442-8. DOI: 10.1182/blood-2004-08-3296
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Mutations of the perforin (PRF1) and MUNC13-4 genes distinguish 2 forms of familial hemophagocytic lymphohistiocytosis (FHL2 and FHL3, respectively), but the clinical and biologic correlates of these genotypes remain in question. We studied the presenting features and cytotoxic T lymphocyte/natural killer (CTL/NK) cell functions of 35 patients for their relationship to distinct FHL subtypes. FHL2 (n = 11) had an earlier onset than either FHL3 (n = 8) or the non-FHL2/FHL3 subtype lacking a PRF1 or MUNC13-4 mutation (n = 16). Deficient NK cell activity persisted after chemotherapy in all cases of FHL2, whereas some patients with FHL3 or the non-FHL2/FHL3 subtype showed partial recovery of this activity during remission. Alloantigen-specific CTL-mediated cytotoxicity was deficient in FHL2 patients with PRF1 nonsense mutations, was very low in FHL3 patients, but was only moderately reduced in FHL2 patients with PRF1 missense mutations. These findings correlated well with Western blot analyses showing an absence of perforin in FHL2 cases with PRF1 nonsense mutations and of MUNC13-4 in FHL3 cases, whereas in FHL2 cases with PRF1 missense mutations, mature perforin was present in low amounts. These results suggest an association between the type of genetic mutation in FHL cases and the magnitude of CTL cytolytic activity and age at onset.

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Available from: Toshiro Hara
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    • "In patients with mutations in STXBP2, severe chronic inflammatory bowel disease (colitis) and hypogammaglobulinemia were frequently found (Ishii et al. 2005). Mutations in the Munc 13-4 (UNC13D) and Munc 18-2 (STXBP2) genes often cause abnormal platelet function, which causes a tendency to hemorrhage and bleeding during surgical procedures (Ishii et al. 2005; Meeths et al. 2011). Crohn-like colitis has been reported in significant proportion of boys and men with a X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 (Speckmann et al. 2013). "
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    ABSTRACT: Hemophagocytic syndrome, also known as hemophagocytic lymphohistiocytosis (HLH), is a heterogenic syndrome, which leads to an acute, life-threatening inflammatory reaction. HLH occurs both in children and adults, and can be triggered by various inherited as well as acquired factors. Depending on the etiology, HLH can be divided into genetic (i.e., primary) and acquired (i.e., secondary) forms. Among genetic HLH forms, one can distinguish between familial HLH and other genetically conditioned forms of HLH. Acquired HLH can be typically triggered by infections, autoimmune diseases, and malignancies. The most common symptoms of HLH are unremitting fever, splenomegaly, and peripheral blood cytopenia. Some severely ill patients present with central nervous system involvement. Laboratory tests reveal hyperferritinemia (often >10,000 μg/L), increased serum concentration of soluble receptor α for interleukin-2 (>2,400 U/L), hypertriglyceridemia, hypofibrinogenemia, coagulopathy, hyponatremia, hypoproteinemia, and elevated liver transaminases and bilirubin. Prognosis in HLH is very serious. Genetic HLH is always lethal if adequate therapy is not administered. Similarly, severe acquired cases often lead to death without appropriate treatment. Since HLH can be encountered by various specialists in the medical field, basic knowledge of this entity such as diagnostic criteria and treatment should be familiar to all physicians.
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    • "It is ubiquitously expressed, but enriched in cells of the hematopoietic lineage (Song et al., 1998; Feldmann et al., 2003). In platelets, the Munc13-4 interaction with activated Rab27a/b is important for SNARE binding (via MHD1 interaction), granule formation and plasma membrane interaction (Figure 3) (Song et al., 1998; Shirakawa et al., 2004; Ishii et al., 2005; Boswell et al., 2012). Boswell et al. (2012) determined that the C2A domain of Munc13-4 is required for Ca2+-dependent SNARE interaction, whereas the C2B domain mediates Ca2+-dependent membrane association. "
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    • "Interestingly, the degrees of cytotoxic activity mediated by CTL lines generated from 2 patients with unknown genetic mutations appeared to be significantly different, i.e. moderately decreased in one and undetectable in the other, as is the case for PRF1 nonsense mutation [21]. A large amount of IFN-γ was produced by both of the CTL lines generated from these patients after stimulation with allogeneic LCL cells, and this cytokine production was abrogated by anti-HLA class I antibody, indicating that the antigen-recognition system mediated via the T-cell receptor/CD3 complex was intact in both cases. "
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    ABSTRACT: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare disease of infancy or early childhood. To clarify the incidence and subtypes of FHL in Japan, we performed genetic and functional analyses of cytotoxic T lymphocytes (CTLs) in Japanese patients with FHL. Among the Japanese children with hemophagocytic lymphohistiocytosis (HLH) registered at our laboratory, those with more than one of the following findings were eligible for study entry under a diagnosis of FHL: positive for known genetic mutations, a family history of HLH, and impaired CTL-mediated cytotoxicity. Mutations of the newly identified causative gene for FHL5, STXBP2, and the cytotoxicity and degranulation activity of CTLs in FHL patients, were analyzed. Among 31 FHL patients who satisfied the above criteria, PRF1 mutation was detected in 17 (FHL2) and UNC13D mutation was in 10 (FHL3). In 2 other patients, 3 novel mutations of STXBP2 gene were confirmed (FHL5). Finally, the remaining 2 were classified as having FHL with unknown genetic mutations. In all FHL patients, CTL-mediated cytotoxicity was low or deficient, and degranulation activity was also low or absent except FHL2 patients. In 2 patients with unknown genetic mutations, the cytotoxicity and degranulation activity of CTLs appeared to be deficient in one patient and moderately impaired in the other. FHL can be diagnosed and classified on the basis of CTL-mediated cytotoxicity, degranulation activity, and genetic analysis. Based on the data obtained from functional analysis of CTLs, other unknown gene(s) responsible for FHL remain to be identified.
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