Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions

Department of Pediatrics, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan.
Blood (Impact Factor: 10.43). 06/2005; 105(9):3442-8. DOI: 10.1182/blood-2004-08-3296
Source: PubMed

ABSTRACT 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, Jul 10, 2015
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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.
    Archivum Immunologiae et Therapiae Experimentalis 02/2014; 62(5). DOI:10.1007/s00005-014-0274-1
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    • "A second, more common outcome (n = 14) was presynaptic dysfunction, which we have previously defined as reduced expression and/or PRF degradation or truncation in the RBL cells (Voskoboinik et al., 2004). As was observed previously with FHL-associated mutations (Ishii et al., 2005; Voskoboinik et al., 2005b), this group of substitutions invariably led to a marked loss of function (Table S1). Most commonly, presynaptic dysfunction occurred at residues that showed extremely high conservation between species as divergent as humans and fish (for instance, residues 189, 220, 221, 231, or 239), presumably because they are critical for protein folding during its biosynthesis. "
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    ABSTRACT: Perforin, a pore-forming protein secreted by cytotoxic lymphocytes, is indispensable for destroying virus-infected cells and for maintaining immune homeostasis. Perforin polymerizes into transmembrane channels that inflict osmotic stress and facilitate target cell uptake of proapoptotic granzymes. Despite this, the mechanism through which perforin monomers self-associate remains unknown. Our current study establishes the molecular basis for perforin oligomerization and pore assembly. We show that after calcium-dependent membrane binding, direct ionic attraction between the opposite faces of adjacent perforin monomers was necessary for pore formation. By using mutagenesis, we identified the opposing charges on residues Arg213 (positive) and Glu343 (negative) to be critical for intermolecular interaction. Specifically, disrupting this interaction had no effect on perforin synthesis, folding, or trafficking in the killer cell, but caused a marked kinetic defect of oligomerization at the target cell membrane, severely disrupting lysis and granzyme B-induced apoptosis. Our study provides important insights into perforin's mechanism of action.
    Immunity 06/2009; 30(5):684-95. DOI:10.1016/j.immuni.2009.03.016
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    • "The study was also approved by the Institutional Review Boards at Kyushu University and Saga University, Japan. As described in our recent report (Ishii et al 2005), all cases were screened for the PRF1 gene, 12 of which were classified as FHL2. Thirty-eight of the remaining 57 cases were tested for MUNC13-4 gene mutations, eight of which were diagnosed as FHL3. "
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    ABSTRACT: Although mutations of perforin, MUNC13-4 and syntaxin 11 genes have been found in children with familial hemophagocytic lymphohistiocytosis (FHL), the incidence of each genetic subtype varies in different ethnic groups. We evaluated mutations of syntaxin 11 and SNAP23 genes in 30 Japanese FHL patients. The patients had no mutations and 10% had one polymorphism (146G>A) of syntaxin 11, while no mutation of SNAP23 was observed. Our results indicate that aberrations in the SNARE system may not cause FHL in Japanese families.
    Journal of Human Genetics 11/2005; 50(11):600-3. DOI:10.1007/s10038-005-0293-1
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