Defective cytotoxic lymphocyte degranulation in syntaxin-11–deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients

• Published in: Blood Vol. 110; no. 6; pp. 1906 - 1915
• Main Authors: Bryceson, Yenan T., Rudd, Eva, Zheng, Chengyun, Edner, Josefine, Ma, Daoxin, Wood, Stephanie M., Bechensteen, Anne Grete, Boelens, Jaap J., Celkan, Tiraje, Farah, Roula A., Hultenby, Kjell, Winiarski, Jacek, Roche, Paul A., Nordenskjöld, Magnus, Henter, Jan-Inge, Long, Eric O., Ljunggren, Hans-Gustaf
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.09.2007; American Society of Hematology
• Series: Immunobiology
• Subjects: Adult; Blotting, Western; Cell Proliferation; Child, Preschool; Cytokines - metabolism; Female; Gene Expression Regulation; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Immunobiology; Infant; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Killer Cells, Natural - cytology; Killer Cells, Natural - metabolism; LIM Domain Proteins; LIM-Homeodomain Proteins; Lymphocyte Subsets; Lymphocytes - cytology; Lymphocytes - metabolism; Lymphohistiocytosis, Hemophagocytic - genetics; Lymphohistiocytosis, Hemophagocytic - metabolism; Lymphohistiocytosis, Hemophagocytic - pathology; Male; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Muscle Proteins - genetics; Muscle Proteins - metabolism; Mutation - genetics; Perforin; Pore Forming Cytotoxic Proteins - genetics; Pore Forming Cytotoxic Proteins - metabolism; Qa-SNARE Proteins - genetics; Qa-SNARE Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-02-074468

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.