Defective cytotoxic lymphocyte degranulation in syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients.
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.
Bryceson
Yenan T
YT
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Rudd
Eva
E
Zheng
Chengyun
C
Edner
Josefine
J
Ma
Daoxin
D
Wood
Stephanie M
SM
Bechensteen
Anne Grete
AG
Boelens
Jaap J
JJ
Celkan
Tiraje
T
Farah
Roula A
RA
Hultenby
Kjell
K
Winiarski
Jacek
J
Roche
Paul A
PA
Nordenskjöld
Magnus
M
Henter
Jan-Inge
JI
Long
Eric O
EO
Ljunggren
Hans-Gustaf
HG
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
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