TY - JOUR
T1 - Defects in neutrophil granule mobilization and bactericidal activity in familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) syndrome caused by STXBP2/Munc18-2 mutations
AU - Zhao, Xi Wen
AU - Gazendam, Roel P
AU - Drewniak, Agata
AU - van Houdt, Michel
AU - Tool, Anton T J
AU - van Hamme, John L
AU - Kustiawan, Iwan
AU - Meijer, Alexander B
AU - Janssen, Hans
AU - Russell, David G
AU - van de Corput, Lisette
AU - Tesselaar, Kiki
AU - Boelens, Jaap J
AU - Kuhnle, Ingrid
AU - Van Der Werff Ten Bosch, Jutte
AU - Kuijpers, Taco W
AU - van den Berg, Timo K
PY - 2013/7/4
Y1 - 2013/7/4
N2 - 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.
AB - 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.
KW - Cell Degranulation/genetics
KW - Cytoplasmic Granules/metabolism
KW - Escherichia coli Infections/genetics
KW - Escherichia coli/immunology
KW - Female
KW - Gastroenteritis/genetics
KW - Genetic Predisposition to Disease
KW - Humans
KW - Killer Cells, Natural/immunology
KW - Lymphohistiocytosis, Hemophagocytic/genetics
KW - Male
KW - Munc18 Proteins/genetics
KW - Neutrophils/immunology
KW - Staphylococcal Infections/genetics
KW - Staphylococcus aureus/immunology
U2 - https://doi.org/10.1182/blood-2013-03-494039
DO - https://doi.org/10.1182/blood-2013-03-494039
M3 - Article
C2 - 23687090
SN - 0006-4971
VL - 122
SP - 109
EP - 111
JO - Blood
JF - Blood
IS - 1
ER -