title: Defects in neutrophil granule mobilization and bactericidal activity in familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) syndrome caused by STXBP2/Munc18-2 mutations.
abstract: Familial hemophagocytic lymphohistiocytosis (FHL) is caused by genetic defects in cytotoxic granule components or their fusion machinery, leading to impaired natural killer cell and/or T lymphocyte degranulation and/or cytotoxicity. This may accumulate into a life-threatening condition known as macrophage activation syndrome. STXBP2, also known as MUNC18-2, has recently been identified as the disease-causing gene in FHL type 5 (FHL-5). A role for STXBP2 in neutrophils, and for neutrophils in FHL in general, has not been documented thus far. Here, we report that FHL-5 neutrophils have a profound defect in granule mobilization, resulting in inadequate bacterial killing, in particular, of gram-negative Escherichia coli, but not of Staphylococcus aureus, which rather depends on intact reduced NAD phosphate oxidase activity. This impairment of bacterial killing may contribute to the apparent susceptibility to gastrointestinal tract inflammation in patients with FHL-5.
authors.affiliation: Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Xi Wen
authors.initials: XW
authors.lastname: Zhao
authors.forename: Roel P
authors.initials: RP
authors.lastname: Gazendam
authors.forename: Agata
authors.initials: A
authors.lastname: Drewniak
authors.forename: Michel
authors.initials: M
authors.lastname: van Houdt
authors.forename: Anton T J
authors.initials: AT
authors.lastname: Tool
authors.forename: John L
authors.initials: JL
authors.lastname: van Hamme
authors.forename: Iwan
authors.initials: I
authors.lastname: Kustiawan
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Meijer
authors.forename: Hans
authors.initials: H
authors.lastname: Janssen
authors.forename: David G
authors.initials: DG
authors.lastname: Russell
authors.forename: Lisette
authors.initials: L
authors.lastname: van de Corput
authors.forename: Kiki
authors.initials: K
authors.lastname: Tesselaar
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Boelens
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kuhnle
authors.forename: Jutte
authors.initials: J
authors.lastname: Van Der Werff Ten Bosch
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
authors.forename: Timo K
authors.initials: TK
authors.lastname: van den Berg
mesh_terms: D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology; D003594:Cytoplasmic Granules / Q000378:metabolism / Q000382:microbiology; D004926:Escherichia coli / Q000276:immunology; D004927:Escherichia coli Infections / Q000235:genetics / Q000276:immunology; D005260:Female; D005759:Gastroenteritis / Q000235:genetics / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000382:microbiology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D008297:Male; D051938:Munc18 Proteins / Q000235:genetics* / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000382:microbiology; D013203:Staphylococcal Infections / Q000235:genetics / Q000276:immunology; D013211:Staphylococcus aureus / Q000276:immunology
chemical_list: D051938:Munc18 Proteins; C497940:STXBP2 protein, human