title: NK cytotoxicity mediated by CD16 but not by NKp30 is functional in Griscelli syndrome.
abstract: Griscelli syndrome (GS) type 2 is an autosomal recessive disorder represented by pigment dilution and impaired cytotoxic T lymphocyte (CTL) activity. NK activity has been scarcely investigated in GS patients. Here, we describe a new patient, possessing a hemophagocytic syndrome with a homozygous Q118X nonsense RAB27A mutation. Single specific primer-polymerase chain reaction (SSP-PCR) was developed based on this mutation and is currently used in prenatal genetic analysis. As expected, CTLs in the patient are not functional and NK cytotoxicity against K562 or 721.221 cells is diminished. Surprisingly, however, we demonstrate that CD16-mediated killing is intact in this patient and is therefore RAB27A independent, whereas NKp30-mediated killing is impaired and is therefore RAB27A dependent. We further analyzed the signaling pathways of these 2 receptors and demonstrated phosphorylation of Vav1 after CD16 activation but not after NKp30 engagement. Thus, we identify a novel homozygous mutation in the RAB27A gene of a new GS patient, observe for the first time that some activating NK receptors function in GS patients, and demonstrate a functional dichotomy in the killing mediated by these human NK-activating receptors.
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, Hadassah Medical School, Jerusalem, Israel.
authors.forename: Roi
authors.initials: R
authors.lastname: Gazit
authors.forename: Memet
authors.initials: M
authors.lastname: Aker
authors.forename: Moran
authors.initials: M
authors.lastname: Elboim
authors.forename: Hagit
authors.initials: H
authors.lastname: Achdout
authors.forename: Gil
authors.initials: G
authors.lastname: Katz
authors.forename: Dana G
authors.initials: DG
authors.lastname: Wolf
authors.forename: Shulamit
authors.initials: S
authors.lastname: Katzav
authors.forename: Ofer
authors.initials: O
authors.lastname: Mandelboim
mesh_terms: D000595:Amino Acid Sequence; D000920:Antibody-Dependent Cell Cytotoxicity / Q000235:genetics / Q000276:immunology; D015703:Antigens, CD / Q000502:physiology*; D001483:Base Sequence; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D004252:DNA Mutational Analysis; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology*; D007223:Infant; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D009154:Mutation; D055628:Natural Cytotoxicity Triggering Receptor 3; D017452:Receptors, IgG / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology*; D020691:rab GTP-Binding Proteins / Q000235:genetics; D000075745:rab27 GTP-Binding Proteins
chemical_list: D015703:Antigens, CD; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; C431710:NCR3 protein, human; D055628:Natural Cytotoxicity Triggering Receptor 3; D017452:Receptors, IgG; D011971:Receptors, Immunologic; D000075745:rab27 GTP-Binding Proteins; C066694:RAB27A protein, human; D020691:rab GTP-Binding Proteins