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Blood, 15 September 2007, Vol. 110, No. 6, pp. 1906-1915. Prepublished online as a Blood First Edition Paper on May 24, 2007; DOI 10.1182/blood-2007-02-074468. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-02-074468v1 110/6/1906    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bryceson, Y. T. Articles by Ljunggren, H.-G. Search for Related Content PubMed PubMed Citation Articles by Bryceson, Y. T. Articles by Ljunggren, H.-G. Related Collections Immunobiology Cytoskeleton Free Research Articles Clinical Trials and Observations Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Defective cytotoxic lymphocyte degranulation in syntaxin-11–deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients Yenan T. Bryceson1,2, Eva Rudd3,4, Chengyun Zheng3,4, Josefine Edner3,4, Daoxin Ma3,4, Stephanie M. Wood1,5, Anne Grete Bechensteen6, Jaap J. Boelens7, Tiraje Celkan8, Roula A. Farah9, Kjell Hultenby10, Jacek Winiarski11, Paul A. Roche12, Magnus Nordenskjöld4, Jan-Inge Henter3, Eric O. Long2, and Hans-Gustaf Ljunggren1 1 Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; 2 Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD; 3 Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden; 4 Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden; 5 Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia; 6 Department of Pediatrics, Ullevål University Hospital, Oslo, Norway; 7 Department of Immunology/Hematology and Bone Marrow Transplantation (BMT), University Medical Center Utrecht/Wilhelmina Children's Hospital, Utrecht, the Netherlands; 8 Department of Pediatric Hematology-Oncology, Istanbul University, Cerrahpasa Faculty of Medicine, Istanbul, Turkey; 9 Department of Pediatrics, St Georges Hospital, Balamand University, Beirut, Lebanon; 10 Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; 11 Pediatrics Unit, Department of Clinical Sciences Intervention and Technology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; 12 Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: FHL4: NK cells pack less punch Kim E. Nichols Blood 2007 110: 1705-1706. [Full Text] [PDF] This article has been cited by other articles: F. Micucci, C. Capuano, E. Marchetti, M. Piccoli, L. Frati, A. Santoni, and R. Galandrini PI5KI-dependent signals are critical regulators of the cytolytic secretory pathway Blood, April 15, 2008; 111(8): 4165 - 4172. [Abstract] [Full Text] [PDF] H. Higashio, N. Nishimura, H. Ishizaki, J. Miyoshi, S. Orita, A. Sakane, and T. Sasaki Doc2{alpha} and Munc13-4 Regulate Ca2+-Dependent Secretory Lysosome Exocytosis in Mast Cells J. Immunol., April 1, 2008; 180(7): 4774 - 4784. [Abstract] [Full Text] [PDF] E Rudd, Y T Bryceson, C Zheng, J Edner, S M Wood, K Ramme, S Gavhed, A Gurgey, M Hellebostad, A G Bechensteen, et al. Spectrum, and clinical and functional implications of UNC13D mutations in familial haemophagocytic lymphohistiocytosis J. Med. Genet., March 1, 2008; 45(3): 134 - 141. [Abstract] [Full Text] [PDF] A Trizzino, U z. Stadt, I Ueda, K Risma, G Janka, E Ishii, K Beutel, J Sumegi, S Cannella, D Pende, et al. Genotype phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations J. Med. Genet., January 1, 2008; 45(1): 15 - 21. [Abstract] [Full Text] [PDF]

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