title: Subtypes of familial hemophagocytic lymphohistiocytosis in Japan based on genetic and functional analyses of cytotoxic T lymphocytes.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Bioregulatory Medicine, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Kozo
authors.initials: K
authors.lastname: Nagai
authors.forename: Ken
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Jun
authors.initials: J
authors.lastname: An
authors.forename: Toshiki
authors.initials: T
authors.lastname: Ochi
authors.forename: Koichiro
authors.initials: K
authors.lastname: Suemori
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yasumi
authors.forename: Hisamichi
authors.initials: H
authors.lastname: Tauchi
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Koh
authors.forename: Maho
authors.initials: M
authors.lastname: Sato
authors.forename: Akira
authors.initials: A
authors.lastname: Morimoto
authors.forename: Toshio
authors.initials: T
authors.lastname: Heike
authors.forename: Eiichi
authors.initials: E
authors.lastname: Ishii
authors.forename: Masaki
authors.initials: M
authors.lastname: Yasukawa
mesh_terms: D015153:Blotting, Western; D015550:Cell Degranulation / Q000276:immunology; D002478:Cells, Cultured; D002648:Child; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004252:DNA Mutational Analysis; D005260:Female; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007564:Japan; D051359:Lymphohistiocytosis, Hemophagocytic / Q000145:classification / Q000235:genetics* / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051938:Munc18 Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D054353:Perforin; D016133:Polymerase Chain Reaction; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D051938:Munc18 Proteins; C510468:PRF1 protein, human; D052899:Pore Forming Cytotoxic Proteins; C497940:STXBP2 protein, human; C507969:UNC13D protein, human; D054353:Perforin