title: Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions.
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.
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan. ishiei@med.saga-u.ac.jp
authors.forename: Eiichi
authors.initials: E
authors.lastname: Ishii
authors.forename: Ikuyo
authors.initials: I
authors.lastname: Ueda
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Shirakawa
authors.forename: Ken
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Hisanori
authors.initials: H
authors.lastname: Horiuchi
authors.forename: Shouichi
authors.initials: S
authors.lastname: Ohga
authors.forename: Kenji
authors.initials: K
authors.lastname: Furuno
authors.forename: Akira
authors.initials: A
authors.lastname: Morimoto
authors.forename: Miyoko
authors.initials: M
authors.lastname: Imayoshi
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Ogata
authors.forename: Masafumi
authors.initials: M
authors.lastname: Zaitsu
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sako
authors.forename: Kenichi
authors.initials: K
authors.lastname: Koike
authors.forename: Akifumi
authors.initials: A
authors.lastname: Sakata
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Takada
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hara
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Imashuku
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
authors.forename: Masaki
authors.initials: M
authors.lastname: Yasukawa
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D003602:Cytotoxicity, Immunologic; D005192:Family Health; D005260:Female; D015616:Histiocytosis, Non-Langerhans-Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000276:immunology*; D060588:LIM Domain Proteins; D060850:LIM-Homeodomain Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D009154:Mutation; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D018389:Codon, Nonsense; C105987:FHL2 protein, human; C117563:FHL3 protein, human; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D060850:LIM-Homeodomain Proteins; D008562:Membrane Glycoproteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D052899:Pore Forming Cytotoxic Proteins; D014157:Transcription Factors; C485548:UNC13B protein, human; D054353:Perforin