title: Defective cytotoxic lymphocyte degranulation in syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients.
abstract: Familial hemophagocytic lymphohistiocytosis (FHL) is typically an early onset, fatal disease characterized by a sepsislike illness with cytopenia, hepatosplenomegaly, and deficient lymphocyte cytotoxicity. Disease-causing mutations have been identified in genes encoding perforin (PRF1/FHL2), Munc13-4 (UNC13D/FHL3), and syntaxin-11 (STX11/FHL4). In contrast to mutations leading to loss of perforin and Munc13-4 function, it is unclear how syntaxin-11 loss-of-function mutations contribute to disease. We show here that freshly isolated, resting natural killer (NK) cells and CD8(+) T cells express syntaxin-11. In infants, NK cells are the predominant perforin-containing cell type. NK cells from FHL4 patients fail to degranulate when encountering susceptible target cells. Unexpectedly, IL-2 stimulation partially restores degranulation and cytotoxicity by NK cells, which could explain the less severe disease progression observed in FHL4 patients, compared with FHL2 and FHL3 patients. Since the effector T-cell compartment is still immature in infants, our data suggest that the observed defect in NK-cell degranulation may contribute to the pathophysiology of FHL, that evaluation of NK-cell degranulation in suspected FHL patients may facilitate diagnosis, and that these new insights may offer novel therapeutic possibilities.
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Yenan T
authors.initials: YT
authors.lastname: Bryceson
authors.forename: Eva
authors.initials: E
authors.lastname: Rudd
authors.forename: Chengyun
authors.initials: C
authors.lastname: Zheng
authors.forename: Josefine
authors.initials: J
authors.lastname: Edner
authors.forename: Daoxin
authors.initials: D
authors.lastname: Ma
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Wood
authors.forename: Anne Grete
authors.initials: AG
authors.lastname: Bechensteen
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Boelens
authors.forename: Tiraje
authors.initials: T
authors.lastname: Celkan
authors.forename: Roula A
authors.initials: RA
authors.lastname: Farah
authors.forename: Kjell
authors.initials: K
authors.lastname: Hultenby
authors.forename: Jacek
authors.initials: J
authors.lastname: Winiarski
authors.forename: Paul A
authors.initials: PA
authors.lastname: Roche
authors.forename: Magnus
authors.initials: M
authors.lastname: Nordenskjöld
authors.forename: Jan-Inge
authors.initials: JI
authors.lastname: Henter
authors.forename: Eric O
authors.initials: EO
authors.lastname: Long
authors.forename: Hans-Gustaf
authors.initials: HG
authors.lastname: Ljunggren
mesh_terms: D000328:Adult; D015153:Blotting, Western; D049109:Cell Proliferation; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology* / Q000378:metabolism; D060588:LIM Domain Proteins; D060850:LIM-Homeodomain Proteins; D016131:Lymphocyte Subsets; D008214:Lymphocytes / Q000166:cytology* / Q000378:metabolism; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics / Q000378:metabolism; D050765:Qa-SNARE Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; 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; D008565:Membrane Proteins; D009124:Muscle Proteins; D052899:Pore Forming Cytotoxic Proteins; D050765:Qa-SNARE Proteins; D014157:Transcription Factors; C507969:UNC13D protein, human; D054353:Perforin