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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 (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 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 Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 15, 2007 Accepted May 11, 2007 Defective cytotoxic lymphocyte degranulation in syntaxin-11-deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients Yenan T Bryceson, Eva Rudd, Chengyun Zheng, Josefine Edner, Daoxin Ma, Stephanie M Wood, Anne Grete Bechensteen, Jaap J Boelens, Tiraje Celkan, Roula A Farah, Kjell Hultenby, Jacek Winiarski, Paul A Roche, Magnus Nordenskjold, Jan-Inge Henter, Eric O Long, and Hans-Gustaf Ljunggren* Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden Childhood Cancer Research Unit, Dept of Woman & Child Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden Clinical Genetics Unit, Dept of Molecular Medicine & Surgery, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia Department of Pediatrics, Ulleval University Hospital, Oslo, Norway Department of Immunology / Hematology and BMT, University Medical Center Utrecht / Wilhelmina Children's Hospital, Utrecht, Netherlands Department of Pediatric Hematology-Oncology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey Department of Pediatrics, St. Georges Hospital,, Balamand University, Beirut, Lebanon Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden Pediatrics Unit, Department of Clinical Sciences, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, United States * Corresponding author; email: hans-gustaf.ljunggren{at}ki.se. Familial hemophagocytic lymphohistiocytosis (FHL) is typically an early onset, fatal disease characterized by a sepsis-like 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 to 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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