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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Blotting, Western
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Cell Proliferation
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Child, Preschool
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Cytokines / metabolism
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Female
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Gene Expression Regulation*
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Infant
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Killer Cells, Natural / cytology*
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Killer Cells, Natural / metabolism
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LIM Domain Proteins
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LIM-Homeodomain Proteins
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Lymphocyte Subsets
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Lymphocytes / cytology*
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Lymphocytes / metabolism
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Lymphohistiocytosis, Hemophagocytic / genetics*
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Lymphohistiocytosis, Hemophagocytic / metabolism
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Lymphohistiocytosis, Hemophagocytic / pathology
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Male
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Muscle Proteins / genetics
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Muscle Proteins / metabolism
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Mutation / genetics
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Perforin
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Pore Forming Cytotoxic Proteins / genetics
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Pore Forming Cytotoxic Proteins / metabolism
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Qa-SNARE Proteins / genetics*
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Qa-SNARE Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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Cytokines
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FHL2 protein, human
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FHL3 protein, human
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Homeodomain Proteins
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Intracellular Signaling Peptides and Proteins
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LIM Domain Proteins
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LIM-Homeodomain Proteins
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Membrane Glycoproteins
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Membrane Proteins
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Muscle Proteins
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Pore Forming Cytotoxic Proteins
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Qa-SNARE Proteins
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Transcription Factors
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UNC13D protein, human
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Perforin